Open Access

Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury

  • Authors:
    • Yonghua Xue
    • Zhikun Li
    • Yi Wang
    • Xiaodong Zhu
    • Ruixi Hu
    • Wei Xu
  • View Affiliations

  • Published online on: July 28, 2020
  • Pages: 2767-2774
  • Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


The hypoxic state of the brain tissue surrounding craniocerebral injury induces an increase in the secretion of HIF‑1α during the healing process. HIF‑1α can promote mesenchymal stem cell (MSC) migration to ischemic and hypoxic sites by regulating the expression levels of molecules such as stromal cell‑derived factor‑1 (SDF‑1) in the microenvironment. Stem cells express the SDF‑1 receptor C‑X‑C chemokine receptor type 4 (CXCR4) and serve a key role in tissue repair, as well as a number of physiological and pathological processes. The present study aimed to determine the role of HIF‑1α/SDF‑1/CXCR4 signaling in the process of accelerated fracture healing during craniocerebral injury. Cultured MSCs underwent HIF‑1α knockdown to elucidate its effect on the proliferative ability of MSCs, and the effect of SDF‑1 in MSCs was investigated. It was also determined whether HIF‑1α could promote osteogenesis via SDF‑1/CXCR4 signaling and recruit MSCs. The results indicated that HIF‑1α knockdown suppressed MSC proliferation in vitro, and SDF‑1 promoted cell migration via binding to CXCR4. Furthermore, HIF‑1α knockdown inhibited MSC migration via SDF‑1/CXCR4 signaling. Considering the wide distribution and diversity of roles of SDF‑1 and CXCR4, the present results may form a basis for the development of novel strategies for the treatment of craniocerebral injury.


Fracture healing is a multi-level and multi-path process regulated by systemic and local factors, involving numerous types of cells and growth factors, such as mesenchymal cells and transforming growth factor-β1 (TGF-β1) (13). Fracture non-union or delayed union is a common complication in orthopedics that causes physical and mental pain, as well as a notable economic burden to patients and society. Long-term clinical studies have revealed that, in the process of fracture healing, callus volume and formation rate are higher in patients with fractures combined with traumatic brain injury than in patients with simple fractures. Heterotopic ossification occurs in patients with craniocerebral trauma combined with a fracture, and fracture healing is accelerated (4,5). Numerous cytokines and neuropeptide factors, such as bone morphogenetic protein (BMP), TGF-β1, vascular endothelial growth factor, insulin-like growth factor, fibroblast growth factor and calcitonin gene-related peptides, can significantly promote osteoblast proliferation, thereby accelerating fracture healing (69). Although there have been advances in the study of osteoblasts in accelerated fracture healing, the underlying mechanisms remain unclear. Elucidating the mechanism by which fracture healing is accelerated may facilitate the development of effective clinical treatments for patients with delayed fracture healing.

During craniocerebral injury, hypoxia promotes the expression of hypoxia-inducible factor-1α (HIF-1α), which can increase cell viability, and promote adhesion, migration and angiogenesis. HIF-1α is the most important hypoxia receptor and hypoxia-induced transcription factor known at present (10,11). An increase in HIF-1α activity can increase the viability of cells in hypoxic environments and promote cell adhesion, migration and angiogenesis (12,13). HIF-1α can promote stem cell migration to ischemic and hypoxic sites by regulating the expression levels of surface molecules as a result of interaction between a number of ligands and receptors including stromal cell-derived factor-1 (SDF-1), a downstream gene of HIF-1α, which binds to its specific receptor C-X-C chemokine receptor type 4 (CXCR4) to form a pair of coupling molecules (14,15). SDF-1 is a CXC-type chemokine produced by mesenchymal stem cells (MSCs). SDF-1 and its unique receptor CXCR4 constitute the biological axis of SDF-1/CXCR4 (16). SDF-1 and CXCR4 are expressed in numerous types of cells and tissues, where they serve a key role in tissue repair and a variety of physiological and pathological processes, including organogenesis, revascularization and response to tissue injury (17,18). However, their role in the process of accelerated fracture healing during craniocerebral injury and the regulatory effect of HIF-1α on SDF-1/CXCR4 in MSCs remains unclear. In the present study, MSCs, which serve a key role in fracture healing, were used as a model to investigate the role of the HIF-1α/SDF-1/CXCR4 signaling axis in accelerated fracture healing during craniocerebral injury in vitro.

