Local renin-angiotensin system regulates the differentiation of mesenchymal stem cells into insulin-producing cells through angiotensin type 2 receptor

Abstract

Differentiation of stem cells into insulin-producing cells (IPCs) suitable for therapeutic transplantation offers a desperately needed approach for the diabetic patients. Elucidation of the molecular mechanisms during the differentiation of mesenchymal stem cells (MSCs) into IPCs assists the successful production of IPCs and provides an important insight into the improvement of the role of MSCs as a therapeutic tool for diabetes mellitus (DM). The present study aimed to investigate the role of local renin-angiotensin system (RAS) on MSCs differentiation into IPCs by measuring the expression of local RAS in MSCs during the differentiation into IPCs and assessing the effect of angiotensin type 1 receptor (AT₁R) blocker and angiotensin type 2 receptor (AT₂R) blocker on the differentiation process. Our data showed that the differentiation of MSCs into IPCs was associated with an increase in cellular angiotensinogen, angiotensin-converting enzyme (ACE), renin, and AT₂R expression and undetectable expression of AT₁R. The net effect was an increase in cellular angiotensin II (Ang II) during the differentiation process. AT₁R blockade allowed the differentiation of MSCs into IPCs, whereas AT₂R blockade alone and blockade of both AT₁R and AT₂R inhibited the differentiation of MSCs into IPCs. Our data demonstrated an important role of local RAS in the regulation of MSCs differentiation into IPCs and that Ang II mainly orchestrates this role through AT₂R activation.

Keywords: Angiotensin type 1 receptor; Angiotensin type 2 receptor; Insulin-producing cells; Mesenchymal stem cells; Renin-angiotensin system.