Induction of Insulin-Producing Cells Derived from Endometrial Mesenchymal Stem-like Cells

Abstract

Studies have demonstrated that mesenchymal stem-like cells can be isolated from endometrium. However, the potential of endometrial-derived stem cells to differentiate into insulin-positive cells and functionally secrete insulin remains undetermined. We isolated endometrial mesenchymal stem-like cells (EMSCs) from human endometrial tissue from six donors. The insulin-secreting function of EMSCs was further analyzed in vitro and in transplanted grafts in vivo. We successfully isolated EMSCs from human endometrium, and our results showed that EMSCs expressed high levels of stemness genes (Nanog, Oct-4, Nestin). Under specific induction conditions for 2 weeks, EMSCs formed three-dimensional spheroid bodies (SBs) and secreted C-peptide. The high insulin content of SB-EMSCs was confirmed by enzymelinked immunosorbent assay, and glucose responsiveness was demonstrated by measuring glucose-dependent insulin secretion. Using cDNA microarrays, we found that the expression profiles of SB-EMSCs are related to those of islet tissues. Insulin and Cpeptide production in response to glucose was significantly higher in SB-EMSCs than in undifferentiated EMSC controls. Furthermore, upon differentiation, SB-EMSCs displayed increased mRNA expression levels of NKx2.2, Glut2, insulin, glucagon, and somatostatin. Our results also showed that SB-EMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than fibroblasts from the same patient. It is noteworthy that SB-EMSCs xenotransplanted into immunocompromised mice with streptozotocin-induced diabetes restored blood insulin levels to control values and greatly prolonged the survival of graft cells. These data suggest that EMSCs not only play a novel role in the differentiation of pancreatic progenitors, but also can functionally enhance insulin production to restore the regulation of blood glucose levels in an in vivo transplantation model.

Mesenchymal-to-Epithelial Transition Contributes to Endometrial Regeneration Following Natural and Artificial Decidualization

“…Likewise, endometrial stem cells can be pushed down a pathway toward insulin production in culture and transplantation experiments using the modified insulin producing cells continued to produce insulin in vivo and regulated blood glucose levels in diabetic mice [38]. In similar studies, Li et al [39] and Hida et al [40] reported transdifferentiation of human endometrial mesenchymal stem-like cells into insulin-producing cells and human menstrual blood-derived mesenchymal cells into cardiac precursor-like cells, respectively, which, when xenotransplanted into diseased mouse models, helped restore tissue function. These results along with our own demonstrate the plasticity of endometrial mesenchymal cells, as well as their potential use in regenerative medicine.…”

Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells

“…MenSCs transferred dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo Toyoda et al, 2007). Furthermore, stem cells isolated from endometrium have been proven to be an excellent cell source for treating experimental disease models, such as critical limb ischemia, stroke, type I diabetes mellitus, Parkinson's disease, and other neurodegenerative disorders (Murphy et al, 2008;Borlongan et al, 2010;Li H.Y. et al, 2010;Sanberg et al, 2011;Santamaria et al, 2011).…”

Menstrual Stem cells

“…In vitro and in vivo assessments of transplanting menstrual blood-derived stem cells reveal their effi cacy and safety in stroke. They are a potential cell source for treating other CNS disorders [13]. Use in diabetes to prolong graft tissue survival is being considered [14].…”