Materials and methods

Mouse bone marrow mesenchymal stem cell (BMSC) culture

A total of 10 C57 mice (male; age, 4 weeks; weight, 18–20 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. Mice were housed in specific-pathogen-free conditions at room temperature (22±1°C) with relative humidity (50±5%), 12-h light/dark cycles, and free access to food and water. BMSCs were isolated as previously described (19). C57 mice were sacrificed via cervical dislocation and soaked in 75% alcohol for 10 min at room temperature. Under sterile conditions, the bilateral leg bones were extracted and separated from the surrounding muscle. The harvested tissue was placed in cold complete DMEM/F12 (DMEM/F12+10% FBS+1% penicillin/streptomycin/amphotericin B solution; Gibco; Thermo Fisher Scientific, Inc.). The culture medium was aspirated repeatedly with a needle and syringe to rinse the marrow cavity. Cells were dispersed by repeated pipetting, and the cell suspension was passed through a 400-mesh sterile mesh and centrifuged at 200 × g for 3 min, after which the supernatant was discarded. The cells were resuspended in complete DMEM/F12, and the density was adjusted to 5×105 cells/ml. Subsequently, the cell suspension (4 ml) was inoculated into a T-25 flask and cultured in a 5% CO2 incubator at 37°C. After 24 h, the flask was shaken horizontally to suspend unattached cells and the supernatant was discarded. Fresh medium was then added to the culture flask and changed every 2–3 days until the primary cells grew to a confluence of 80–90%.

Cells were then sub-cultured as follows: Supernatant media was aspirated, and the cells were washed with 1 ml PBS and treated with 1 ml 0.25% trypsin for 2 min at 37°C. Cell morphology was observed by light microscopy (magnification, ×100). When the cells were rounded, 1 ml complete medium was added to terminate digestion, and the cells were gently pipetted to detach them from the bottom of the bottle completely. The cell suspension was transferred to a centrifuge tube and centrifuged at 200 × g for 3 min at room temperature, and the supernatant was removed. The cells were resuspended in complete DMEM/F12 and inoculated into a new culture flask at a ratio of 1:2. After passage, the cells were cultured in the same manner as the primary culture until the next generation.

Flow cytometry and MSC sorting

Third generation MSC cells were digested with 0.25% trypsin for 2 min at 37°C, and a single cell suspension was obtained by adjusting the cell density to 1×106 cells/ml. The cell suspension was incubated for 30 min at room temperature with PBS, anti-CD29-FITC (1.5 µl; cat. no. ab21845; Abcam), anti-CD44-FITC (2 µg; cat. no. ab25064; Abcam) or anti-CD45-FITC (10 µl; cat. no. ab27287; Abcam), and analyzed using a Coulter Epics XL-MCL flow cytometer (BD Biosciences) with EXPO32 software (version 1.2; BD Biosciences).

HIF-1α siRNA transfection

MSC cells were seeded in 6-well culture plates (5×105 cells/well) overnight. The inoculated cells were washed twice with PBS, and 500 µl serum-free DMEM/F12 (Gibco; Thermo Fisher Scientific, Inc.) was added. The HilyMax-HIF-1α siRNA transfection mixture (Dojindo Molecular Technologies, Inc.) and siRNA control were premixed (0.2 µg/µl), added to the MSCs and mixed. siRNA and siRNA control were obtained from Sangon Biotech Co., Ltd. After incubating the cells in the cell culture incubator for 6 h at 37°C, the medium was replaced with fresh medium. The cells were trypsinized and collected for subsequent experiments after transfection for 48 h. The sequences of siRNAs used are presented in Table I.

