Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

Abstract

A B S T R A C TBackground: A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is b cell dysfunction.Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore b cell function is of utmost importance.Methods: This study aims to unveil the mechanistic action of mesenchymal stem cells (MSCs) by investigating its impact on isolated human T2DM islets ex vivo and in vivo.Findings: We propose that MSCs can attenuate b cell dysfunction by reversing b cell dedifferentiation in an IL-1Ra-mediated manner. In response to the elevated expression of proinflammatory cytokines in human T2DM islet cells, we observed that MSCs was activated to secret IL-1R antagonist (IL-1Ra) which acted on the inflammed islets and reversed b cell dedifferentiation, suggesting a crosstalk between MSCs and human T2DM islets. The co-transplantation of MSCs with human T2DM islets in diabetic SCID mice and intravenous infusion of MSCs in db/db mice revealed the reversal of b cell dedifferentiation and improved glycaemic control in the latter. Interpretation: This evidence highlights the potential of MSCs in future cell-based therapies regarding the amelioration of b cell dysfunction.

Systemic administration of human umbilical cord‑derived mesenchymal stem cells effectively ameliorates the outcomes of a critically ill elderly patient with COVID‑19 with multiple comorbidities: A case report

“…For decades, the authors of the present study, as well as others, have reported the clinical and preclinical applicability of MSCs in refractory and recurrent diseases, such as Crohn's disease, aplastic anemia, acute myocardial infarction, GVHD and even H5N1-infected pneumonia which cause acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which are similar to the symptoms of SARS-CoV-2 infection (20,24,25,42,43,45). Very recently, Leng et al and Wang et al reported the clinical remission of a 65-year-old female critically ill patient with COVID-19 with hUC-MSC transplantation for 3 times as well, whereas the lung damage was relatively mild, which was confirmed by another studies (14,32). However, the safety and effectiveness assessment on elderly patients critically ill with COVID-19 with severe pneumonia-induced ARDS and MODS-associated multiple comorbidities remains largely unknown.…”

“…In general,SARS-CoV-2 belongs to the genus and exhibits great phylogenetic similarity to the coronavirus from bats, which is distinguished from the 2003 SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV) at the molecular level (7,8,32,(34)(35)(36)(37). Despite the early outbreak of COVID-19 in Wuhan of China, yet increasingly evidences were inclined to dismiss the possibility from the classification of SARS-CoV-2 (33,34,37,38).…”

“…For decades, low-immunogenic MSCs have been shown to be safe and preferable for use in the management of recurrent and refractory diseases, such as spinal injury, type 2 diabetes, graft-vs.-host disease (GVHD), autoimmune diseases and hematological malignancies, as well as for severe influenza H5N1 caused by acute respiratory distress syndrome (ARDS) (20,24,(29)(30)(31). Recently, Leng et al and Wang et al reported the exploration of adult tissue-derived MSCs upon 7 mild and severe patients and revealed a favorable prognosis (14,32). According to the ClinicalTrials.gov of NIH, a total number of 10 clinical trials focusing on MSC-based COVID-19 treatment from China, France, Brazil and Jordan (https://clinicaltrials.gov/ct2/results?cond=Covid19&term=me senchymal+stem+cells&cntry=&state=&city=&dist=) have been newly registered among the 1,074 clinical trials upon MSCs (https://clinicaltrials.gov/ct2/results?cond=&term=mes enchymal+stem+cells&cntry=&state=&city=&dist=), which indicate the expectations of clinicians upon MSC-based cytotherapy for ameliorating the outcomes of patients with COVID-19; however, the unequivocal clinical efficacy remains to be determined.…”

Adipose Tissue-Derived Stem Cells from Type 2 Diabetics Reveal Conservative Alterations in Multidimensional Characteristics

“…Total RNA extraction and cDNA synthesis were performed by utilizing the RNeasy Mini Kit (QIAGEN) and PrimeScript RT reagent Kit with gDNA Eraser (Takara) as we described ( 23 ). qRT-PCR was performed with SYBR Premix ExTaq II (Takara) and LightCycler96 System (Roche).…”

“…Similar phenomenon was also observed in ASCs derived from subcutaneous adipose tissue compared with ND-ASCs ( 3 , 22 ). With regard to DM, MSCs have been recognized as a pivotal microenvironmental ingredient for the secretion of multiple cytokines and inflammatory factors (e.g., VEGF , IL-6 , TNF- α ) and the transdifferentiation into insulin-secreting β cells in the pancreas as well ( 7 , 17 , 23 ). Studies on experimental type 1 diabetic mouse model showed that T1DM mice-derived BM-MSCs exhibited indistinguishable characteristics including cytomorphology, immunosuppressive and migration capabilities as the control mice but with abnormally elevated expression of mediators such as MIP-1 α / β , MCP-1/5 , CCL-2 , CCL-3 and IL-6 , which facilitated recruitment and accumulation of inflammatory M1 macrophages and aggravated the occurrence of diabetic complications ( 2 , 6 , 17 , 22 ).…”