Harnessing MSC‑derived exosomes to modulate the pathophysiology of ASD: Recent advances and therapeutic implications (Review)

The concept of autism spectrum disorder and recent progress

Core symptoms and current epidemiological status

Autism spectrum disorder (ASD) encompasses a group of pervasive neurodevelopmental conditions characterized by a broad spectrum of symptoms, broadly categorized into core and associated symptoms. Core symptoms include persistent deficits in social interaction and communication, as well as restricted and repetitive patterns of behavior and interests that significantly impair daily functioning. By contrast, associated symptoms encompass attention deficits, mood disturbances, sensory processing abnormalities, sleep disorders, language impairment, anxiety, epilepsy, mania and self-injurious behaviors. Core symptoms typically emerge in early childhood and persist throughout life (1-3). In recent years, increasing public awareness of ASD has coincided with a steady increase in its rate of diagnosis, rendering it a significant global public health concern. According to 2022 data from the US Centers for Disease Control and Prevention (CDC), the incidence of ASD in the USA reached ~1 in 31 children. Moreover, the prevalence of ASD among boys is notably higher than that among girls, with a male-to-female ratio of ~3.44:1 (4). Furthermore, advances in early screening and diagnostic tools have enabled the identification of a greater number of individuals with milder ASD phenotypes, thereby enhancing epidemiological research in this field.

Large-scale genome-wide association studies (GWAS) (5) and family-based genetic analyses (6) have revealed that ASD possesses a complex and highly heterogeneous genetic background. Genetic factors are estimated to account for ~81% of the risk of developing ASD, whereas environmental factors contribute to a ~14-22% risk. Of note, >100 ASD-associated risk genes have been identified, including neurexin 1 (NRXN1), Src homology 3 and multiple ankyrin repeat domains 2/3 (SHANK2, SHANK3) and chromodomain helicase DNA binding protein 8 (CHD8). The principal mutation types include de novo truncating mutations, missense mutations and copy number variations (CNVs). These risk-associated genes influence gene expression, neurogenesis, synaptic function and chromatin regulatory networks (6-8).

By contrast, environmental factors primarily influence early fetal development through maternal health conditions and external exposures. A previous large-scale study involving 22,156 cases of ASD across three Nordic countries underscored the crucial role of perinatal and prenatal factors. Maternal gestational hypertension (odds ratio, 1.4), preeclampsia [relative risk (RR), 1.3], overweight or obesity (RR, 1.3) and an advanced maternal age (≥35 years; RR, 1.3) were all shown to be significantly associated with an increased risk of offspring developing ASD. Moreover, an advanced paternal age (each 10-year increase corresponding to a 21% rise in the risk of ASD), interpregnancy intervals that are either too short (<12 months) or too long (≥72 months) and exposure to specific medications, such as valproic acid (VPA) during pregnancy, were also closely linked to elevated risk of developing ASD (5). A previous study demonstrated that the absolute risk of developing ASD reached 4.4% in the VPA-exposed group as compared to the unexposed group with 1.5%. Thus, beyond genetic predisposition, aberrations in the intrauterine environment and maternal metabolic dysregulation may play a critical role in disrupting fetal neurodevelopment and represent important triggers for ASD (9).

Current treatment strategies and key challenges

Early diagnosis and intervention for ASD are deemed pivotal for improving the quality of life of affected children. Such early interventions can enhance language abilities, social communication skills and behavioral regulation, particularly when administered during the rapid phase of neurodevelopment (<3 years of age). This timing is critical for optimizing long-term outcomes, helping to maximize the cognitive, linguistic and social capacities of children (8,10). The American Academy of Pediatrics recommends autism screening at 18 and 24 months of age (https://www.aap.org/en/patient-care/autism). Currently, the primary diagnostic tools include the Modified Checklist for Autism in Toddlers Revised (M-CHAT-R) (11), the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) (12). Children who screen positive require comprehensive evaluations, including behavioral observation and an in-depth analysis of developmental history (3,8). However, as the symptoms of ASD are heterogeneous and vary greatly among individuals, early diagnosis remains challenging, particularly in cases with atypical or mild presentations.

At present, treatment for ASD primarily focuses on behavioral interventions and symptom management, as there is no universally accepted cure (3). The behavioral intervention remains the first-line approach, commonly implemented through Early Intensive Behavioral Intervention (EIBI) and Naturalistic Developmental Behavioral Interventions (NDBI) (13).

EIBI is grounded in the principles of Applied Behavior Analysis (ABA) and is typically designed for children <5 years of age. It involves intensive therapy, usually at least 25 h per week over a minimum period of 1 year, to strengthen social, language, cognitive and adaptive behaviors. Among NDBI, the Early Start Denver Model (ESDM) (14) is the most representative approach. It integrates multiple developmental domains, including cognition, language, social interaction, motor skills and imitation, into behavioral interventions. ESDM emphasizes creating meaningful activities for children, fostering interactive relationships and emotional engagement, and promoting the generalization of learning. Motivating activities are incorporated into daily routines to help children acquire new skills, improve language, social and cognitive functioning, and reduce disruptive behaviors (15). These behavioral strategies currently constitute the cornerstone of ASD therapy.

Pharmacological interventions are mainly used to address comorbid symptoms, such as risperidone and aripiprazole, which effectively reduce irritability and aggressive behaviors (16). Methylphenidate, atomoxetine and guanfacine may alleviate hyperactivity and attention deficits. For sleep disturbances, melatonin is commonly prescribed (8).

These interventions mainly aim to alleviate symptoms and minimize the effect on daily life and quality of life, rather than addressing the underlying causes of ASD. To date, to the best of our knowledge, no medication has been shown to effectively treat the core symptoms of ASD, and treatment outcomes vary widely among individuals. Consequently, there is an urgent need to explore novel treatment strategies, particularly those targeting the underlying pathophysiological mechanisms, which have become a central focus of contemporary ASD research.

Future directions for early diagnosis and intervention

The future of early ASD diagnosis and intervention hinges on precision, personalization and enhanced accessibility. First, personalized intervention plans are crucial for addressing the heterogeneity of ASD (17). By integrating assessments of the behavioral, cognitive and language abilities of a child, along with data-driven analytical methods, more tailored interventions can be designed to meet individual needs (18). In addition, using biomarkers (e.g., miRNAs or exosomal components) to aid in diagnosis and treatment offers a potential avenue for refining interventions (19), such as identifying neuroinflammatory features, which may enable more targeted immunomodulatory therapies (20).

The integration of emerging technologies presents new opportunities for the treatment of ASD. For instance, mesenchymal stem cells (MSCs) exhibit tremendous promise owing to their multilineage differentiation potential, immunomodulatory properties, and capacity to secrete various neuroprotective factors (21,22). Beyond enhancing the neuroinflammatory microenvironment and supporting neuroplasticity in vivo, MSCs also release exosomes that transport essential proteins, nucleic acids, and miRNAs to repair damaged neurons and glial cells (23). These molecules, in turn, modulate gene expression and cell function, mitigate neuroinflammation and repair synaptic structures (24). Exosomes possess low immunogenicity, the ability to cross the blood-brain barrier, and the capacity for targeted delivery of specific bioactive molecules (25,26). A number of studies have focused on the use of MSC-derived exosomes (MSC-Exos) in ASD interventions, exploring their potential mechanisms and translational applications for improving social, communication and cognitive functions (22,27-29).

Moreover, developing novel evaluation metrics is crucial for assessing the efficacy of interventions. Researchers can more comprehensively track the progress of a child in detection and intervention by integrating behavioral data, neuroimaging findings (30,31) and biomarker changes (32). Long-term follow-up assessments further elucidate how specific strategies affect social adaptation and overall quality of life in adulthood (33).

Lastly, enhancing the social awareness of ASD and strengthening policy support are also required. Public education campaigns can help reduce societal bias, and training programs for parents and educators can improve the effectiveness of early diagnosis and intervention (34). In this regard, additional funding from government research agencies and related organizations can expand the reach of innovative research and healthcare services for individuals with ASD.

Overall, the advancements in ASD diagnosis and intervention hinge on technological progress, cross-disciplinary collaboration, and strategic resource allocation. By harmonizing scientific breakthroughs with robust policy support, current treatment barriers can be addressed and this may help foster renewed optimism for children with ASD and their families.

Molecular genetics and neuropathology of ASD

With deepening insight into ASD, research on its etiology and pathogenesis has expanded from early, straightforward genetic associations to a comprehensive framework encompassing molecular pathology, neural network disruptions and interdisciplinary approaches. In recent years, emerging technologies, such as high-throughput single-cell sequencing (35) and brain organoid models (36), have rapidly evolved, enabling a more in-depth analysis of gene-environment interactions and neurodevelopmental abnormalities in ASD. These advances also provide novel approaches to potential interventions and therapies. Against this backdrop, the following sections provide a systematic review of current research on ASD, focusing on genetic landscapes, synaptic imbalances, inflammatory regulation, glial cell activation and immune dysregulation (37).

Genetic characteristics and polygenic complexity of ASD

Epidemiological studies in recent years have underscored the dominant role of genetic factors in ASD, which is recognized as a complex disorder driven largely by heritability. Multiple twin studies consistently demonstrate much higher concordance for ASD in monozygotic (MZ) than dizygotic (DZ) twins. In a population-based study using standardized ADI-R/ADOS assessments, probandwise concordance ranged from ~58-77% for MZ twins and ~21-36% for DZ twins across strict-autism and broader ASD definitions; rare sex-specific DZ subgroups can be lower (38). A previous meta-analysis further indicates near-perfect MZ correlations (~98%) with DZ correlations that vary by the assumed prevalence threshold, yielding substantial heritability (~64-91%) and showing that estimates of the shared environmental component are sensitive to modelled prevalence (39). Through GWAS and familial genetic analyses comparing large-scale datasets of individuals with ASD and healthy controls, numerous ASD-associated susceptibility genes and variations have been identified, including CHD8, NRXN1, SHANK2, SHANK3 and contactin associated protein 2 (CNTNAP2) (6-8,40). Among these genes, CHD8 encodes a chromatin remodeler that regulates a wide array of neurodevelopmental genes by binding to their promoters and enhancers. Previous studies have reported that CHD8 haploinsufficiency results in dysregulated transcriptional programs, aberrant neurogenesis, and epigenetic abnormalities (41). NRXN1 encodes the presynaptic adhesion molecule neurexin-1, which interacts with postsynaptic ligands such as neuroligins to form trans-synaptic connections and is essential for synapse formation and homeostasis. In ASD mouse models carrying NRXN1 mutations, CNVs have been shown to cause synaptic connectivity defects, impairments in neural circuit development and synaptic transmission, ultimately leading to deficits in social interaction and communication (42). The SHANK gene family, particularly SHANK3, functions as a core scaffolding and signaling component of the postsynaptic density (PSD) at excitatory synapses, orchestrating the organization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors, cytoskeletal structures, and intracellular signaling pathways. SHANK deficiency leads to PSD disassembly, impaired synaptic plasticity, altered dendritic spine morphology and excitatory/inhibitory imbalance, thereby contributing to ASD-related behavioral abnormalities. Both animal models and patient-derived induced pluripotent stem cells studies have provided strong evidence supporting these mechanisms (43,44). The CNTNAP2, a member of the neurexin superfamily, is involved in axon-myelin interactions, synaptic function and neuronal positioning. Early candidate gene studies identified CNTNAP2 as being associated with ASD, language impairment and epilepsy. The loss or mutation of CNTNAP2 has been linked to abnormal neuronal migration during development, defects in axonal and myelin function, and disrupted excitatory neuronal activity (45).