Table I.

Sequences of siRNA.

Table I.

Sequences of siRNA.

siRNASequence (5′→3′)

[i] siRNA, small interfering RNA; F, forward; R, reverse.

Reverse transcription-quantitative (RT-q) PCR analysis

Total RNA was extracted from cells with TRIzol (Invitrogen; Thermo Fisher Scientific, Inc.). cDNA synthesis was performed using the TOYOBO ReverTra Ace qPCR RT kit, according to the manufacturer's protocol. qPCR was performed using the KAPA SYBR-Green Supermix PCR kit (Kapa Biosystems). RT-qPCR primers were obtained from Sangon Biotech Co., Ltd.; sequences are listed in Table II. The reaction was started at 95°C for 5 min, followed by 40 cycles of 95°C for 30 sec, 61°C for 30 sec, and 72°C for 30 sec. Relative gene expression levels were measured using the cycle threshold values and the 2−ΔΔCq method (20).

Table II.

Sequences of reverse transcription-quantitative PCR primers.

Table II.

Sequences of reverse transcription-quantitative PCR primers.

GeneSequence (5′→3′)

[i] F, forward; R, reverse.

Western blotting and antibodies

Cells treated with siRNA were harvested for protein extraction using the RIPA reagent (Pierce; Thermo Fisher Scientific, Inc.). The protein concentration was determined via BCA protein assay reagent. After measuring protein concentration, 50–100 µg protein was subjected to 10% SDS-PAGE gel and transferred to a PVDF membrane. The membrane was blocked with 5% non-fat milk powder for 1 h at room temperature and incubated with primary antibodies against HIF-1α (1:1,000; cat. no. ab179483; Abcam), SDF-1 (1:1,000; cat. no. ab25117; Abcam), and CXCR4 (1:1,000; cat. no. ab124824; Abcam) at 4°C overnight, followed by goat-anti-rabbit (1:2,000; cat. no. ab205718; Abcam) secondary antibody for 1 h at 37°C. The chemiluminescent signaling was detected via ECL reagents (Pierce; Thermo Fisher Scientific, Inc.).

Cell proliferation assay

Cell proliferation was assessed using Cell Counting Kit-8 (CCK-8; Dojindo Molecular Technologies, Inc.). Briefly, MSCs were seeded on 96-well microplates at a density of 1×104 cells/well. The cells were transfected with HilyMax-siRNA and cultured for 0, 24 or 48 h at 37°C. A total of 5 µl CCK-8 solution was then added to each well and incubated at 37°C for an additional 2 h. Optical density (OD) was determined at a wavelength of 450 nm.

Migration assay

Migration assays were performed using 24-well plate with permeable Transwell inserts (pore size 0.4 mm; Corning, Inc.). BMSCs were suspended in serum-free DMEM/F12 medium (5×104 cells/well) and equal amounts of cell suspension (200 µl) was added to the upper chambers on the migration plate. The same amount (200 µl) of complete medium (DMEM/F12+10% FBS) with different treatment was added to the lower chamber of the migration plate separately. There were two sets of experiments. In the first, cells were divided into the following treatment groups for 24 h at 37°C: 0 ng/ml SDF-1+0 µM AMD3100 (a specific antagonist that blocks the binding of SDF-1 to CXCR4; cat. no. A5602; Sigma-Aldrich; Merck KGaA); 10 ng/ml SDF-1+0 µM AMD3100; 100 ng/ml SDF-1+0 µM AMD3100; 100 ng/ml SDF-1+1 µM AMD3100; and 100 ng/ml SDF-1+10 µM AMD3100. For the second experiment, cells were divided into the following treatment groups for 24 h at 37°C: NC (siRNA-NC), siRNA (HIF-1α-siRNA), SDF-1 (siRNA-NC+100 ng/ml SDF-1), and siRNA and SDF-1 group (HIF-1α siRNA+100 ng/ml SDF-1). After 24 h, the migrated cells on the bottom of the insert were fixed with 4% paraformaldehyde solution for 24 h at room temperature and stained with crystal violet (1%) for 15 min at room temperature. The cells were processed as described in the cell migration assay, and migrated cells were counted, and the relative number was calculated with light microscopy (magnification, ×100).

