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Background Aims: Mesenchymal stromal cell (MSC) therapy for diabetic neuropathy (DN) has been extensively researched in vitro and in pre-clinical studies; however, the clinical scenario thus far has been disappointing. Temporary recovery, a common feature of these studies, indicates that either the retention of transplanted cells deteriorates with time or recovery of supportive endogenous cells, such as bone marrow-derived MSCs (BM-MSCs), does not occur, requiring further replenishment. In DN, BM-MSCs are recognized mediators of Schwann cell regeneration, and we have earlier shown that they suffer impairment in the pre-neuropathy stage. In this study, we attempted to further elucidate the mechanisms of functional recovery by focusing on changes occurring at the cellular level in the sciatic nerve, in conjunction with the biodistribution and movement patterns of the transplanted cells, to define the interval between doses., Method & Results: We found that two doses of 1 × 10 6 dental pulp stromal cells (DPSCs) transplanted intramuscularly at an interval of 4 weeks effectively improved nerve conduction velocity (NCV) and restored motor coordination through improving sciatic nerve architecture, Schwann cell survival and myelination. Despite very minimal recovery of endogenous BM-MSCs, a temporary restoration of NCV and motor function was achieved with the first dose of DPSC transplantation. However, this did not persist, and a repeat dose was needed to consolidate functional improvement and rehabilitate the sciatic nerve architecture., Conclusion: Thus, repeat intramuscular transplantation of DPSCs is more effective for maintenance of Schwann cell survival and myelination for functional recovery after onset of DN., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Mesenchymal stromal cells (MSCs) are under active consideration as a treatment strategy for controlling the hyper-inflammation and slow disease progression associated with coronavirus disease 2019 (COVID-19). The possible mechanism of protection through their immunoregulatory and paracrine action has been reviewed extensively. However, the importance of process control in achieving consistent cell quality, maximum safety and efficacy-for which the three key questions are which, when and how much-remains unaddressed. Any commonality, if it exists, in ongoing clinical trials has yet to be analyzed and reviewed. In this review, the authors have therefore compiled study design data from ongoing clinical trials to address the key questions of "which" with regard to tissue source, donor profile, isolation technique, culture conditions, long-term culture and cryopreservation of MSCs; "when" with regard to defining the transplantation window by identifying and staging patients based on their pro-inflammatory profile; and "how much" with regard to the number of cells in a single administration, number of doses and route of transplantation. To homogenize MSC therapy for COVID-19 on a global scale and to make it readily available in large numbers, a shared understanding and uniform agreement with respect to these fundamental issues are essential., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Diabetic neuropathy (DN) is among the most debilitating complications of diabetes. Here, we investigated the effects of human dental pulp stem cell (DPSC) transplantation in Streptozotocin (STZ)-induced neuropathic rats. Six weeks after STZ injection, DPSCs were transplanted through two routes, intravenous (IV) or intramuscular (IM), in single or two repeat doses. Two weeks after transplantation, a significant improvement in hyperalgesia, grip-strength, motor coordination and nerve conduction velocity was observed in comparison with controls. A rapid improvement in neuropathic symptoms was observed for a single dose of DPSC IV; however, repeat dose of DPSC IV did not bring about added improvement. A single dose of DPSC IM showed steady improvement, and further recovery continued upon repeat IM administration. DPSC single dose IV showed greater improvement than DPSC single dose IM, but IM transplantation brought about better improvement in body weight. A marked reduction in tumor necrosis factor (TNF) α and C-reactive protein (CRP) levels was observed in the blood plasma for all treated groups, as compared with controls. With respect to inflammatory cytokines, repeat dose of DPSC IM showed further improvement, suggesting that a repeat dose is required to maintain the improved inflammatory state. Gene expression of inflammatory markers in liver confirmed amelioration in inflammation. Arachidonic acid level was unaffected by IV DPSC transplantation but showed noticeable increase through IM administration of a repeat dose. These results suggest that DPSC transplantation through both routes and dosage was beneficial for the retrieval of neuropathic parameters of DN; transplantation via the IM route with repeat dose was the most effective., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background Aims: Mesenchymal stromal cells (MSC) derived from Wharton's jelly (WJ) of the umbilical cord are increasingly gaining prominence as substitutes for bone marrow (BM) MSC. While MSC isolated from different tissue sources may share common mesenchymal properties, the difference in their plasticity to individual lineages is ill-defined. Thus the focus of this study was to estimate the neuronal plasticity of WJ MSC to the dopaminergic (DA) cell type in comparison with BM MSC., Methods: For neuronal differentiation, MSC were exposed to developmentally relevant cues for midbrain DA neurons: sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8), along with basic fibroblast growth factor (bFGF)., Results: Naive MSC from both sources constitutively expressed neuronal markers. Flow cytometry data revealed that the control WJ MSC shared a signature similar to BM MSC for early neuronal markers (nestin, musashi12 and A2B5) and DA-specific markers [tyrosine hydroxylase (TH) and Nuclear Receptor related protein 1 (Nurr1) but differed for mature neuronal proteins [β-tubulin III and microtubule-associated protein 2 (Map2ab)]. Similar populations of cells in both sources of MSC were positive for the SHH receptors [patched (PTCH) and smoothened (SMO)]. In induced BM and WJ MSC, real-time reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis showed similar levels of DA-related transcription factors Nurr1 and Engrailed (En) 1. Immunocytochemical and flow cytometry analysis showed an increase in mature neuronal marker Map2ab. Kv4.2, a K(+) channel marker, was observed only in the induced MSC. Induced MSC also expressed several DA-specific markers, TH, dopamine and cyclic AMP regulated phosphoprotein (DARPP) 32, paired-like homeodomain transcription factor (PitX) 3 and vesicular monoamine transporter (VMAT) 2, in comparable levels between the two sources. The efficiency (c. 65%) of transdifferentiation of WJ MSC to TH-positive cells was similar to that of induced BM MSC. Constitutive and inducible release of dopamine was found to be similar between induced BM and WJ MSC, as measured by dopamine enzyme-linked immunosorbent assay (ELISA). Interestingly, an adenosine triphosphate (ATP)-stimulated change in intracellular Ca(2+) was observed in both control and induced MSC, but only the induced MSC was capable of releasing dopamine., Conclusions: Our data demonstrate that MSC from the two different sources respond similarly to inductive cues to differentiate terminally to a DA cell type, and the neuronal plasticity of human WJ MSC is comparable with that of BM MSC.