The analysis of the Simons Simplex Collection (SSC) has identified six key risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13 and 22q11.2). These large CNVs likely harbor multiple risk genes of moderate effect, primarily involving upstream regulators of gene expression during neural development, as well as synapse-related genes that directly impact neuronal structure and function (6).

Exome sequencing data, when integrated with functional annotations of different types of genetic variants (e.g., rare single-nucleotide variants, insertions/deletions and CNVs) and selection-pressure metrics, e.g., Loss of Function Observed and Expected Upper Bound Fraction (LOEUF) scores, indicate that the risk of developing ASD is strongly associated with rare coding variants and de novo mutations. Among the genes significantly linked to ASD (false discovery rate ≤0.001), de novo protein-truncating variants, damaging missense variants and CNVs account for 57.5, 21.1 and 8.44% of the genetic risk, respectively. Notably, CNVs carry a markedly high relative risk since they alter the copy number of large genomic segments, potentially affecting multiple genes and leading to cumulative effects (7).

CNVs frequently occur in gene-dense, functionally important regions critical for neurodevelopment, synaptic plasticity and chromatin regulation. Abnormalities in these regions may lead to extensive functional disruption (46). In addition, CNVs can alter gene dosage (e.g., an increase or decrease in gene copies), and dosage-sensitive genes can exhibit significant biological effects when copy numbers deviate from the normal (47,48). A number of CNVs also exhibit pleiotropy, where a single gene may influence multiple biological processes or phenotypes, so its dysregulation can affect various systems concurrently (49). Moreover, CNVs can disrupt regulatory elements (e.g., enhancers and promoters) in non-coding regions, thereby altering gene expression and regulatory networks (48).

The Genes associated with ASD exhibit a higher expression in mature neurons, aligning with their roles in neuronal maturation and synaptic connectivity. By contrast, genes linked to developmental delay are predominantly active in immature neurons and progenitor cells. This suggests that different gene networks affect the nervous system at specific developmental stages (7).

Core neuropathological mechanisms of ASD

A primary pathological hallmark of ASD is abnormal synaptic development and plasticity, primarily manifested as disruptions in synapse formation and pruning. This leads to excessive or insufficient synaptic connections, compromising the precise establishment of neuronal networks (50-52). The excitatory and inhibitory ratio, a core mechanism in synaptic signaling, is critically disrupted in a number of cases, typically manifesting as excessive excitatory activity [e.g., elevated glutamate receptor function (53)] or diminished inhibitory signaling (e.g., reduced gamma-aminobutyric acid receptor levels), both of which may lead to neuronal circuit instability, driving hyperexcitability or network dysregulation (54). Either scenario can result in hyperactive or imbalanced neuronal networks. Furthermore, mutations in ASD-associated genes, such as neuroligin 4 (NLGN4) (55) and SHANK3 (56) can impair presynaptic neurotransmitter release and postsynaptic receptor responsiveness, thereby reducing synaptic transmission efficiency. Abnormalities in synaptic plasticity processes, including long-term potentiation (LTP) and long-term depression, further exacerbate these dysfunctions, as reflected by impaired modulation of synaptic strength in key brain regions, such as the hippocampus, prefrontal cortex and amygdala (57).

Additionally, synaptic protein misfolding and the activation of endoplasmic reticulum stress can lead not only to a loss of synaptic function, but also to heightened neuroinflammation via the unfolded protein response, thereby aggravating ASD pathophysiology (58). Collectively, these disruptions in synaptic development and plasticity underlie prominent deficits in social interaction, cognitive function, and behavioral patterns in ASD, providing essential clues for understanding its molecular mechanisms and for developing potential therapeutic approaches (59).

Developmental abnormalities in specific brain regions are a crucial aspect of the neurobiological features of ASD. Research indicates that both structure and function are significantly affected in the prefrontal cortex (60), hippocampus (61) and basal ganglia (62). Alterations in causal connectivity within the prefrontal cortex are closely linked to deficits in social behaviors and cognitive functions, typified by an excitatory/inhibitory signaling imbalance and diminished synaptic plasticity (60). In the central region of the hippocampus, which is critical for learning and memory, reduced synaptic density and impaired LTP are commonly observed in ASD and directly correlate with decreases in spatial memory (61). Moreover, abnormalities in basal ganglia circuitry, particularly those involved in gating motor output, have been implicated in repetitive and stereotypic behaviors; changes in synaptic transmission within these pathways may affect behavior by modulating motor control and reward mechanisms (62).

Such developmental anomalies manifest at the micro-level of neuronal connections and alter interregional network communication, thereby contributing to the diverse and complex behavioral phenotypes of ASD. In-depth research into these brain regions' developmental perturbations is instrumental in elucidating the pathological mechanisms of ASD and lays the groundwork for precision-targeted therapies.

Cytological basis of neuroinflammation in ASD

Neuroinflammation and aberrant immune regulation play pivotal roles in the pathogenesis of ASD, with the activation of microglia and astrocytes constituting a core cellular foundation of this neuroinflammatory process. Microglia and astrocytes exhibit distinct polarization states in the neuroinflammatory microenvironment of ASD, with M1/A1 subtypes promoting injury and M2/A2 subtypes supporting repair. The interplay of these brain cells is summarized below and illustrated in Fig. 1.

Microglia: Dual polarization and synaptic phagocytosis

Microglia are the primary immune cells of the central nervous system (CNS) and exhibit dual polarization states, i.e., M1 (classical activation) and M2 (alternative activation). In response to inflammatory stimuli, M1-type microglia secrete proinflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 (63-65) and reactive oxygen species (66), driving neuroinflammation and pathological damage. They can also enhance phagocytic activity, causing direct harm to neurons and synapses (67). Conversely, M2-type microglia are induced by anti-inflammatory factors, such as IL-4 and IL-13 (68), and promote the release of neuroprotective mediators, including IL-10 and transforming growth factor-β (TGF-β) (68-70). This balance between M1 and M2 polarization is crucial for regulating neuronal activity, synaptic plasticity, and the clearance of apoptotic cells, thus helping maintain CNS homeostasis under normal conditions.

Microglial synaptic phagocytosis plays a critical role in shaping neural circuits; however, its dysregulation can occur in either direction, either through excessive elimination of synapses or insufficient pruning. This bidirectional imbalance contributes to abnormal neural connectivity, underscoring the complex and multifaceted role of microglia in the pathophysiology of ASD. During normal development, microglia refine neural circuits by pruning superfluous synapses. However, the hyperactivation of microglia in ASD may lead to aberrant over-pruning of synapses, thereby reducing synaptic density and impairing neural circuits, particularly in brain regions linked to social behavior and cognition. This phenomenon may underlie the synaptic deficits observed in specific ASD subtypes (71). By contrast, a dysregulated microglial function can result in insufficient synaptic pruning, leading to excessive synaptic connections and abnormal network synchronization, as well as reduced information-processing efficiency. This effect may be more pronounced in other ASD subgroups. This imbalance in synaptic pruning is influenced by pro-inflammatory cytokines, microglial signaling pathways [e.g., TREM2 (72,73) and STING (74)] and region-specific factors. Consequently, the dual role of microglial phagocytosis highlights the complexity and heterogeneity of the pathogenesis of ASD, supporting the rationale for therapeutic strategies that target microglial modulation.

Astrocytes: Reactive transformation and neuroinflammatory regulation

Astrocytes are instrumental in maintaining CNS homeostasis and supporting neuronal function. However, in ASD, astrocyte activation is likewise closely tied to the progression of neuroinflammation (75). Activated astrocytes can release both pro-inflammatory and anti-inflammatory mediators, such as IL-6 (76) and IL-10 (77), exerting a bidirectional influence on the inflammatory process. Moreover, intermediate filament proteins in astrocytes, including glial fibrillary acidic protein (78) and vimentin (79), exhibit an altered expression and distribution. These proteins regulate the degradation of extracellular matrix components (80). In the brains of patients with ASD, astrocytes often display morphological changes characteristic of reactive astrocytes, i.e., hypertrophic, with thicker and shorter processes, particularly the neurotoxic A1 subtype. These alterations are linked to astrocyte dysfunction, disrupted neurogenesis and neuroinflammation, thereby exacerbating neurological abnormalities in individuals with ASD (81-83).

Pro-inflammatory cytokines and neuroinflammatory signaling

Pro-inflammatory cytokines are key factors driving neuroinflammation in ASD. Their dysregulated expression signifies aberrant immune activation and may directly or indirectly inflict neuronal damage. Elevated levels of IL-1β and TNF-α have been strongly associated with compromised synaptic function and reduced neuronal viability (84). Furthermore, cytokines can modify neurotransmitter metabolism and release, further destabilizing neural networks. For example, IL-6 has been shown to regulate glutamate transporter expression, thereby exacerbating excitotoxicity (85). These inflammatory mediators also function through signaling cascades, such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and JAK-STAT to regulate the intensity and duration of the immune response, thereby exacerbating neuronal dysfunction and cell death (86).

In summary, the activation of microglia and astrocytes significantly modulates neuroinflammation and immune responses in ASD, profoundly influencing pathological progression. By releasing pro-inflammatory cytokines and altering synaptic function, aberrant glial activation not only promotes neuronal damage, but also undermines the stability of neuronal networks. A more precise understanding of the atypical inflammatory and immune mechanisms in ASD is therefore pivotal for illuminating its pathophysiology and developing effective therapeutic strategies.

Mesenchymal stem cells and their derived exosomes in ASD: Research and applications

Biological characteristics and immunoregulatory mechanisms of action of MSCs

MSCs are adult stem cells characterized by multipotent differentiation and self-renewal capacities, initially identified in bone marrow by Friedenstein et al (87). These cells adhere to plastic culture flasks and exhibit robust biological functions. They are widely distributed in various tissues, such as bone marrow, adipose tissue, umbilical cord, placenta, and dental pulp (88). A schematic overview of these MSC sources is illustrated in Fig. 2. Owing to their diverse sources and distinct functional properties, have emerged as a significant research focus in regenerative medicine and cell therapy.

Firstly, MSCs possess notable multipotent differentiation potential under specific conditions; they can differentiate into various cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, and neuron-like cells. This property is under precise genetic regulation (89). For instance, RUNX family transcription factor 2 (RUNX2) plays a pivotal role in osteogenic differentiation (90); peroxisome proliferator-activated receptor γ (PPAR-γ) controls adipogenic differentiation (91); SRY-Box transcription factor 9 (SOX9) is crucial for chondrogenesis (92); and the differentiation of neuron-like cells relies on the expression of proteins, such as Nestin and neuronal differentiation 1 (NeuroD1) under the induction of neurotrophic factors (93). These genes, which fine-tune the Wnt/β-catenin TGF-β/bone morphogenetic protein (BMP) and Notch 1 signaling pathways, provide the molecular underpinnings for the applications of MSCs in regenerative medicine.

Secondly, MSCs play a prominent role in immunomodulation. Research suggests that MSCs can secrete multiple immunoregulatory factors and interact with immune cells, thus exerting immunosuppressive and immunobalancing effects. For example, PGE2, TGF-β, IL-10 and HLA-G secreted by MSCs can effectively inhibit T-cell proliferation and induce the generation of regulatory T-cells (Tregs), thereby promoting immune tolerance (94). Furthermore, by causing the polarization of macrophages toward the M2 phenotype, MSCs can significantly reduce the release of pro-inflammatory cytokines, such as IL-6 and TNF-α (95), thereby improving the pathological environment associated with inflammation. These properties render MSCs promising therapeutic candidates for various immune-related diseases (96).