Statistical analysis

Results are representative of three independent experiments. GraphPad Prism (version 7.0; GraphPad Software, Inc.) and SPSS software (version 19; IBM Corp.) were used for statistical analysis of cell proliferation, as well as the results of the Transwell assay and RT-qPCR. Differences between two groups were analyzed using an unpaired t-test. Comparisons between multiple groups were analyzed using one-way ANOVA followed by Tukey's post hoc test. P<0.05 was considered to indicate a statistically significant difference.


Morphological identification of MSCs

The present study determined whether the HIF-1α/SDF-1/CXCR4-axis serves a role in fracture combined with traumatic brain injury in an in vitro BMSC model. MSCs exhibited a typical spindly morphology (Fig. 1A). Cells in the third passage were characterized via flow cytometry. The results demonstrated that the expression levels of CD29 and CD44 on the surface of BMSCs were >95%, whereas the expression level of the hematopoietic stem cell marker CD45 was <5% (Fig. 1B), which was consistent with the characteristics of BMSCs.

HIF-1α knockdown suppresses MSC proliferation in vitro

Next, the effects of HIF-1α on the migration of MSCs were investigated. In order to assess the effect of HIF-1α knockdown on cell proliferation, CCK-8 was used to detect proliferation at different time-points. The OD value of HIF-1α-knockdown cells was significantly decreased at 450 nm (Fig. 2), indicating that HIF-1α knockdown inhibits MSC proliferation.

SDF-1 promotes cell migration by binding to CXCR4

In order to confirm the effect of SDF-1 in MSCs, its impact on cell migration was analyzed. Treatment of MSCs with various concentrations of SDF-1 caused a dose-dependent increase in cell migration (Fig. 3A). Cell migration induced by SDF-1 was abrogated by AMD3100, indicating that AMD3100 inhibits MSC migration via obstructing SDF-1 binding with CXCR4 (Fig. 3B). Collectively, these results indicated that SDF-1 promoted MSC migration via binding to CXCR4, which was impaired by AMD3100.

HIF-1α knockdown inhibits MSC migration via SDF-1/CXCR4 signaling

It was then determined whether knockdown of HIF-1α impairs the chemotactic function of SDF-1/CXCR4 signaling in MSCs. The mRNA and protein levels of SDF-1 and CXCR4 were decreased in MSCs stably transfected with siHIF-1α compared with NC group (Fig. 4A). Moreover, HIF-1α knockdown inhibited MSC migration; replenishment of SDF-1 increased cell migration (Fig. 4B and C). Thus, HIF-1α likely regulates MSC migration via SDF-1/CXCR4 signaling.


In the present study, the proliferation rate of MSCs transfected with HIF-1α siRNA significantly decreased at 24 and 48 h. MSCs are essential for the repair of bone defects, and improving the effects of MSCs in bone is of clinical interest. In patients with skull injuries, ischemia and hypoxia surrounding brain tissue often occur, and the skull bone repair process must be adapted to the hypoxic environment (10,21). HIF-1α can maintain homeostasis of oxygen under hypoxia, allowing the body to adapt to hypoxia (22). HIF-1α can induce the formation of blood vessels and bone tissue via numerous factors, including vascular endothelial growth factor, angiopoietin, platelet growth factor and transforming growth factor, making it a potential candidate for the treatment of bone defects and other types of disease (23,24). HIF-1α is a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation and endochondral bone formation (25). HIF-1α and BMP2 have been revealed to synergistically induce MSC differentiation and promote the expansion of the proliferating chondrocyte zone (25). HIF-1 also serves an important role in coupling osteogenesis and angiogenesis during skeletal development and bone regeneration, and HIF-1α overexpression may represent a therapeutic option to improve cellular functions of MSCs in the treatment of critical-sized bone defects (26). Thus, HIF-1α may improve the cellular functions of MSCs; however, the underlying molecular mechanisms are still unclear.

