MiR-410 enhanced hESC-derived pancreatic endoderm transplant to alleviate gestational diabetes mellitus

Abstract

Gestational diabetes mellitus (GDM) is a condition commonly encountered during mid to late pregnancy with pathologic manifestations including hyperglycemia, hyperinsulinemia, insulin resistance, and fetal mal-development. The deficit and dysfunction of insulin secreting b-cells are signature symptoms for GDM. Pancreatic progenitors derived from human embryonic stem cells (hESCs) were shown to be able to effectively treat diabetes in mice. In this study, we first identified that microRNA-410 (miR-410) directly targets lactate dehydrogenase A (LDHA), a gene selectively repressed in normal insulin secreting b-cells. hESCs that can be induced to express miR-410 hence keeping LDHA levels in check were then differentiated in vitro into pancreatic endoderm, followed by transplantation into dbl+ mouse model of GDM. The transplant greatly improved glucose metabolism and reproductive outcome of the pregnant females suffering from GDM. Our findings describe for the first time the method of combining miRNA with hESCs, providing proof of concept by employing genetically modified stem cell therapy for treating GDM.