The effects of culture-expanded, non-cryopreserved adipose tissue mesenchymal stem cells (AT-MSCs) on neurological and immunological paradigms in females with secondary progressive multiple sclerosis: a phase I/II clinical trial

Abstract

Abstract Objective Mesenchymal stem cells (MSCs) due to their immunomodulatory, neurogenerative and self-renewal features have achieved fascinating prospects in regenerative medicine. Adipose tissue is an optimal source of MSCs because of the high abundance and high proliferative rate of MSCs in this tissue. To date, MSCs utilized for curing of MS have been cryopreserved, almost derived from bone marrow, and infused at standard doses (1–2×106 cell/Kg). Methods Here, we explored the safety, tolerability and functionality of fresh and high dose (4.4×106 cell/Kg) autologous adipose tissue MSCs (AT-MSCs) in 10 female patients with secondary progressive MS (SPMS, EDSS = 4–6). To this end, we assessed adverse events of AT-MSCs administration 9 months following transplantation. Additionally, we measured the number and volume of lesions, as well as the number of contrast-enhancing lesions from magnetic resonance imaging (MRI) data. Furthermore, we evaluated the expanded disability status scale (EDSS), depression, and quality of life status of the patients over 9 months. Also, the immunomodulatory effect of MSCs was investigated by evaluating gene expression of inflammatory (IL1, IL6, IL17, IFN-γ) and anti-inflammatory (TGF-β, IL4, IL10, FOXP3) cytokines besides the proportion of peripheral blood T regulatory cells as important modifier cells in hemostasis of autoimmune responses in MS diseases. Results In our study, high doses of non-cryopreserved AT-MSCs were successfully administrated into 10 SPMS patients during two injections seven days apart. Our findings have shown that AT-MSCs have no serious side effects after one year. Furthermore, we noted the efficacy of AT-MSCs in terms of reduction of numbers and volume of T2-FLAIR lesions, ameliorating of EDSS, and improvement in psychological criteria. Moreover, the immunomodulatory effects of AT-MSCs were confirmed by enhancing of Tregs population and anti-inflammatory cytokines as well as lowering inflammatory cytokines in patients. Conclusion Administration of high-dose (4.4×106 cell/Kg) of non-cryopreserved autologous adipose tissue MSCs (AT-MSCs) is safe and tolerated well in SPMS patients. Furthermore, AT-MSCs can be considered as an efficient treatment to stop or even reverse neurological manifestations in the progressive phase of multiple sclerosis. Trial registration : This clinical trial study was registered with the Iranian Registry of Clinical Trials (Reference: IRCT20091127002778N1 at 2018-01-10).