SDF-1 is a protein secreted primarily by MSCs. When SDF-1 specifically binds to CXCR4 on a number of types of cell surface, activated SDF-1/CXCR4 can stimulate downstream signaling pathways associated with the regulation of stem cell mobilization and migration (27), induce MSC migration to the damaged site and participate in injury repair (28,29). Activation of the ERK-AKT pathway mediates SDF1-induced cell migration. SDF1/CXCR4 signaling is required for MSC homing and retention to their niche in the bone marrow (30). Secretion of SDF-1 has been revealed to increase during bone regeneration, allowing CXCR4-expressing MSCs to enter the stretch region with the concentration gradient of SDF-1 following induction via the SDF-1/CXCR4 molecular axis, and to participate in new bone formation and cardiovascular generation (3133). In order to confirm the effect of SDF-1 in MSCs, the present study analyzed the chemotactic effect of the SDF-1/CXCR4 axis on MSCs. SDF-1 was demonstrated to promote the migration of MSCs in a dose-dependent manner. This result is similar to that reported by Zhou et al (25), who demonstrated that HIF-1α can regulate cell migration by influencing the expression levels of CXCR4. Additionally, by using AMD3100 to block the binding of SDF-1 to CXCR4, SDF-1-induced cell migration in the present study was abrogated, indicating that AMD3100 inhibits MSC migration by obstructing SDF-1 binding with CXCR4. Therefore, the SDF-1/CXCR4 axis serves a key role in MSC function.

SDF-1/CXCR4 signaling has been revealed to play an important role in cell migration, chemotaxis as well as other biological behaviors. SDF-1-induced transendothelial behavior has been revealed to be positively associated with the density of cell surface receptor CXCR4 and is affected by a number of factors (34). HIF-1α is a central transcription factor of hypoxia-specific gene expression levels (30). HIF-1α can bind to the SDF-1 promoter and specifically regulate the expression levels of SDF-1 (30,35). Hypoxia can upregulate the expression levels of CXCR4 in human monocytes and macrophages, as well as endothelial and tumor cells, via the activation of HIF-1α (36). The hypoxia/HIF-1α/CXCR4 pathway may be a mechanism of regulating the migration of different types of cells under hypoxia (37). A number of CXCR4-positive stem cells are involved in angiogenesis in locally damaged areas in a hypoxic environment. The adhesion, migration and homing of these CXCR4-positive stem cells are initiated via binding of SDF-1, containing hypoxia response elements, to CXCR4; the expression levels of SDF-1 are regulated by HIF-1α (38). The present study therefore determined whether HIF-1α can recruit MSCs and promote osteogenesis via the SDF-1/CXCR4 molecular axis. Following HIF-1α knockdown, it was demonstrated that the mRNA and protein levels of SDF-1 and CXCR4 in MSCs were significantly decreased. HIF-1α gene silencing inhibited the migration of MSCs (P<0.05). This confirmed that SDF-1 promotes the migration of MSC cells and indicated that HIF-1α acts on MSCs via the SDF-1/CXCR4 molecular axis. However, further investigation is required to elucidate the mechanisms underlying the effect of HIF-1α on oxidative stress in the healing process of skull injury, which may involve complex signaling pathways.

During craniocerebral injury healing, the hypoxic state of surrounding brain tissue induces an increase in the secretion of HIF-1α (39), which accelerates the fracture repair process via chemotaxis due to the SDF-1/CXCR4 axis. In the present study, a gene silencing plasmid was successfully constructed based on the HIF-1α gene sequence, and the regulatory association between HIF-1α and SDF-1/CXCR4 was elucidated. Silencing of HIF-1α decreased MSC migration, as well as the mRNA and protein levels of SDF-1 and CXCR4 in MSCs. Due to the wide distribution and diversity of roles of SDF-1 and CXCR4, they may represent prognostic biomarkers or therapeutic targets for a number of neurological diseases.