Additionally, the low immunogenicity of MSCs aids in their long-term survival in the host. This advantage arises from their low expression of Major Histocompatibility Complex (MHC) class I molecules and the lack of MHC class II and costimulatory molecules (e.g., CD80 and CD86) (97). Such features markedly reduce T-cell activation and diminish strong host immune rejection. Moreover, MSCs secrete multiple immunosuppressive factors (e.g., PGE2, IDO1 and HLA-G) to attenuate immune responses further (98). These combined mechanisms enable MSCs to survive and exert therapeutic effects in allogeneic transplantation settings, with minimal reliance on immunosuppressants.

Research advances of MSCs in ASD

MSCs promote neuroprotection and functional recovery in various neurological disorders through multiple pathways. For instance, MSCs secrete brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and neurotrophin-3 (NT-3), which can enhance neuronal survival, axonal regeneration, and synaptic function by activating the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and MAPK/ERK signaling pathways (99,100). Through reducing neuroinflammation and oxidative stress, MSCs have been shown to attenuate disease progression in Alzheimer's disease and Parkinson's disease, while improving neurological and cognitive functions (101,102). In spinal cord injury models, MSCs facilitate axonal regeneration and functional recovery (103).

Notably, relevant studies on ASD also demonstrate promising results. In a rat model of VPA-induced ASD, MSC transplantation was shown to markedly improve social interaction, mitigate repetitive behaviors and alleviate anxiety-like behaviors (104). These effects may be attributed to the immunomodulatory and neuroprotective functions of MSCs which reduce neuroinflammation and enhance synaptic plasticity, ultimately improving core behavioral symptoms.

Despite the considerable therapeutic potential of MSCs in ASD, challenges remain regarding clinical translation, including immunorejection, diminished proliferative capacity over time, and concerns over transplantation safety. In this regard, exosomes secreted by MSCs have emerged as a research hotspot in recent years due to their critical roles in immune regulation and tissue repair (105). Compared with conventional cell transplantation, MSC-derived exosomes offer a 'cell-free therapy' strategy characterized by small size, ease of storage, low immunogenicity, and suitability for standardized production and quality control. These features not only provide new perspectives and directions for the precision treatment of neurodevelopmental disorders such as ASD, but may also enhance the feasibility of clinical translation (106).

Structure and biological functions of exosomes

Exosomes are extracellular vesicles measuring ~30-150 nm in diameter, originating from endosomal pathways and released into bodily fluids through the fusion of multivesicular bodies with the cell membrane (107,108). A lipid bilayer encases exosomes enriched with various biologically active components, including proteins, nucleic acids (mRNAs, miRNAs and lncRNAs, etc.) and lipids. Their stable structure enables exosomes to serve as unique mediators of intercellular communication and regulation, thus providing a theoretical basis for potential therapeutic applications (109). The composition and biogenesis pathways of MSC-Exos, as well as their downstream effects on neuronal and glial cells in ASD models, are summarized in Fig. 3. Exosomes exert their therapeutic effects primarily through interacting with their cargo in recipient cells. Exosomes deliver their contents directly into target cells, either by fusing with the plasma membrane or undergoing receptor-mediated endocytosis, and thereby modulate gene expression and signaling pathways.

Nucleic acid cargo and gene regulation

The miRNAs in exosomes play vital roles in regulating gene expression, as they can modulate inflammation, neuronal survival, and synaptic plasticity by targeting specific signaling cascades (110,111). Previous studies have demonstrated that miRNAs encapsulated in exosomes, such as miR-124 packaged within exosomes, have been demonstrated to enhance neuronal regeneration and reduce neuroinflammation (112-115). Other miRNAs, such as miR-21, miR-155 and miR-146a, can suppress the NF-κB pathway, thereby reducing the secretion of pro-inflammatory factors (e.g., IL-6 and TNF-α) and increasing the levels of anti-inflammatory IL-10, ultimately mitigating neuroinflammation. These miRNAs may also inhibit excessive activation of the mTOR pathway, reducing aberrant neuronal activity (115-118). Additionally, miR-873a-5p within exosomes can promote microglial polarization toward the anti-inflammatory M2 phenotype (120). Apart from miRNAs, mRNAs and lncRNAs, exosomes can also contain these molecules, which can affect recipient cell functions through translation or transcriptional regulation, influencing tissue repair and immune modulation (121-123).

Protein cargo and neural repair

Exosomes also harbor proteins, such as heat shock proteins (HSPs) (124), neuronal adhesion molecules [e.g., intercellular adhesion molecule 1 (125)] and cytokines [e.g., TGF-β (126)] that can directly modulate axonal growth, promote synaptic remodeling, and strengthen neural network connectivity, are considered critical processes in immune regulation, neuroprotection, and tissue repair. Furthermore, exosomal membrane lipids (e.g., sphingomyelin and phosphatidylserine) can enhance synapse formation and stability, thereby influencing the functional properties of recipient cells (127). These molecular mechanisms provide a basis for improving cognitive and behavioral deficits in ASD.

Neurotrophic factors and signaling pathways

Exosomes are often enriched with neurotrophic factors and neurodevelopmental molecules, such as Nestin, NeuroD1, BDNF and VEGF. These factors act through signaling pathways, including the Wnt/β-catenin, TGF-β/BMP and PI3K/Akt pathways, thereby supporting neuronal proliferation, migration and differentiation (128-130).

Gut microbiota and the gut-brain axis

ASD has been closely linked to gut microbiome dysbiosis. Exosomes can modulate gut microbiota diversity by increasing the abundance of bifidobacteria and lactobacilli and improving gut barrier function (131). Exosomes containing miR-155, miR-181a and TGF-β can reduce intestinal inflammation and permeability. Exosomes containing miR-155, miR-181a and TGF-β can reduce intestinal inflammation and permeability, ultimately influencing the gut-brain axis and indirectly affecting the central nervous system function (132-134).

Exosomes carry a versatile repertoire of bioactive molecules that can modulate inflammatory responses, promote neural repair and regulate the gut-brain axis. These properties underscore the potential of exosome-based, cell-free therapy for ASD and other neurodevelopmental disorders.

Potential value of exosomes in the treatment of ASD

In recent years, MSC-Exos have exhibited immense promise in ASD research and interventions due to their unique composition and diverse functionalities (29,129). Compared with direct cell transplantation, exosomes provide greater safety, controllability and ease of storage. By carrying various miRNAs, proteins and bioactive molecules, MSC-Exos can exert immunomodulatory, neuroprotective and synaptic repair effects in the CNS (135,136). Their ability to regulate neuroinflammation, restore synaptic plasticity, and rebalance the gut-brain axis underscores the potential of exosome-based 'cell-free therapy' (129), paving the way for new avenues of research and clinical applications in ASD.

Studies using animal models of ASD have demonstrated that the intranasal administration of MSC-Exos markedly improves social interaction, cognition and repetitive behaviors (22,29,135,136). These effects may be attributed to miRNAs and anti-inflammatory agents delivered by exosomes, which modulate immune responses and neuronal network functionality. For example, exosomal miRNAs [such as miR-21-5p (137), miR-17-92 (138) and miR-146a (139)] and multiple bioactive proteins [including HSP70 and TGF-β (140)] help regulate neuroinflammation, synaptic plasticity, and neurogenesis via intercellular signaling. Additionally, research suggests that neurotrophic factors present in exosomes can enhance neuronal survival and differentiation, thereby improving behavioral outcomes. These factors also enhance synaptic plasticity, promote network-level functional integration, and reduce CNS inflammation by increasing anti-inflammatory cytokines (22,29,135,141).

In summary, MSC-Exos, owing to their diverse bioactive molecules and stable delivery system repertoire, have shown comprehensive effects on immunoregulation, neural repair and synaptic regeneration in ASD. They are thus emerging as a promising therapeutic alternative to conventional cell-based treatments. Ongoing research will further elucidate the underlying mechanisms of exosomes in ASD, optimize exosome preparation and administration strategies, and, through multidisciplinary collaboration, develop safe, efficacious and scalable exosome-based therapeutics. These efforts hold the potential to propel the field toward precision interventions and clinical translation for ASD.

Clinical progress of stem cells and exosomes in ASD

In recent years, stem cell-based therapy has emerged as one of the key areas of interest for the treatment of ASD. By employing stem cells or their exosomes, researchers aim to modulate immune responses, improve cerebral blood flow, and enhance neuronal repair in individuals with ASD (21). Early clinical trials have documented varying degrees of improvement in behavior, language skills and social abilities among ASD patients receiving MSC therapy (142) with minimal adverse events (143). Additionally, these trials noted decreases in inflammatory markers and improvements in brain metabolic activity, further supporting the potential role of MSCs in the treatment of ASD (142).

Current status of clinical research and key findings

Several completed clinical trials worldwide have investigated the use of stem cell therapy for the treatment of ASD. The following paragrpahs summarizes the primary clinical studies and their principal outcomes:

Use of umbilical cord blood-derived stem cells

Lv et al (144) conducted a study combining cord blood mononuclear cells (CBMNCs) with umbilical cord-derived mesenchymal stem cells, enrolling 37 patients with ASD. Their results revealed that the combination treatment group had significantly greater improvements in the Childhood Autism Rating Scale (CARS) and Aberrant Behavior Checklist (ABC) scores compared to either the CBMNC-only group or the control group (which received only rehabilitative interventions). No severe adverse events were reported, underscoring both the safety and the superior efficacy of combination therapy (144).

Preliminary attempts with human embryonic stem cells

Shroff (145) reported outcomes for 3 patients with ASD treated with human embryonic stem cells. Improvements were observed in motor skills, cognition, social interaction and sensory sensitivities, with no adverse events noted. Although the sample size was small, this study highlights the potential of stem cell therapies for alleviating core symptoms of ASD (145).

Potential of autologous umbilical cord blood therapy

Chez et al (146) conducted a randomized, double-masked, placebo-controlled crossover study involving 29 children with ASD aged 2 to 6 years, evaluating the safety and efficacy of autologous umbilical cord blood transfusions. Although treatment did not significantly improve its primary endpoints, some participants exhibited trends toward improved socialization and language skills. No severe adverse events occurred, suggesting that stem cell therapy may hold promise for enhancing social functioning (146).

Changes in brain network connectivity

Simhal et al (147) used diffusion tensor imaging to assess the effect of umbilical cord blood stem cell therapy on white matter networks in patients with ASD. Their study revealed that post-treatment, the robustness of the white matter network was markedly increased, especially in regions involved in social and communication functions. These findings may be related to the ability of stem cells to regulate neuroinflammation and promote neuroplasticity (147).

Stem cells combined with behavioral interventions

Thanh et al (148) conducted an open-label clinical trial in Vietnam, enrolling 30 children with ASD aged 3 to 7 years. The intervention combined autologous bone marrow mononuclear cell transplantation with the ESDM, an early behavioral intervention. The results revealed a reduction in median CARS scores from 50 to 46.5 (P<0.05) and an increase in Vineland Adaptive Behavior Scale scores from 53.5 to 60.5, indicating substantial improvements in social interaction, language abilities, and daily living skills, with no severe adverse events reported (148).

