ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 P241 | DOI: 10.1530/endoabs.65.P241

Investigating the role of microRNA-7 in pancreatic islet development

Eva Kane1,2, Tracy C S Mak1,2 & Mathieu Latreille1,2

1MRC London Institute of Medical Sciences (LMS), London, UK; 2Imperial College London, London, UK

Cadaveric islet transplantation can cure diabetes, however scarcity of donor islets means that this approach cannot be used for large-scale treatment. An alternative source of insulin-producing β-cells or whole islets would be step-wise in vitro differentiation from either human embryonic stem cells or induced pluripotent stem cells, which could be transplanted directly into patients. However, ‘β-like’ cells generated from existing differentiation protocols are produced at very low efficiency and lack numerous markers of functional maturity, indicating that our current understanding of in vivo β-cell specification is incomplete. Mice with genetic inactivation of Dicer1, a key component of the microRNA (miRNA) biogenesis pathway, show decreased β-cell mass indicating that miRNAs play a crucial role in the differentiation of pancreatic endocrine progenitors during development. miR-7 is highly expressed in pancreatic endocrine cells of the embryo and in mature β-cells of adult mice, suggesting it may be a key factor in driving β-cell specification. Here, we delete the miR-7 gene family in mouse endocrine progenitors using a neurogenin3 (Ngn3)-Cre transgene (NKO). miR-7 will be deleted at the initiation of endocrine specification, at which time Ngn3LOW cells are still capable of acquiring a pancreatic ductal fate. We find that adult NKO mice are hyperglycemic and show reduced α- and β-cell mass. Lineage tracing experiments demonstrated that Ngn3+ progenitors of NKO mice do not leave the epithelial plexus and instead contribute to the developing ductal network. Our results suggest that the miR-7 gene family is a key regulator of cell fate decisions in the pancreas by promoting endocrine differentiation of Ngn3LOW bipotent pancreatic progenitors toward α- or β-cell fates as opposed to a ductal fate. We believe that modulation of miR-7 expression in in vitro differentiation protocols may thus be used to increase the efficiency and maturity of β-like cells.

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