Not applicable.


The present study was supported by the Shanghai Excellent Young Medical Talents Training Program (grant no. 2018YQ46), the National Natural Science Foundation of China (grant no. 81501897), the Shanghai Municipal Commission of Health and Family Planning of Science and Research Fund (grant no. 20154Y0070) and K.C. Wong Education Foundation.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

WX and YX conceived the study. WX, YX, ZL, RH and XZ performed the experiments and contributed to writing the manuscript. WX, YX and YW analyzed the data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the Animal Research Ethics Committee of TongRen Hospital, School of Medicine, Shanghai JiaoTong University (approval no. 170004).

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



van Baardewijk LJ, van der Ende J, Lissenberg-Thunnissen S, Romijn LM, Hawinkels LJA, Sier CFM and Schipper IB: Circulating bone morphogenetic protein levels and delayed fracture healing. Int Orthop. 37:2767–527. 2013. View Article : Google Scholar


Hara Y, Ghazizadeh M, Shimizu H, Matsumoto H, Saito N, Yagi T, Mashiko K, Mashiko K, Kawai M and Yokota H: Delayed expression of circulating TGF-β1 and BMP-2 levels in human nonunion long bone fracture healing. J Nippon Med Sch. 84:12–18. 2017. View Article : Google Scholar : PubMed/NCBI


Hankenson KD, Zimmerman G and Marcucio R: Biological perspectives of delayed fracture healing. Injury. 45 (Suppl 2):S8–S15. 2014. View Article : Google Scholar : PubMed/NCBI


Seemann R, Graef F, Garbe A, Keller J, Huang F, Duda G, Schmidt-Bleek K, Schaser KD and Tsitsilonis S: Leptin-deficiency eradicates the positive effect of traumatic brain injury on bone healing: Histological analyses in a combined trauma mouse model. J Musculoskelet Neuronal Interact. 18:32–41. 2018.PubMed/NCBI


Huang H, Cheng WX, Hu YP, Chen JH, Zheng ZT and Zhang P: Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification. J Orthop Translat. 12:16–25. 2018. View Article : Google Scholar : PubMed/NCBI


Liu S, Liu Y, Jiang L, Li Z, Lee S, Liu C, Wang J and Zhang J: Recombinant human BMP-2 accelerates the migration of bone marrow mesenchymal stem cells via the CDC42/PAK1/LIMK1 pathway in vitro and in vivo. Biomater Sci. 7:362–372. 2018. View Article : Google Scholar : PubMed/NCBI


Manzano-Moreno FJ, Medina-Huertas R, Ramos-Torrecillas J, García-Martínez O and Ruiz C: The effect of low-level diode laser therapy on early differentiation of osteoblast via BMP-2/TGF-β1 and its receptors. J Craniomaxillofac Surg. 43:1926–1932. 2015. View Article : Google Scholar : PubMed/NCBI


Wang T, Guo S and Zhang H: Synergistic effects of controlled-released BMP-2 and VEGF from nHAC/PLGAs scaffold on osteogenesis. BioMed Res Int. 2018:35164632018.PubMed/NCBI


Quarles LD: Fibroblast growth factor 23 and α-Klotho co-dependent and independent functions. Curr Opin Nephrol Hypertens. 28:16–25. 2019. View Article : Google Scholar : PubMed/NCBI


Wan C, Shao J, Gilbert SR, Riddle RC, Long F, Johnson RS, Schipani E and Clemens TL: Role of HIF-1alpha in skeletal development. Ann N Y Acad Sci. 1192:322–326. 2010. View Article : Google Scholar : PubMed/NCBI


