Journal
CELL DEATH & DISEASE
Volume 11, Issue 6, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-2668-9
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Funding
- National Natural Science Foundation of China [81700683, 81670702, 31900619]
- Natural Science Foundation of Guangdong Province [2017A030310646]
- Science and Technology Project of Shenzhen [JCYJ20180228164515747, SZSM201612037, JCYJ20190807153413130]
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Generating insulin-producing cells (IPCs) from human pluripotent stem cells is a promising method for studying the molecular mechanism underlying pancreas development and a potential treatment source for type 1 diabetes. Previous studies have shown that miR-181c-5p is highly enriched in adult islets; however, its role in pancreatic beta cell differentiation is poorly understood. In this study, we differentiated human induced pluripotent stem cells (hiPSCs) into IPCs in a stepwise process that recapitulated pancreas organogenesis and observed that miR-181c-5p continuously accumulated throughout the entire differentiation process. hiPSCs were transduced with lentiviral vectors containing human miR-181c-5p precursor, which significantly increased the endodermal markers SOX17, FOXA2, CXCR4 and GATA4 and pancreatic endocrine-specific gene expression, including PDX1, NKX6.1, MAFA and Insulin. miR-181c-5p overexpression exerted little effect on the efficiency of definitive endoderm, whereas it promoted the differentiation of pancreatic progenitors and IPCs, especially for NKX6.1-positive and insulin-positive cells differentiation. Transplanted these cells exhibit glucose-stimulated C-peptide secretion in vivo and protect mice from chemically induced diabetes. It was found that miR-181c-5p directly targets the 3 ' UTR of smad7 and TGIF2 mRNA, which are known to be endogenous repressors of TGF-beta-smad2/3 signaling, to decrease their mRNA and protein levels. Furthermore, overexpressed miR-181c-5p led to an elevation of the smad2/3 phosphorylation levels in hiPSC-derived cells, while treatment with smad2/3 inhibitors following miR-181c-5p overexpression had opposite effects on IPC formation. These results suggest that miR-181c-5p is critically involved in pancreatic lineage commitment through direct repression of smad7 and TGIF2 and that it modulates TGF-beta-smad2/3 signaling activation and increases the feasibility of using patient-specific hiPSCs for beta cell replacement therapy for type 1 diabetes.
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