Collectively, the aforementioned clinical studies suggest that MSC-based and MSC exosome therapies hold promise for improving social communication, language skills, behavioral challenges and cognition in individuals with ASD. Notably, combined treatments, including the incorporation of behavioral interventions or personalized therapeutic regimens that appear effective, may be due to their multi-target mechanisms of action. The majority of studies did not report severe adverse events, reflecting an overall favorable safety profile. However, a number of existing studies involve small sample sizes and open-label designs, lacking the robust evidence from large-scale randomized controlled trials (RCTs). Additionally, the precise mechanisms underlying the observed therapeutic effects remain incompletely understood. Future investigations should further refine treatment protocols, clarify the role of exosomes in cell therapy, and establish the long-term safety and efficacy of these interventions. Expanding multicenter, large-sample RCTs is crucial for evaluating the performance of different stem cell types and administration strategies. Moreover, exploring synergistic effects between stem cells and behavioral or pharmacological interventions will help optimize individualized treatment plans. Finally, integrating gene-editing technologies and engineered exosomes could enhance their clinical utility. Such efforts will provide a more robust theoretical and practical foundation for applying stem cell and exosome-based therapies in ASD.

Potential for clinical translation and existing barriers

Due to pronounced immunomodulatory properties, tissue repair potential and favorable safety profile, MSCs have attracted widespread attention in recent years, gradually becoming an essential focus of stem cell-based therapies. As MSC research advances, the exosomes they secrete (MSC-Exos) have been identified as a key functional mediator and are expected to play a potential role in ASD interventions (149). The majority of clinical studies on MSCs and MSC-Exos remain in phase I/II trials (150). Early data suggest that patients with ASD treated with these therapies experience improved social interaction and language skills, as well as decreased inflammatory markers, such as TNF-α and IL-6 (151,152). Nonetheless, the clinical translation of MSCs and their exosomes depends on the efficacy of preclinical studies, as well as substantial practical and regulatory challenges. Although preliminary findings are encouraging, limitations in sample size, follow-up duration, and study design mean that large-scale, multicenter clinical data are still required to confirm their long-term efficacy and safety. A discussion of the advantages and challenges inherent in clinical translation is presented below:

Core advantages and multifaceted mechanisms

Multifunctionality: Immunomodulation and neuroprotection

The immunomodulatory and neuroprotective properties of MSCs render them attractive for addressing multiple pathological mechanisms underlying ASD. Research indicates that MSC-Exos can regulate T- and B-cell activation, induce immune tolerance, and suppress the secretion of inflammatory cytokines, thus improving neuroinflammatory conditions (22). Growth factors, miRNAs, and other bioactive substances in MSC-Exos also promote neuronal survival and synaptic plasticity (111). Owing to their differentiation potential, MSCs and their exosomes may also serve as tools for neural repair, providing potential therapeutic value for ASD-related neurodevelopmental anomalies.

Low immunogenicity and favorable safety profile

MSCs exhibit relatively low immunogenicity in allogeneic transplantation (153). Their exosomes, which lack complete cell-surface antigen expression (154) and do not carry a nucleus or full genomic content (155), further minimize risks of immune rejection and tumorigenesis. Consequently, MSC-Exos do not require stringent donor-recipient matching to the same extent as allogeneic MSCs, reducing potential complications and ethical concerns.

Targeted action and personalized therapy

Exosomes can enter target cells through receptor-mediated endocytosis or membrane fusion, delivering a diverse array of active molecules that influence cell proliferation, differentiation, apoptosis, and immune responses. Owing to their nanoscale size and lipid bilayer structure, exosomes demonstrate relatively high transmembrane delivery efficiency; research suggests that exosomes can traverse the blood-brain barrier (156). As the pathogenesis of ASD involves abnormal neural networks and central neuroinflammation, MSC-Exos capable of penetrating the CNS may help restructure the brain microenvironment and enhance therapeutic outcomes. Moreover, engineering MSCs or modifying exosome cargo based on individual patient pathology (e.g., through gene editing) may enable more precise, personalized treatments.

Large-scale production, transport and storage

Under specific culture conditions, exosomes can be produced and purified in large quantities. Compared to cell transplantation, which requires highly viable, well-characterized cells in sufficient numbers, exosomes are easier to standardize and mass-produce, rendering clinical deployment more feasible. Additionally, exosomes can be stored for extended periods under appropriate conditions while retaining their bioactivity, thereby circumventing many of the stability challenges encountered with live MSCs. This facilitates large-scale manufacturing, clinical stockpiling, and broader geographic distribution.

Real-world challenges and bottlenecks

Production techniques and quality control

Variations in MSC culture conditions and tissue sources can produce substantial differences in exosome yield and quality. Standard protocols for extracting, purifying and characterizing exosomes have yet to be universally adopted. Reagents, equipment and technical approaches vary greatly among laboratories, which can potentially affect the reproducibility of results. To achieve industrial-scale production and clinical adoption of MSC-Exos, international or national-level standardization is needed, encompassing MSC culture conditions, exosome extraction, purification, and the establishment of quality metrics. Key parameters include identifying and quantifying cargo molecules, particle size distribution and surface markers. Without such standards, ensuring the stability and consistency of MSC-Exos across different batches remains difficult.

Heterogeneity in sources and cell states

MSCs can be derived from various sources, including bone marrow, adipose tissue, umbilical cord, and other tissues, resulting in variability based on tissue origin, donor characteristics and passage number. For instance, adipose-derived MSCs generally have more substantial adipogenic potential, whereas bone marrow-derived MSCs may be more adept at osteogenic differentiation (157). In the context of ASD therapy, MSC-Exos from different sources or differing cell expansion histories may yield divergent immunomodulatory and neuroprotective effects. A systematic investigation is required to determine an optimal source or a combination strategy for clinical use.

Complexity of mechanisms

Although a number of studies have documented the neuroprotective, immunoregulatory and neural network repair functions of MSC-Exos, the precise molecular mechanisms underlying these functions remain incompletely understood (22,136,149). It remains to be determined which miRNAs or proteins in MSC-Exos are essential for regulating neuronal repair and immune balance in ASD. In addition, the mechanisms through which exosomes interact with target cells and influence downstream signaling pathways remain to be elucidated. Further research using in vitro and in vivo models is required to clarify these mechanisms, improving the specificity and reliability of future clinical applications.

Safety and ethical oversight

While MSC-Exos are associated with a lower immunogenicity and tumorigenic risk than direct cell transplantation, comprehensive preclinical safety evaluations and multicenter clinical trials are necessary to assess long-term risks. The clinical use of stem cells and their derivatives is strictly regulated in many countries, requiring compliance with guidelines for pharmaceutical and biological products, as well as adherence to ethical considerations, including donor sourcing and traceability during preparation and application (158).

Large-scale manufacturing and cost-effectiveness

Generating MSC-Exos on a large scale requires efficient isolation and concentration protocols for MSC culture. Once translated to clinical practice, cost and patient accessibility become critical factors. In the event that production remains prohibitively costly without relevant policy support, the widespread adoption of MSC-Exos in the treatment of ASD may be limited.

Delivery efficiency and long-term safety

Achieving the efficient, targeted delivery of exosomes to the CNS and specific lesion sites to enhance therapeutic specificity poses a significant challenge. Moreover, current exosome-related clinical trials typically feature short follow-up periods (144,146,147). Exosomes hold potential as a long-term intervention strategy; however, their extended use may carry unknown risks, including effects on the immune system and neural function. Rigorous long-term monitoring and evaluation are therefore necessary.

Individual differences and clinical applicability

ASD is highly heterogeneous, with variability in age, subtype and comorbid conditions affecting treatment responses to MSCs or MSC-Exos. Personalized therapies tailored to individual disease stages and pathological profiles remain a significant challenge. Biomarker analysis and molecular subtyping may enhance individualized treatment strategies. Systematic clinical trials are necessary to establish optimal dosing and administration protocols for diverse patient populations.

Conclusion

In conclusion, MSCs and MSC-Exos have demonstrated considerable therapeutic potential in the treatment of ASD. MSCs and MSC-Exos can alleviate neuroinflammation, enhance synaptic plasticity, and promote neural network repair through their immunomodulatory and neuroprotective effects. MSC-Exos offers substantial advantages for ASD treatment, including multifaceted therapeutic mechanisms, low immunogenicity and potential for large-scale production. Nevertheless, critical hurdles, such as manufacturing protocols, quality control, elucidation of the mechanism, long-term safety, and personalized application, need to be overcome before MSC-Exos can be widely integrated into ASD therapies. Addressing these challenges through multidisciplinary collaboration and further research will pave the way for more precise, safe, and effective interventions. With their low immunogenicity, ability to cross the blood-brain barrier, and efficient delivery of bioactive molecules, exosomes are promising candidates for treating ASD and other neurodevelopmental disorders. However, several critical challenges remain, including issues related to large-scale production, quality control, and elucidation of underlying mechanisms. Moreover, rigorous clinical trials under strict regulatory and ethical frameworks are required to establish the safety and efficacy of MSC-Exos. Therefore, it is urgent to clarify their mechanisms of action, develop standardized manufacturing and quality control protocols, and optimize long-term safety and personalized treatment strategies. With the integration of high-throughput omics technologies, interdisciplinary collaboration, and continuous innovation, MSC-Exos are expected to advance in basic research and clinical application, offering greater precision and broader therapeutic potential in ASD. Ultimately, only by overcoming key scientific and technical hurdles can MSC-Exos become a viable strategy for individualized interventions.

Future perspectives and application directions

Advancing the therapeutic efficacy and clinical translation of MSC-derived exosomes in ASD will require sustained innovation across multiple dimensions. To improve in vivo delivery efficiency, various delivery platforms, such as magnetic nanoparticles (159) and hydrogels (160), have been developed to enhance targeting and stability in the central nervous system. Additionally, chemical modifications (161) and genetic engineering techniques (162) have been employed to increase the therapeutic specificity and prolong the half-life of exosomes. Engineered MSCs that overexpress functional proteins and miRNAs, such as neurotrophic factors or anti-inflammatory molecules (163), have shown promise in enhancing the neuroprotective and immunoregulatory effects of their exosomes, thereby broadening their application potential in ASD and other neurological disorders. To meet the demands of personalized medicine, customized exosome formulations and treatment protocols tailored to individual patient profiles may improve therapeutic outcomes and reduce adverse effects. The application of high-throughput omics technologies, such as genomics, proteomics and metabolomics continues to unveil the key molecular pathways and networks through which MSCs and their exosomes modulate neurorepair and immune responses. In particular, in-depth investigations into the roles and interactions of miRNAs, proteins, and other bioactive cargos will provide a robust foundation for evaluating therapeutic efficacy and guiding the engineering of exosomes. For clinical translation, it is essential to establish standardized and efficient protocols for MSC cultivation and exosome purification, along with internationally recognized quality control standards to ensure batch-to-batch and inter-institutional consistency. Large-scale, multicenter randomized controlled trials will be crucial for validating the safety and efficacy of MSC-Exos, necessitating refined trial designs that address patient selection, dosage regimens, outcome measures, and long-term follow-up. Given the complexity of ASD pathogenesis and its clinical heterogeneity, future breakthroughs in MSC-Exos therapy will depend on interdisciplinary collaboration across neuroscience, molecular biology, immunology, and materials science, combined with pharmacological and behavioral interventions. Continuous technological innovation and integrative strategies will ultimately pave the way for more effective and safer treatment options for individuals with ASD.

Availability of data and materials

Not applicable.

Authors' contributions

ZS was involved in the conceptualization of the study. ZS and NA were involved in the collection and curation data from the literature, and in the writing and preparation of the original draft of the manuscript. MM was involved in visualization and literature analysis. ZL supervised the study. ZS, NA and ZL reviewed and edited the final manuscript. All authors have read and approved the final manuscript. Data authentications is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

During the preparation of this work, AI tools were used to improve the readability and language of the manuscript or to generate images, and subsequently, the authors revised and edited the content produced by the AI tools as necessary, taking full responsibility for the ultimate content of the present manuscript.