Tirpe AA, Gulei D, Ciortea SM, Crivii C and Berindan-Neagoe I: Hypoxia: Overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. Int J Mol Sci. 20:61402019. View Article : Google Scholar


Kanichai M, Ferguson D, Prendergast PJ and Campbell VA: Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: A role for AKT and hypoxia-inducible factor (HIF)-1alpha. J Cell Physiol. 216:708–715. 2008. View Article : Google Scholar : PubMed/NCBI


Kim A and Ma JY: Rhaponticin decreases the metastatic and angiogenic abilities of cancer cells via suppression of the HIF1α pathway. Int J Oncol. 53:1160–1170. 2018.PubMed/NCBI


Luo Y, Cai J, Xue H, Miura T and Rao MS: Functional SDF1 alpha/CXCR4 signaling in the developing spinal cord. J Neurochem. 93:452–462. 2005. View Article : Google Scholar : PubMed/NCBI


Knerlich-Lukoschus F, von der Ropp-Brenner B, Lucius R, Mehdorn HM and Held-Feindt J: Spatiotemporal CCR1, CCL3(MIP-1α), CXCR4, CXCL12(SDF-1α) expression patterns in a rat spinal cord injury model of posttraumatic neuropathic pain. J Neurosurg Spine. 14:583–597. 2011. View Article : Google Scholar : PubMed/NCBI


Merino JJ, Gutiérrez-Fernández M, Rodríguez-Frutos B, Alvarez-Grech J, Alcalde ME, Vallejo-Cremades MT and Díez-Tejedor E: CXCR4/SDF-1α-chemokine regulates neurogenesis and/or angiogenesis within the vascular niche of ischemic rats; however, does SDF-1α play a role in repair? Int J Stroke. 6:466–467. 2011. View Article : Google Scholar : PubMed/NCBI


Petit I, Jin D and Rafii S: The SDF-1-CXCR4 signaling pathway: A molecular hub modulating neo-angiogenesis. Trends Immunol. 28:299–307. 2007. View Article : Google Scholar : PubMed/NCBI


Wen J, Zhang JQ, Huang W and Wang Y: SDF-1α and CXCR4 as therapeutic targets in cardiovascular disease. Am J Cardiovasc Dis. 2:20–28. 2012.PubMed/NCBI


Liu X, Zheng L, Zhou Y, Chen Y, Chen P and Xiao W: BMSC transplantation aggravates inflammation, oxidative stress, and fibrosis and impairs skeletal muscle regeneration. Front Physiol. 10:872019. View Article : Google Scholar : PubMed/NCBI


Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI


Knight MN and Hankenson KD: Mesenchymal stem cells in bone regeneration. Adv Wound Care (New Rochelle). 2:306–316. 2013. View Article : Google Scholar : PubMed/NCBI


Yuan G, Peng YJ, Reddy VD, Makarenko VV, Nanduri J, Khan SA, Garcia JA, Kumar GK, Semenza GL and Prabhakar NR: Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis. Proc Natl Acad Sci USA. 110:E1788–E1796. 2013. View Article : Google Scholar : PubMed/NCBI


Maes C: Signaling pathways effecting crosstalk between cartilage and adjacent tissues: Seminars in cell and developmental biology: The biology and pathology of cartilage. Semin Cell Dev Biol. 62:16–33. 2017. View Article : Google Scholar : PubMed/NCBI


Johnson RW, Schipani E and Giaccia AJ: HIF targets in bone remodeling and metastatic disease. Pharmacol Ther. 150:169–177. 2015. View Article : Google Scholar : PubMed/NCBI


Zhou N, Hu N, Liao JY, Lin LB, Zhao C, Si WK, Yang Z, Yi SX, Fan TX, Bao W, et al: HIF-1α as a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral ossification in stem cells. Cell Physiol Biochem. 36:44–60. 2015. View Article : Google Scholar : PubMed/NCBI


