Atopic dermatitis (AD), a heterogeneous skin lesion with an increasing prevalence worldwide, is recognized as the most common chronic and relapsing inflammatory disorder among infants, children and even adults of all races, particularly among families with a history of related allergic diseases (1,2). Overall, AD can be divided into the intrinsic and extrinsic subtypes, which approximately comprises up 20 and 80% of patients, respectively (3). The disease has been reported to have a complex causality due to a series of immunological, genetic and environmental elements, with resultant comorbidities, such as respiratory diseases, food allergies, inflammatory skin infections and relative autoimmune disorders (1,4). As previously reported by Kim et al, the curative efficacy of the current clinical regimens against AD is relatively insufficient, along with marked ambiguity and side-effects (5). Moreover, complications, including xerosis, pruritus and eczematous skin ulcers, further complicate the exploration of the pathogenesis and management of AD (4,6). Thus, considering the increasing evidence that AD has caused a tremendous burden upon patients and their caregivers, there is an urgent need for the establishment of a more systemic therapeutic strategy with which to eliminate the complex pathophysiology together with the accompanied non-allergic and allergic comorbidities (2,7).

Mesenchymal stem cells (MSCs) are immunomodulating cell populations with static adherence and a typically fusiform morphology, with a high-level expression of mesenchymal-associated surface markers, and a multi-lineage differentiation capacity towards adipocytes, osteoblasts and chondroblasts (8). For decades, numerous fundamental research and clinical applications have collectively demonstrated the vast prospects of the use of MSCs in regenerative medicine and the coordinate contributions to the physiological and pathological microenvironment (8-10). For instance, researchers have extensively investigated the cultivate prospects of MSCs in a variety of refractory and relapsing diseases, such as the sports-related injuries (e.g., meniscal injuries) and osteoarthritis (11,12), nervous system disorders (e.g., Alzheimer's disease and spinal cord injuries) (13,14), digestive disorders (e.g., acute-on-chronic liver failure and fulminant hepatic disease) (15,16), endocrine disorders (e.g., diabetes mellitus and related complications) (17,18), reproductive disorders (e.g., premature ovarian failure and intrauterine adhesions) (19,20), haematological disorders (e.g., aplastic anaemia and acute myelogenous leukaemia) (21,22), and in particular, immunodysregulation (graft-vs.-host disease and Crohn's disease) (23,24). Kim et al reported that the first-in-class clinical trial upon AD administration with human umbilical cord blood-derived MSCs (hUCB-MSCs), even though hUCB-MSC infusion was well tolerated without noteworthy adverse events; yet, the efficiency together with the crucial effects did not yield statistical significance (5). Above all, the detailed effects of MSCs upon AD-associated skin ulcers and vital signs of elderly patient >60 years of age remain unexplored.

The present study describes the case of a 65-year-old female patient with typical symptoms of severe AD, including unbearable pruritus, xeroderma and systemic eczema plaques with refractory foot skin ulcer. With the aid of hormone and other drug treatments, the pruritus of the elderly patient was transiently attenuated, but relapsed quickly, whereas the other complications did not exhibit a visible improvement. Thus, with the consent of the patient and approval by the relevant ethics committee, 5x10⁷ human umbilical cord-derived MSCs (hUC-MSCs) were administered into the body of the patient via intravenous infusion. Notably, the aforementioned symptoms of AD and multiple complications of the patient were completely eliminated without visible side-effects upon examination of systematic vital signs, and in particular, the severe foot ulcers in both feet had subsided. Taken together, the findings of the present study confirm the safety and efficacy of the proof-of-concept use of hUC-MSCs for the treatment of AD. In addition, the present study highlights the prospects of the use of hUC-MSCs for elderly patients with refractory AD-associated severe skin ulcers.