Abbreviations:

ASD	autism spectrum disorder
CNV	copy number variation
MSC	mesenchymal stem cell
MSC-Exos	mesenchymal stem cell-derived exosomes
NF-κB	nuclear factor κ-light-chain-enhancer of activated B cells
PSD	postsynaptic density
PI3K	phosphatidylinositol 3 kinase
Akt	protein kinase B
RR	relative risk
TGF-β	transforming growth factor β
BMP	bone morphogenetic protein
VPA	valproic acid

Acknowledgements

Not applicable.

Funding

The present study was supported by a grant from the Enterprise Joint Fund Project of Hunan Provincial Natural Science Foundation (grant no. 2024JJ9097).

References

1	Hung LY and Margolis KG: Autism spectrum disorders and the gastrointestinal tract: Insights into mechanisms and clinical relevance. Nat Rev Gastroenterol Hepatol. 21:142–163. 2024. View Article : Google Scholar
2	Kanner L: Autistic disturbances of affective contact. Nerv Child. 2:217–250. 1943.
3	Association AP: Diagnostic and Statistical Manual of Mental Disorders. 2022.
4	Shaw KA, Williams S, Patrick ME, Valencia-Prado M, Durkin MS, Howerton EM, Ladd-Acosta CM, Pas ET, Bakian AV, Bartholomew P, et al: Prevalence and early identification of autism spectrum disorder among children aged 4 and 8 years-autism and developmental disabilities monitoring network, 16 sites, United States, 2022. MMWR Surveill Summ. 74:1–22. 2025. View Article : Google Scholar : PubMed/NCBI
5	Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, Glasson E, Mahjani B, Suominen A, Leonard H, et al: Association of genetic and environmental factors with autism in a 5-country cohort. JAMA Psychiatry. 76:1035–1043. 2019. View Article : Google Scholar : PubMed/NCBI
6	Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, Murtha MT, Bal VH, Bishop SL, Dong S, et al: Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 87:1215–1233. 2015. View Article : Google Scholar : PubMed/NCBI
7	Fu JM, Satterstrom FK, Peng M, Brand H, Collins RL, Dong S, Wamsley B, Klei L, Wang L, Hao SP, et al: Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet. 54:1320–1331. 2022. View Article : Google Scholar : PubMed/NCBI
8	Hirota T and King BH: Autism spectrum disorder: A review. JAMA. 329:157–168. 2023. View Article : Google Scholar : PubMed/NCBI
9	Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH and Vestergaard M: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 309:1696–1703. 2013. View Article : Google Scholar : PubMed/NCBI
10	Zwaigenbaum L, Brian J and Ip A: Early detection for autism spectrum disorder in young children. Paediatr Child Health. 24:424–443. 2019.In English, French. View Article : Google Scholar : PubMed/NCBI
11	Robins DL, Casagrande K, Barton M, Chen CMA, Dumont-Mathieu T and Fein D: Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 133:37–45. 2014. View Article : Google Scholar :
12	Volkmar F, Siegel M, Woodbury-Smith M, King B, McCracken J and State M; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI): Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 53:237–257. 2014. View Article : Google Scholar : PubMed/NCBI
13	Song J, Reilly M and Reichow B: Overview of meta-analyses on naturalistic developmental behavioral interventions for children with autism spectrum disorder. J Autism Dev Disord. 55:1–13. 2024. View Article : Google Scholar : PubMed/NCBI
14	Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A and Varley J: Randomized, controlled trial of an intervention for toddlers with autism: The early start denver model. Pediatrics. 125:e17–e23. 2010. View Article : Google Scholar
15	Wang Z, Loh S, Tian J and Chen QJ: A meta-analysis of the effect of the early start denver model in children with autism spectrum disorder. Int J Dev Disabil. 68:587–597. 2021. View Article : Google Scholar : PubMed/NCBI
16	Fieiras C, Chen M, Liquitay CE, Meza N, Rojas V, Franco J and Madrid E: Risperidone and aripiprazole for autism spectrum disorder in children: an overview of systematic reviews. BMJ Evid Based Med. 28:7–14. 2022. View Article : Google Scholar : PubMed/NCBI
17	Aglinskas A, Hartshorne J and Anzellotti S: Contrastive machine learning reveals the structure of neuroanatomical variation within autism. Science. 376:1070–1074. 2022. View Article : Google Scholar : PubMed/NCBI
18	Pizzano M, Shire S, Shih W, Levato L, Landa R, Lord C, Smith T and Kasari C: Profiles of minimally verbal autistic children: Illuminating the neglected end of the spectrum. Autism Res. 17:1218–1229. 2024. View Article : Google Scholar : PubMed/NCBI
19	Konečná B, Radošinská J, Keményová P and Repiská G: Detection of disease-associated microRNAs-application for autism spectrum disorders. Rev Neurosci. 31:757–769. 2020. View Article : Google Scholar
20	Yao TT, Chen L, Du Y, Jiang ZY and Cheng Y: MicroRNAs as regulators, biomarkers, and therapeutic targets in autism spectrum disorder. Mol Neurobiol. 62:5039–5056. 2024. View Article : Google Scholar : PubMed/NCBI
21	Chen W, Ren Q, Zhou J and Liu W: Mesenchymal stem cell-induced neuroprotection in pediatric neurological diseases: Recent update of underlying mechanisms and clinical utility. Appl Biochem Biotechnol. 196:5843–5858. 2024. View Article : Google Scholar : PubMed/NCBI
22	Liang Y, Duan L, Xu X, Li X, Liu M, Chen H, Lu J and Xia J: Mesenchymal stem cell-derived exosomes for treatment of autism spectrum disorder. ACS Appl Bio Mater. 3:6384–6393. 2020. View Article : Google Scholar : PubMed/NCBI
23	Hedayat M, Ahmadi M, Shoaran M and Rezaie J: Therapeutic application of mesenchymal stem cells derived exosomes in neurodegenerative diseases: A focus on non-coding RNAs cargo, drug delivery potential, perspective. Life Sci. 320:1215662023. View Article : Google Scholar : PubMed/NCBI
24	Su R: Mesenchymal stem cell exosomes as nanotherapeutic agents for neurodegenerative diseases. Highl Sci Eng Technol. 2:7–14. 2022. View Article : Google Scholar
25	Tian MS and Yi XN: The role of mesenchymal stem cell exosomes in the onset and progression of Alzheimer's Disease. Biomed Sci. 10:6–13. 2024.
26	Ge Y, Wu J, Zhang L, Huang N and Luo Y: A new strategy for the regulation of neuroinflammation: Exosomes derived from mesenchymal stem cells. Cell Mol Neurobiol. 44:242024. View Article : Google Scholar : PubMed/NCBI
27	Elsherif R, Abdel-Hafez AM, Hussein O, Sabry D, Abdelzaher L and Bayoumy AA: The potential ameliorative effect of mesenchymal stem cells-derived exosomes on cerebellar histopathology and their modifying role on PI3k-mTOR signaling in rat model of autism spectrum disorder. J Mol Histol. 56:652025. View Article : Google Scholar : PubMed/NCBI
28	Zhao S, Zhong Y, Shen F, Cheng X, Qing X and Liu J: Comprehensive exosomal microRNA profile and construction of competing endogenous RNA network in autism spectrum disorder: A pilot study. Biomol Biomed. 24:292–301. 2024. View Article : Google Scholar :
29	Perets N, Oron O, Herman S, Elliott E and Offen D: Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B. Mol Autism. 11:1–13. 2020. View Article : Google Scholar
30	Ressa HJ, Newman BT, Jacokes Z, McPartland JC, Kleinhans NM, Druzgal TJ, Pelphrey KA and Van Horn JD: Widespread associations between behavioral metrics and brain microstructure in ASD suggest age mediates subtypes of ASD. BioRxiv. 28:2024.09.04.611183. 2024.
31	Almuqhim F and Saeed F: ASD-GResTM: Deep learning framework for ASD classification using Gramian angular field. Proceedings (IEEE Int Conf Bioinforma Biomed). 2023:2837–2843. 2023.
32	Tang X, Ran X, Liang Z, Zhuang H, Yan X, Feng C, Qureshi A, Gao Y and Shen L: Screening biomarkers for autism spectrum disorder using plasma proteomics combined with machine learning methods. Clin Chim Acta. 565:1200182025. View Article : Google Scholar
33	Herbrecht E, Lazari O, Notter M, Kievit E, Schmeck K and Spiegel R: Short-term and highly intensive early intervention FIAS: Two-year outcome results and factors of influence. Front Psychiatry. 11:6872020. View Article : Google Scholar : PubMed/NCBI
34	Manohar H and Kandasamy P: Clinical outcomes of children with ASD-preliminary findings from a 18 month follow up study. Asian J Psychiatry. 64:1028162021. View Article : Google Scholar
35	Yuan B, Wang M, Wu X, Cheng P, Zhang R, Zhang R, Yu S, Zhang J, Du Y, Wang X and Qiu Z: Identification of de novo Mutations in the Chinese autism spectrum disorder cohort via whole-exome sequencing unveils brain regions implicated in autism. Neurosci Bull. 39:1469–1480. 2023. View Article : Google Scholar : PubMed/NCBI
36	Levy RJ and Paşca SP: What have organoids and assembloids taught us about the pathophysiology of neuropsychiatric disorders? Biol Psychiatry. 93:632–641. 2023. View Article : Google Scholar : PubMed/NCBI
37	Al-Beltagi M, Saeed NK, Bediwy AS, Bediwy EA and Elbeltagi R: Decoding the genetic landscape of autism: A comprehensive review. World J Clin Pediatr. 13:984682024. View Article : Google Scholar : PubMed/NCBI
38	Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, et al: Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 68:1095–1102. 2011. View Article : Google Scholar : PubMed/NCBI
39	Tick B, Bolton P, Happé F, Rutter M and Rijsdijk F: Heritability of autism spectrum disorders: A meta-analysis of twin studies. J Child Psychol Psychiatry. 57:585–595. 2016. View Article : Google Scholar
40	Shaw KA, Bilder DA, McArthur D, Williams AR, Amoakohene E, Bakian AV, Durkin MS, Fitzgerald RT, Furnier SM, Hughes MM, et al: Early identification of autism spectrum disorder among children aged 4 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2020. MMWR Surveill Summ. 72:1–15. 2023. View Article : Google Scholar : PubMed/NCBI
41	Barnard RA, Pomaville MB and O'Roak BJ: Mutations and modeling of the chromatin remodeler CHD8 define an emerging autism etiology. Front Neurosci. 9:4772015. View Article : Google Scholar
42	Xu B, Ho Y, Fasolino M, Medina J, O'Brien WT, Lamonica JM, Nugent E, Brodkin ES, Fuccillo MV, Bucan M and Zhou Z: Allelic contribution of Nrxn1α to autism-relevant behavioral phenotypes in mice. PLoS Genet. 19:e10106592023. View Article : Google Scholar
