Pancreatic endocrine‐like cells differentiated from human umbilical cords Wharton’s jelly mesenchymal stem cells using small molecules

Abstract

Following success of pancreatic islet transplantation in the treatment of Type I diabetes mellitus, there is a growing interest in using cell-based treatment approaches. However, severe shortage of donor islets-pancreas impeded the growth, and made researchers to search for an alternative treatment approaches. In this context, recently, stem cell-based therapy has gained more attention. The current study demonstrated that epigenetic modification improves the in vitro differentiation of Wharton's jelly mesenchymal stem cells (WJMSCs) into pancreatic endocrine-like cells. Here we used two histone deacetylase (HDAC) inhibitors namely trichostatin A (TSA) and TMP269. TSA inhibits both class I and II HDACs whereas TMP269 inhibits only class IIa HDACs. WJMSCs were differentiated using a multistep protocol in a serum-free condition with or without TSA pretreatment. A marginal improvement in differentiation was observed after TSA pretreatment though it was not significant. However, exposing endocrine precursor-like cells derived from WJMSCs to TMP269 alone has significantly improved the differentiation toward insulin-producing cells. Further, increase in the expression of paired box 4 (PAX4), insulin, somatostatin, glucose transporter 2 (GLUT2), MAF bZIP transcription factor A (MAFA), pancreatic duodenal homeobox 1 (PDX-1), and NKX6.1 was observed both at messenger RNA and protein levels. Nevertheless, TMP269-treated cells secreted higher insulin upon glucose challenge, and demonstrated increased dithizone staining. These findings suggest that TMP269 may improve the in vitro differentiation of WJMSCs into insulin-producing cells.

In vitro differentiation of single donor derived human dental mesenchymal stem cells into pancreatic β cell-like cells

“…Upon pancreatic differentiation of MSCs, both control and differentiated cells were analyzed for their ability to secrete insulin upon glucose challenge following previous protocol with minor modifications [28,29]. In brief, cells were washed thrice with Krebs (Krb) buffer and were then preincubated in low glucose (2 mM) Krb for 2 h in order to remove the residual insulin.…”

Mesenchymal Stem Cells: An Excellent Candidate for the Treatment of Diabetes Mellitus

“…Previous study showed that the use of viral vectors to introduce exogenous genetic material into cells carries the risk of tumorigenesis [ 55 ]. As for chemically induced differentiation, some small molecular compounds commonly used to induce stem cells to differentiate into IPCs, such as TSA, can increase the apoptosis rate of cells [ 56 ]. Therefore, it is important to improve the existing induction methods and find new induction methods to obtain effective and safe IPCs.…”

Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

“…Additionally, pluripotent cells have teratoma-related ethical issues, while MSCs have no risk of teratoma formation and have unique immune-modulation 1). Additionally, factors like sodium butyrate, TSA, TMP269, RG, Par, and NECA amplify the definitive endodermal differentiation of stem cells (ESCs, iPSCs, and MSCs) [40][41][42]. Along with their cost effective use and ease of delivery and to removal, they also minimize the risk of contamination.…”