State-of-the-art renewal has enlightened the promising prospects of MSCs in the management of refractory and relapsing disorders. This is mainly attribute to their unique hematopoietic-supporting and immunoregulatory properties (21,25,26). However, their potential application in elderly patients with refractory allergic dermatitis with multiple complications are largely unknown. The present study describes the case of a 65-year-old female patient with AD accompanied by an unbearable itch, extensive eczema, severe foot ulcers, urinary tract infection, and in particular, resistance to conventional drug therapy. With the aid of only one single systemic hUC-MSC injection, the major symptoms of AD were effectively relieved within 10 days following the MSC administration. Finally, a positive outcome without palindromia was observed with the patient during the 14-month follow-up visit, including the significant elimination of pathophysiological manifestations and persistent improvement in the quality of life.

The pathogenesis of AD typically manifests in epidermal barrier disruption, dysbiosis of the skin microbiota and the overactivation of the helper T lymphocyte subpopulations (Th1, Th2, Th17 and Th22), as well as increased eosinophils and IgE in blood (3,27). However, the detailed underlying mechanisms, as well as the absolute magnitude of the risks of AD remain largely unknown (2,3,27). For instance, the impact of gene-environment interactions upon epidermal barrier destruction and the resultant variations in clinical presentations have not yet been clearly demonstrated (5). In addition, AD is considered to be an initiating factor for other atopic disorders, including food allergies, allergic asthma and rhinitis, which can continue for a long period of time, maintaining a relapsing-remitting status in affected patients (6). In general, the systematic and precise clarification of AD-associated epidemiologic features, clinical phenotypes, genetic subtype, clinical remission and the underlying pathogenic mechanisms are not yet fully understood (5,27). As a consequence, even though current treatment modalities, including pharmacological-associated interventions alone or in combination with non-pharmacological strategies may be able to relieve pain in patients with moderate to severe AD, their effectiveness is not satisfactory due to the complexity and indeterminacy of the underlying pathogenesis. For example, a recent advancement has been made in the monoclonal antibody (mAb), dupilumab, which has exhibited satisfactory effectiveness against AD with a remission rate of 85% via a subcutaneous administration (11 times) by blocking IL-3 and IL-13(28). However, in spite of its effectiveness, the accompanied adverse reactions, inconvenience and unexpected clinical outcomes (e.g., headache, injection-site reaction and conjunctivitis), would largely hinder its use in the rational and effective application in patients with AD (29,30).

Distinguishing from the traditional or late-model drug-based strategies, MSC-based cytotherapy has been proven to be safe and effective against multiple disorders associated with immune abnormalities (31-34). Since the first separation and identification in the 1960s, MSCs have been successfully isolated from adult tissues, perinatal tissues and even derived from human pluripotent stem cells (35-37). Of these, the natural bone marrow- and umbilical cord-segregated MSCs are acknowledged with the most popular and proliferative characteristics, respectively (21,23,24). MSCs function mainly via cytokine paracrine mechanisms [e.g., prostaglandin E2 (PGE2) and transforming growth factor (TGF)-β1], the inhibition of inflammatory factor production [e.g., interferon (IFN)-γ and tumour necrosis factor (TNF)-α], the recruitment and regulation of other cell constituents (e.g., mast cells, T lymphocytes) and direct differentiation, together with providing a favourable microenvironment (9,38-40). As for the management of AD, by administering a high-dose of hUCB-MSCs (5x10⁷) via local subcutaneous injection, Kim et al reported few adverse events and a certain improvement of patients with AD with an overall response rate of 55% at week 12(40).

However, the systemic infusion and long-term effects of MSCs against AD remain unknown. To the best of our knowledge, the present study demonstrates for the first time that hUC-MSCs were effective in the treatment of a patient with AD with other complications, including foot ulcers and a urinary tract infection, leading to a full, rather than partial remission, via a single and convenient intravenous injection. In particular, the severe ulcers and refractory urinary tract infection in the elderly patient with AD were completely eliminated without recrudesce during the 14-month follow-up visit. Simultaneously, according to the systematic clinical and biochemical examinations, and in particular, the tumour-related indicators, the consistent safety and continuous efficacy of MSC-based cytotherapy for AD was confirmed. Nevertheless, more patients with AD need to be enrolled and examined in order to evaluate the reliability and validity of hUC-MSC infusion via intravenous injection. Overall, the data presented herein provide a paradigm and prospect for further investigations towards AD treatment, and may help to predominantly ameliorate the refractory disorder in the future.