43	Chiola S, Napan KL, Wang Y, Lazarenko RM, Armstrong CJ, Cui J and Shcheglovitov A: Defective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex. Mol Psychiatry. 26:4670–4686. 2021. View Article : Google Scholar : PubMed/NCBI
44	Guo B, Chen J, Chen Q, Ren K, Feng D, Mao H, Yao H, Yang J, Liu H, Liu Y, et al: Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci. 22:1223–1234. 2019. View Article : Google Scholar : PubMed/NCBI
45	Vogt D, Cho KKA, Shelton SM, Paul A, Huang ZJ, Sohal VS and Rubenstein JLR: Mouse Cntnap2 and human CNTNAP2 ASD alleles cell autonomously regulate PV+ cortical interneurons. Cereb Cortex. 28:3868–3879. 2018. View Article : Google Scholar
46	Kushima I, Nakatochi M, Aleksic B, Okada T, Kimura H, Kato H, Morikawa M, Inada T, Ishizuka K, Torii Y, et al: Cross-Disorder analysis of genic and regulatory copy number variations in bipolar disorder, schizophrenia, and autism spectrum disorder. Biol Psychiatry. 92:362–374. 2022. View Article : Google Scholar : PubMed/NCBI
47	Rein B and Yan Z: 16p11.2 copy number variations and neurodevelopmental disorders. Trends Neurosci. 43:886–901. 2020. View Article : Google Scholar : PubMed/NCBI
48	Zarrei M, Burton C, Engchuan W, Young EJ, Higginbotham EJ, MacDonald JR, Trost B, Chan AJS, Walker S, Lamoureux S, et al: A large data resource of genomic copy number variation across neurodevelopmental disorders. NPJ Genomic Med. 4:262019. View Article : Google Scholar
49	Costain G, Walker S, Argiropoulos B, Baribeau DA, Bassett AS, Boot E, Devriendt K, Kellam B, Marshall CR, Prasad A, et al: Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders. J Neurodev Disord. 11:32019. View Article : Google Scholar : PubMed/NCBI
50	Hauw JJ, Hausser-Hauw C and Barthélémy C: Synapse and primary cilia dysfunctions in autism spectrum disorders. Avenues to normalize these functions. Rev Neurol (Paris). 180:1059–1070. 2024. View Article : Google Scholar : PubMed/NCBI
51	Ferrucci L, Cantando I, Cordella F, Di Angelantonio S, Ragozzino D and Bezzi P: Microglia at the tripartite synapse during postnatal development: implications for autism spectrum disorders and schizophrenia. Cells. 12:28272023. View Article : Google Scholar : PubMed/NCBI
52	Pagani M, Barsotti N, Bertero A, Trakoshis S, Ulysse L, Locarno A, Miseviciute I, De Felice A, Canella C, Supekar K, et al: mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity. Nat Commun. 12:60842021. View Article : Google Scholar : PubMed/NCBI
53	Giansante G, Marte A, Romei A, Prestigio C, Onofri F, Benfenati F, Baldelli P and Valente P: Presynaptic L-type Ca2+ channels increase glutamate release probability and excitatory strength in the hippocampus during chronic neuroinflammation. J Neurosci. 40:6825–6841. 2020. View Article : Google Scholar : PubMed/NCBI
54	Riekki R, Pavlov I, Tornberg J, Lauri S, Airaksinen M and Taira T: Altered synaptic dynamics and hippocampal excitability but normal long-term plasticity in mice lacking hyperpolarizing GABA A receptor-mediated inhibition in CA1 pyramidal neurons. J Neurophysiol. 99:3075–3089. 2008. View Article : Google Scholar : PubMed/NCBI
55	Cast T, Boesch D, Smyth K, Shaw A, Ghebrial M and Chanda S: An autism-associated mutation impairs neuroligin-4 glycosylation and enhances excitatory synaptic transmission in human neurons. J Neurosci. 41:392–407. 2020. View Article : Google Scholar : PubMed/NCBI
56	Amal H, Barak B, Bhat V, Gong G, Joughin BA, Wang X, Wishnok JS, Feng G and Tannenbaum S: Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function. Mol Psychiatry. 25:1835–1848. 2018. View Article : Google Scholar : PubMed/NCBI
57	Higa GSV, Viana FJC, Francis-Oliveira J, Cruvinel E, Franchin TS, Marcourakis T, Ulrich H and De Pasquale R: Serotonergic neuromodulation of synaptic plasticity. Neuropharmacology. 257:1100362024. View Article : Google Scholar : PubMed/NCBI
58	Liu W, Chen QY, Li XH, Zhou Z and Zhuo M: Cortical tagged synaptic long-term depression in the anterior cingulate cortex of adult mice. J Neurosci. 44:e00282420242024. View Article : Google Scholar : PubMed/NCBI
59	Hagena H and Manahan-Vaughan D: Interplay of hippocampal long-term potentiation and long-term depression in enabling memory representations. Philos Trans R Soc Lond B Biol Sci. 379:202302292024. View Article : Google Scholar : PubMed/NCBI
60	Cong J, Zhuang W, Liu Y, Yin S, Jia H, Yi C, Chen K, Xue K, Li F, Yao D, et al: Altered default mode network causal connectivity patterns in autism spectrum disorder revealed by Liang information flow analysis. Hum Brain Mapp. 44:2279–2293. 2023. View Article : Google Scholar : PubMed/NCBI
61	Kember J, Patenaude P, Sweatman H, Van Schaik L, Tabuenca Z and Chai X: Specialization of anterior and posterior hippocampal functional connectivity differs in autism. Autism Res. 17:1126–1139. 2024. View Article : Google Scholar : PubMed/NCBI
62	Grossberg S and Kishnan D: Neural dynamics of autistic repetitive behaviors and fragile X syndrome: Basal ganglia movement gating and mGluR-modulated adaptively timed learning. Front Psychol. 9:2692018. View Article : Google Scholar : PubMed/NCBI
63	Xiao T, Wan J, Qu H and Li Y: Tripartite-motif protein 21 knockdown extenuates LPS-triggered neurotoxicity by inhibiting microglial M1 polarization via suppressing NF-κB-mediated NLRP3 inflammasome activation. Arch Biochem Biophys. 30:1089182021. View Article : Google Scholar
64	Zhou L, Wang D, Qiu X, Zhang W, Gong Z, Wang Y and Xu X: DHZCP Modulates microglial M1/M2 polarization via the p38 and TLR4/NF-κB signaling pathways in LPS-stimulated microglial Cells. Front Pharmacol. 11:11262020. View Article : Google Scholar
65	Tao W, Hu Y, Chen Z, Dai Y, Hu Y and Qi M: Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway. Phytomedicine. 91:1536922021. View Article : Google Scholar : PubMed/NCBI
66	Tsai C, Chen G, Chen YC, Shen CK, Lu DY, Yang LY, Chen JH and Yeh WL: Regulatory effects of quercetin on M1/M2 macrophage polarization and oxidative/antioxidative balance. Nutrients. 14:672021. View Article : Google Scholar
67	Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD, Umemori H, Chen C and Stevens B: CD47 protects synapses from excess microglia-mediated pruning during development. Neuron. 100:120–134.e6. 2018. View Article : Google Scholar : PubMed/NCBI
68	Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, Urushitani M and Kojima H: Transplantation of M2-Deviated microglia promotes recovery of motor function after spinal cord injury in mice. Mol Ther. 28:254–265. 2020. View Article : Google Scholar :
69	Li Y, Liu Z, Song Y, Pan JJ, Jiang Y, Shi X, Liu C, Ma Y, Luo L, Mamtilahun M, et al: M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice. Theranostics. 12:3553–3573. 2022. View Article : Google Scholar : PubMed/NCBI
70	Li Z, Xiao J, Xu X, Li W, Zhong R, Qi L, Chen J, Cui G, Wang S, Zheng Y, et al: M-CSF, IL-6, and TGF-β promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery. Sci Adv. 7:eabb62602021. View Article : Google Scholar
71	Ding X, Wang J, Huang M, Chen Z, Liu J, Zhang Q, Zhang C, Xiang Y, Zen K and Li L: Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration. Nat Commun. 12:20302021. View Article : Google Scholar
72	Penney J, Ralvenius WT, Loon A, Cerit O, Dileep V, Milo B, Pao PC, Woolf H and Tsai LH: iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss. Glia. 72:452–469. 2024. View Article : Google Scholar
73	Nugent A, Lin K, Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J, Kim DJ, Xia D, et al: TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron. 105:837–854. 2019. View Article : Google Scholar
74	Kong L, Li W, Chang E, Wang W, Shen N, Xu X, Wang X, Zhang Y, Sun W, Hu W, et al: mtDNA-STING axis mediates microglial polarization via IRF3/NF-κB signaling after ischemic stroke. Front Immunol. 13:8609772022. View Article : Google Scholar
75	Diaz-Castro B, Bernstein AM, Coppola G, Sofroniew MV and Khakh BS: Molecular and functional properties of cortical astrocytes during peripherally induced neuroinflammation. Cell Rep. 36:1095082021. View Article : Google Scholar : PubMed/NCBI
76	Chistyakov D, Gavrish G, Goriainov S, Chistyakov V, Astakhova A, Azbukina N and Sergeeva M: Oxylipin profiles as functional characteristics of acute inflammatory responses in astrocytes pre-treated with IL-4, IL-10, or LPS. Int J Mol Sci. 21:17802020. View Article : Google Scholar : PubMed/NCBI
77	Burmeister A, Johnson M, Yaemmongkol J and Marriott I: Murine astrocytes produce IL-24 and are susceptible to the immunosuppressive effects of this cytokine. J Neuroinflammation. 16:552019. View Article : Google Scholar : PubMed/NCBI
78	Li D, Liu X, Liu T, Liu H, Tong L, Jia SW and Wang YF: Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes. Glia. 68:878–897. 2020. View Article : Google Scholar
79	Wilhelmsson U, Pozo-Rodrigalvarez A, Kalm M, de Pablo Y, Widestrand Å, Pekna M and Pekny M: The role of GFAP and vimentin in learning and memory. Biol Chem. 400:1147–1156. 2019. View Article : Google Scholar : PubMed/NCBI
80	Ribot J, Breton R, Calvo C, Moulard J, Ezan P, Zapata J, Samama K, Moreau M, Bemelmans AP, Sabatet V, et al: Astrocytes close the mouse critical period for visual plasticity. Science. 373:77–81. 2021. View Article : Google Scholar : PubMed/NCBI
81	Hasel P, Rose I, Sadick J, Kim R and Liddelow S: Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci. 24:1475–1487. 2021. View Article : Google Scholar : PubMed/NCBI
82	Ziff O, Clarke B, Taha D, Crerar H, Luscombe N and Patani R: Meta-analysis of human and mouse ALS astrocytes reveals multi-omic signatures of inflammatory reactive states. Genome Res. 32:71–84. 2021. View Article : Google Scholar : PubMed/NCBI
83	Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, et al: Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 541:481–487. 2017. View Article : Google Scholar : PubMed/NCBI
84	Versele R, Sevin E, Gosselet F, Fenart L and Candela P: TNF-α and IL-1β modulate blood-brain barrier permeability and decrease amyloid-β peptide efflux in a human blood-brain barrier model. Int J Mol Sci. 23:102352022. View Article : Google Scholar