Lampert FM, Kutscher C, Stark GB and Finkenzeller G: Overexpression of Hif-1α in mesenchymal stem cells affects cell-autonomous angiogenic and osteogenic parameters. J Cell Biochem. 117:760–768. 2016. View Article : Google Scholar : PubMed/NCBI


Kucia M, Ratajczak J, Reca R, Janowska-Wieczorek A and Ratajczak MZ: Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. Blood Cells Mol Dis. 32:52–57. 2004. View Article : Google Scholar : PubMed/NCBI


Sun J, Zhao Y, Li Q, Chen B, Hou X, Xiao Z and Dai J: Controlled release of collagen-binding SDF-1α improves cardiac function after myocardial infarction by recruiting endogenous stem cells. Sci Rep. 6:266832016. View Article : Google Scholar : PubMed/NCBI


Ji JF, He BP, Dheen ST and Tay SS: Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem cells. 22:415–427. 2004. View Article : Google Scholar : PubMed/NCBI


Yu Q, Liu L, Lin J, Wang Y, Xuan X, Guo Y and Hu S: SDF-1α/CXCR4 axis mediates the migration of mesenchymal stem cells to the hypoxic-ischemic brain lesion in a rat model. Cell J. 16:440–447. 2015.PubMed/NCBI


Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T and Gronthos S: Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood. 105:3793–3801. 2005. View Article : Google Scholar : PubMed/NCBI


Periyasamy-Thandavan S, Burke J, Mendhe B, Kondrikova G, Kolhe R, Hunter M, Isales CM, Hamrick MW, Hill WD and Fulzele S: MicroRNA-141-3p negatively modulates SDF-1 expression in age-dependent pathophysiology of human and murine bone marrow stromal cells. J Gerontol A Biol Sci Med Sci. 74:1368–1374. 2019. View Article : Google Scholar : PubMed/NCBI


Kristocheck M, Dias LD, Ghem C, Eibel B, Kalil RAK and Markoski MM: The homing of bone marrow stem cells is differentially activated in ischemic and valvular heart diseases and influenced by beta-blockers. J Transl Med. 16:1332018. View Article : Google Scholar : PubMed/NCBI


van Buul JD, Voermans C, van Gelderen J, Anthony EC, van der Schoot CE and Hordijk PL: Leukocyte-endothelium interaction promotes SDF-1-dependent polarization of CXCR4. J Biol Chem. 278:30302–30310. 2003. View Article : Google Scholar : PubMed/NCBI


Sun X, Wei L, Chen Q and Terek RM: CXCR4/SDF1 mediate hypoxia induced chondrosarcoma cell invasion through ERK signaling and increased MMP1 expression. Mol Cancer. 9:172010. View Article : Google Scholar : PubMed/NCBI


Liu H, Liu S, Li Y, Wang X, Xue W, Ge G and Luo X: The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One. 7:e346082012. View Article : Google Scholar : PubMed/NCBI


Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, et al: Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 198:1391–1402. 2003. View Article : Google Scholar : PubMed/NCBI


Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP and Gurtner GC: Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 10:858–864. 2004. View Article : Google Scholar : PubMed/NCBI


Liu X, Zhou C, Li Y, Ji Y, Xu G, Wang X and Yan J: SDF-1 promotes endochondral bone repair during fracture healing at the traumatic brain injury condition. PLoS One. 8:e540772013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 22 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Xue Y, Li Z, Wang Y, Zhu X, Hu R and Xu W: Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury. Mol Med Rep 22: 2767-2774, 2020
Xue, Y., Li, Z., Wang, Y., Zhu, X., Hu, R., & Xu, W. (2020). Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury. Molecular Medicine Reports, 22, 2767-2774.
Xue, Y., Li, Z., Wang, Y., Zhu, X., Hu, R., Xu, W."Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury". Molecular Medicine Reports 22.4 (2020): 2767-2774.
Xue, Y., Li, Z., Wang, Y., Zhu, X., Hu, R., Xu, W."Role of the HIF‑1α/SDF‑1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury". Molecular Medicine Reports 22, no. 4 (2020): 2767-2774.