85	Takahashi K, Ishibashi Y, Chujo K, Suzuki I and Sato K: Neuroprotective potential of L-glutamate transporters in human induced pluripotent stem cell-derived neural cells against excitotoxicity. Int J Mol Sci. 24:126052023. View Article : Google Scholar : PubMed/NCBI
86	Luo Y, Yu Y, He H and Fan N: Acute ketamine induces neuronal hyperexcitability and deficits in prepulse inhibition by upregulating IL-6. Prog Neuropsychopharmacol Biol Psychiatry. 130:1109132024. View Article : Google Scholar
87	Friedenstein AJ, Chailakhjan RK and Lalykina KS: The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3:393–403. 1970.PubMed/NCBI
88	Brown SE, Tong W and Krebsbach PH: The derivation of mesenchymal stem cells from human embryonic stem cells. Cells Tissues Organs. 189:256–260. 2009. View Article : Google Scholar :
89	Stefańska K, Němcová L, Blatkiewicz M, Zok A, Kaczmarek M, Pieńkowski W, Mozdziak P, Piotrowska-Kempisty H and Kempisty B: Expression profile of new marker genes involved in differentiation of human Wharton's Jelly-derived mesenchymal stem cells into chondrocytes, osteoblasts, adipocytes and neural-like cells. Int J Mol Sci. 24:129392023. View Article : Google Scholar
90	Lee H, Kim SHL, Yoon H, Ryu J, Park HH, Hwang NS and Park TH: Intracellular delivery of recombinant RUNX2 facilitated by cell-penetrating protein for the osteogenic differentiation of hMSCs. ACS Biomater Sci Eng. 6:5202–5214. 2020. View Article : Google Scholar
91	Zhang X, Liu L, Dou C, Cheng P, Liu L, Liu H, Ren S, Wang C, Jia S, Chen L, et al: PPAR gamma-regulated MicroRNA 199a-5p underlies bone marrow adiposity in aplastic anemia. Mol Ther Nucleic Acids. 17:678–687. 2019. View Article : Google Scholar : PubMed/NCBI
92	Caron M, Eveque M, Cillero-Pastor B, Heeren RMA, Housmans B, Derks K, Cremers A, Peffers MJ, van Rhijn LW, van den Akker G and Welting TJM: Sox9 determines translational capacity during early chondrogenic differentiation of ATDC5 cells by regulating expression of ribosome biogenesis factors and ribosomal proteins. Front Cell Dev Biol. 9:6860962021. View Article : Google Scholar : PubMed/NCBI
93	Yan Z, Shi X, Wang H, Si C, Liu Q and Du Y: Neurotrophin-3 promotes the neuronal differentiation of BMSCs and improves cognitive function in a rat model of Alzheimer's disease. Front Cell Neurosci. 15:6293562021. View Article : Google Scholar : PubMed/NCBI
94	Chen QH, Wu F, Liu L, Chen HB, Zheng R, Wang HL and Yu LN: Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro. Stem Cell Res Ther. 11:912020. View Article : Google Scholar : PubMed/NCBI
95	Chen L, Zhang Q, Chen QH, Ran FY, Yu LM, Liu X, Fu Q, Song GY, Tang JM and Zhang T: Combination of G-CSF and AMD3100 improves the anti-inflammatory effect of mesenchymal stem cells on inducing M2 polarization of macrophages through NF-κB-IL1RA signaling pathway. Front Pharmacol. 10:5792019. View Article : Google Scholar
96	Soufihasanabad S, Mahmoudi M, Taghavi-Farahabadi M, Mirsanei Z, Mahmoudi R, Abdallah JK, Babaei E and Hashemi SM: In vivo polarization of M2 macrophages by mesenchymal stem cell-derived extracellular vesicles: A novel approach to macrophage polarization and its potential in treating inflammatory diseases. Med Hypotheses. 187:1113532024. View Article : Google Scholar
97	Huaman O, Bahamonde J, Cahuascanco B, Jervis M, Palomino J, Torres C and Peralta O: Immunomodulatory and immunogenic properties of mesenchymal stem cells derived from bovine fetal bone marrow and adipose tissue. Res Vet Sci. 124:212–222. 2019. View Article : Google Scholar : PubMed/NCBI
98	Yang S, Wei Y, Sun R, Lu W, Lv H, Xiao X, Cao Y, Jin X and Zhao M: Umbilical cord blood-derived mesenchymal stromal cells promote myeloid-derived suppressor cell proliferation by secreting HLA-G to reduce acute graft-versus-host disease after hematopoietic stem cell transplantation. Cytotherapy. 22:718–733. 2020. View Article : Google Scholar : PubMed/NCBI
99	He J, Zhang N, Zhu Y, Jin R and Wu F: MSC spheroids-loaded collagen hydrogels simultaneously promote neuronal differentiation and suppress inflammatory reaction through PI3K-Akt signaling pathway. Biomaterials. 265:1204482020. View Article : Google Scholar : PubMed/NCBI
100	Huang W, Wang C, Xie L, Wang X, Zhang L, Chen C and Jiang B: Traditional two-dimensional mesenchymal stem cells (MSCs) are better than spheroid MSCs on promoting retinal ganglion cells survival and axon regeneration. Exp Eye Res. 185:1076992019. View Article : Google Scholar : PubMed/NCBI
101	Zavatti M, Gatti M, Beretti F, Palumbo C and Maraldi T: Exosomes derived from human amniotic fluid mesenchymal stem cells preserve microglia and neuron cells from Aβ. Int J Mol Sci. 23:49672022. View Article : Google Scholar
102	Angeloni C, Gatti M, Prata C, Hrelia S and Maraldi T: Role of mesenchymal stem cells in counteracting oxidative stress-related neurodegeneration. Int J Mol Sci. 21:32992020. View Article : Google Scholar : PubMed/NCBI
103	Zeng CW: Multipotent mesenchymal stem cell-based therapies for spinal cord injury: Current progress and future prospects. Biology (Basel). 12:6532023.PubMed/NCBI
104	Sun S, Luo S, Chen J, Zhang O, Wu Q, Zeng N, Bi J, Zheng C, Yan T, Li Z, et al: Human umbilical cord-derived mesenchymal stem cells alleviate valproate-induced immune stress and social deficiency in rats. Front Psychiatry. 15:14316892024. View Article : Google Scholar : PubMed/NCBI
105	Yang Y, Peng Y, Li Y, Shi T, Luan Y and Yin C: Role of stem cell derivatives in inflammatory diseases. Front Immunol. 14:11539012023. View Article : Google Scholar : PubMed/NCBI
106	Moghadasi S, Elveny M, Rahman H, Suksatan W, Jalil AT, Abdelbasset WK, Yumashev AV, Shariatzadeh S, Motavalli R, Behzad F, et al: A paradigm shift in cell-free approach: The emerging role of MSCs-derived exosomes in regenerative medicine. J Transl Med. 19:3022021. View Article : Google Scholar : PubMed/NCBI
107	Krylova S and Feng D: The machinery of exosomes: Biogenesis, release, and uptake. Int J Mol Sci. 24:13372023. View Article : Google Scholar : PubMed/NCBI
108	Zheng D, Huo M, Li B, Wang W, Piao H, Wang Y, Zhu Z, Li D, Wang T and Liu K: The role of exosomes and exosomal MicroRNA in cardiovascular disease. Front Cell Dev Biol. 8:6161612021. View Article : Google Scholar : PubMed/NCBI
109	Tenchov R, Sasso J, Wang X, Liaw W, Chen CA and Zhou Q: Exosomes-Nature's lipid nanoparticles, a rising star in drug delivery and diagnostics. ACS Nano. 16:17802–17846. 2022. View Article : Google Scholar : PubMed/NCBI
110	Wu J, Li H, He J, Tian X, Luo S, Li J, Li W, Zhong J, Zhang H, Huang Z, et al: Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury. Cell Death Dis. 12:92021. View Article : Google Scholar :
111	Corradi E, Costa ID, Gavoci A, Iyer A, Roccuzzo M, Otto TA, Oliani E, Bridi S, Strohbuecker S, Santos-Rodriguez G, et al: Axonal precursor miRNAs hitchhike on endosomes and locally regulate the development of neural circuits. EMBO J. 39:e1025132020. View Article : Google Scholar
112	Li R, Zhao K, Ruan Q, Meng C and Yin F: Bone marrow mesenchymal stem cell-derived exosomal microRNA-124-3p attenuates neurological damage in spinal cord ischemia-reperfusion injury by downregulating Ern1 and promoting M2 macrophage polarization. Arthritis Res Ther. 22:752020. View Article : Google Scholar : PubMed/NCBI
113	Jiang D, Gong F, Ge X, Lv C, Huang C, Feng S, Zhou Z, Rong Y, Wang J, Ji C, et al: Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes. J Nanobiotechnology. 18:1052020. View Article : Google Scholar : PubMed/NCBI
114	Song Y, Li Z, He T, Qu M, Jiang L, Li W, Shi X, Pan J, Zhang L, Wang Y, et al: M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124. Theranostics. 9:2910–2923. 2019. View Article : Google Scholar : PubMed/NCBI
115	Cui Y, Yin Y, Xiao Z, Zhao Y, Chen B, Yang B, Xu B, Song H, Zou Y, Ma X and Dai J: LncRNA Neat1 mediates miR-124-induced activation of Wnt/β-catenin signaling in spinal cord neural progenitor cells. Stem Cell Res Ther. 10:4002019. View Article : Google Scholar
116	Han P, Sunada-Nara K, Kawashima N, Fujii M, Wang S, Kieu TQ, Yu Z and Okiji T: MicroRNA-146b-5p suppresses pro-inflammatory mediator synthesis via targeting TRAF6, IRAK1, and RELA in lipopolysaccharide-stimulated human dental pulp cells. Int J Mol Sci. 24:74332023. View Article : Google Scholar : PubMed/NCBI
117	Ho D, Lynd TO, Jun C, Shin J, Millican RC, Estep BK, Chen J, Zhang X, Brott BC, Kim DW, et al: MiR-146a encapsulated liposomes reduce vascular inflammatory responses through decrease of ICAM-1 expression, macrophage activation, and foam cell formation. Nanoscale. 15:3461–3474. 2023. View Article : Google Scholar : PubMed/NCBI
118	Venuti A, Musarra-Pizzo M, Pennisi R, Tankov S, Medici MA, Mastino A, Rebane A and Sciortino M: HSV-1\EGFP stimulates miR-146a expression in a NF-κB-dependent manner in monocytic THP-1 cells. Sci Rep. 9:51572019. View Article : Google Scholar
119	Riazifar M, Mohammadi M, Pone E, Yeri A, Lässer C, Segaliny AI, McIntyre LL, Shelke GV, Hutchins E, Hamamoto A, et al: Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders. ACS Nano. 13:6670–668. 2019. View Article : Google Scholar : PubMed/NCBI
120	Long X, Yao X, Jiang QQ, Yang Y, He X, Tian W, Zhao K and Zhang H: Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury. J Neuroinflammation. 17:892020. View Article : Google Scholar : PubMed/NCBI
121	Wang QM, Lian GY, Sheng SM, Xu J, Ye LL, Min C and Guo SF: Exosomal lncRNA NEAT1 inhibits NK-Cell activity to promote multiple myeloma cell immune escape via an EZH2/PBX1 axis. Mol Cancer Res. 22:125–136. 2024. View Article : Google Scholar
122	Zhao F, Li Z, Dong Z, Wang Z, Guo P, Zhang D and Li S: Exploring the potential of exosome-related LncRNA pairs as predictors for immune microenvironment, survival outcome, and microbiotain landscape in esophageal squamous cell carcinoma. Front Immunol. 13:9181542022. View Article : Google Scholar : PubMed/NCBI
123	Zhang W, Yan Y, Peng J, Thakur A, Bai N, Yang K and Xu Z: Decoding roles of exosomal lncRNAs in tumor-immune regulation and therapeutic potential. Cancers (Basel). 15:2862022. View Article : Google Scholar
124	Taha E, Ono K and Eguchi T: Roles of extracellular HSPs as biomarkers in immune surveillance and immune evasion. Int J Mol Sci. 20:45882019. View Article : Google Scholar : PubMed/NCBI
125	Montesinos JJ, López-García L, Cortés-Morales VA, Arriaga-Pizano L, Valle-Ríos R, Fajardo-Orduña GR and Castro-Manrreza ME: Human bone marrow mesenchymal stem/stromal cells exposed to an inflammatory environment increase the expression of ICAM-1 and release microvesicles enriched in this adhesive molecule: Analysis of the participation of TNF-α and IFN-γ. J Immunol Res. 2020:88396252020. View Article : Google Scholar
126	Wu D, Deng S, Li L, Liu T, Zhang T, Li J, Yu Y and Xu Y: TGF-β1-mediated exosomal lnc-MMP2-2 increases blood-brain barrier permeability via the miRNA-1207-5p/EPB41L5 axis to promote non-small cell lung cancer brain metastasis. Cell Death Dis. 12:7212021. View Article : Google Scholar
127	Cauvi D, Hawisher D, Derunes J, Rodriguez E and De Maio A: Membrane phospholipids activate the inflammatory response in macrophages by various mechanisms. FASEB J. 38:e236192024. View Article : Google Scholar : PubMed/NCBI
128	Zhou W, Silva M, Feng C, Zhao S, Liu L, Li S, Zhong J and Zheng W: Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis. Stem Cell Res Ther. 12:1742021. View Article : Google Scholar : PubMed/NCBI
129	Harrell CR, Volarevic A, Djonov V and Volarevic V: Mesenchymal stem cell-derived exosomes as new remedy for the treatment of neurocognitive disorders. Int J Mol Sci. 22:14332021. View Article : Google Scholar : PubMed/NCBI
130	Xun C, Ge L, Tang F, Wang L, Zhuo Y, Long L, Qi J, Hu L, Duan D, Chen P and Lu M: Insight into the proteomic profiling of exosomes secreted by human OM-MSCs reveals a new potential therapy. Biomed Pharmacother. 131:1105842020. View Article : Google Scholar : PubMed/NCBI
131	Liu A, Li C, Wang C, Liang X and Zhang X: Impact of mesenchymal stem cells on the gut microbiota and microbiota associated functions in inflammatory bowel disease: A systematic review of preclinical evidence on animal models. Curr Stem Cell Res Ther. 19:981–992. 2023. View Article : Google Scholar : PubMed/NCBI
132	Ocansey D, Zhang Z, Xu X, Liu L, Amoah S, Chen X, Wang B, Zhang X and Mao F: Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics-metabolomics-farnesoid X receptor axis. Biomater Sci. 10:4822–4836. 2022. View Article : Google Scholar : PubMed/NCBI
133	Gu L, Ren F, Fang X, Yuan L, Liu G and Wang S: Exosomal MicroRNA-181a derived from mesenchymal stem cells improves gut microbiota composition, barrier function, and inflammatory status in an experimental colitis model. Front Med (Lausanne). 8:6606142021. View Article : Google Scholar : PubMed/NCBI
134	Alexandrov P, Zhai Y, Li W and Lukiw W: Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain. Folia Neuropathol. 57:211–219. 2019. View Article : Google Scholar : PubMed/NCBI
135	Geffen Y, Perets N, Horev R, Yudin D, Oron O, Elliott E, Marom E, Danon U and Offen D: Exosomes derived from adipose mesenchymal stem cells: A potential non-invasive intranasal treatment for autism. Cytotherapy. 22:S492020.
136	Geffen Y, Horev R, Perets N, Marom E, Danon U and Offen D: Immuno-modulation and neuroprotection mediate the therapeutic effect of exosomes in mice model of autism. Cytotherapy. 22:S49–S50. 2020.
137	Garcia G, Pinto S, Ferreira S, Lopes D, Serrador MJ, Fernandes A, Vaz AR, Mendonça A, Edenhofer F, Malm T, et al: Emerging role of miR-21-5p in neuron-glia dysregulation and exosome transfer using multiple models of Alzheimer's disease. Cells. 11:33772022. View Article : Google Scholar : PubMed/NCBI
138	Zhang Y, Zhang Y, Chopp M, Pang H, Zhang Z, Mahmood A and Xiong Y: MiR-17-92 cluster-enriched exosomes derived from human bone marrow mesenchymal stromal cells improve tissue and functional recovery in rats after traumatic brain injury. J Neurotrauma. 38:1535–1550. 2021. View Article : Google Scholar : PubMed/NCBI
139	Fan B, Chopp M, Zhang Z and Liu X: Treatment of diabetic peripheral neuropathy with engineered mesenchymal stromal cell-derived exosomes enriched with microRNA-146a provide amplified therapeutic efficacy. Exp Neurol. 341:1136942021. View Article : Google Scholar : PubMed/NCBI
140	Chen Y, Tian Z, He L, Liu C, Wang N, Rong L and Liu B: Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury. Stem Cell Res Ther. 12:2242021. View Article : Google Scholar : PubMed/NCBI
141	Perets N, Hertz S, London M and Offen D: Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice. Mol Autism. 9:1–12. 2018. View Article : Google Scholar
142	Kabataş S, Civelek E, Savrunlu E, Karaaslan U, Yıldız Ö and Karaöz E: Advances in the treatment of autism spectrum disorder: Wharton jelly mesenchymal stem cell transplantation. World J Methodol. 15:958572025. View Article : Google Scholar
143	Barmada A, Sharan J, Band N and Prodromos C: Serious adverse events have not been reported with spinal intrathecal injection of mesenchymal stem cells: A systematic review. Curr Stem Cell Res Ther. 18:829–833. 2022. View Article : Google Scholar : PubMed/NCBI
144	Lv YT, Zhang Y, Liu M, Qiuwaxi JN, Ashwood P, Cho SC, Huan Y, Ge RC, Chen XW, Wang ZJ, et al: Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 11:1962013. View Article : Google Scholar : PubMed/NCBI
145	Shroff G: Human embryonic stem cells in the treatment of autism: A case series. Innov Clin Neurosci. 14:12–16. 2017.PubMed/NCBI
146	Chez M, Lepage C, Parise C, Dang-Chu A, Hankins A and Carroll M: Safety and observations from a placebo-controlled, crossover study to assess use of autologous umbilical cord blood stem cells to improve symptoms in children with Autism. Stem Cells Transl Med. 7:333–341. 2018. View Article : Google Scholar : PubMed/NCBI
147	Simhal AK, Carpenter KLH, Nadeem S, Kurtzberg J, Song A, Tannenbaum A, Sapiro G and Dawson G: Measuring robustness of brain networks in autism spectrum disorder with Ricci curvature. Sci Rep. 10:108192020. View Article : Google Scholar : PubMed/NCBI
148	Thanh LN, Nguyen HP, Ngo MD, Bui VA, Dam PTM, Bui HTP, Ngo DV, Tran KT, Dang TTT, Duong BD, et al: Outcomes of bone marrow mononuclear cell transplantation combined with interventional education for autism spectrum disorder. Stem Cells Transl Med. 10:14–26. 2021. View Article : Google Scholar
149	Al-Dhalimy A, Salim HM, Shather A, Naser IH, Hizam M and Alshujery MK: The pathological and therapeutically role of mesenchymal stem cell (MSC)-derived exosome in degenerative diseases; Particular focus on LncRNA and microRNA. Pathol Res Prract. 250:1547782023. View Article : Google Scholar
150	Dilsiz N: Mesenchymal Stem Cell-Derived Exosomes in Clinical Trial. Pak BioMed J. 8:12025.
151	Hadizadeh A, Akbari-Asbagh R, Heirani-Tabasi A, Soleimani M, Gorovanchi P, Daryani NE, Vahedi A, Nazari H, Banikarimi SP, Dibavar MA, et al: Localized administration of mesenchymal stem cell-derived exosomes for the treatment of refractory perianal fistula in Crohn's disease patients: A phase II clinical trial. Dis Colon Rectum. 67:1564–1575. 2024. View Article : Google Scholar : PubMed/NCBI
152	Fahlevie F, Apriningsih H, Sutanto Y, Reviono R, Adhiputri A, Aphridasari J and Prasetyo W: Effects of secretome supplementation on interleukin-6, tumor necrosis factor-α, procalcitonin, and the length of stay in acute exacerbation COPD patients. Narra J. 3:e1712023. View Article : Google Scholar
153	Xie M, Tao L, Zhang Z and Wang W: Mesenchymal stem cells mediated drug delivery in tumor-targeted therapy. Curr Drug Deliv. 18:876–891. 2020.PubMed/NCBI
154	Xu S, Liu B, Fan J, Xue C, Lu Y, Li C and Cui D: Engineered mesenchymal stem cell-derived exosomes with high CXCR4 levels for targeted siRNA gene therapy against cancer. Nanoscale. 14:4098–4113. 2022. View Article : Google Scholar : PubMed/NCBI
155	Tang Y, Zhou Y and Li HJ: Advances in mesenchymal stem cell exosomes: A review. Stem Cell Res Ther. 12:712021. View Article : Google Scholar : PubMed/NCBI
156	Abdelsalam M, Ahmed M, Osaid Z, Hamoudi R and Harati R: Insights into exosome transport through the blood-brain barrier and the potential therapeutical applications in brain diseases. Pharmaceuticals (Basel). 16:5712023. View Article : Google Scholar : PubMed/NCBI
157	Mohamed-Ahmed S, Fristad I, Lie S, Suliman S, Mustafa K, Vindenes H and Idris S: Adipose-derived and bone marrow mesenchymal stem cells: A donor-matched comparison. Stem Cell Res Ther. 9:1682018. View Article : Google Scholar : PubMed/NCBI
158	Gowen A, Shahjin F, Chand S, Odegaard KE and Yelamanchili SV: Mesenchymal stem cell-derived extracellular vesicles: Challenges in clinical applications. Front Cell Dev Biol. 8:1492020. View Article : Google Scholar : PubMed/NCBI
159	Li B, Chen X, Qiu W, Zhao R, Duan J, Zhang S, Pan Z, Zhao S, Guo Q, Qi Y, et al: Synchronous disintegration of ferroptosis defense axis via engineered exosome-conjugated magnetic nanoparticles for glioblastoma therapy. Adv Sci (Weinh). 9:e21054512022. View Article : Google Scholar : PubMed/NCBI
160	Zhang M, Zhang R, Chen H, Zhang X, Zhang Y, Liu H, Li C, Chen Y, Zeng Q and Huang G: Injectable supramolecular hybrid hydrogel delivers IL-1β-stimulated exosomes to target neuroinflammation. ACS Appl Mater Interfaces. 15:6486–6498. 2023. View Article : Google Scholar : PubMed/NCBI
161	Feng C, Xiong Z, Wang C, Xiao W, Xiao H, Xie K, Chen K, Liang H, Zhang X and Yang H: Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis. Bioact Mater. 6:963–974. 2021.
162	Zhan Q, Yi K, Qi H, Li S, Li X, Wang Q, Wang Y, Liu C, Qiu M, Yuan X, et al: Engineering blood exosomes for tumor-targeting efficient gene/chemo combination therapy. Theranostics. 10:7889–7905. 2020. View Article : Google Scholar : PubMed/NCBI
163	Zhao Y, Gan YM, Xu G, Hua K and Liu D: Exosomes from MSCs overexpressing microRNA-223-3p attenuate cerebral ischemia through inhibiting microglial M1 polarization mediated inflammation. Life Sci. 260:1184032020. View Article : Google Scholar : PubMed/NCBI