miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells

Chunyu Bai; Qiwei Ren; Haifeng Liu; Xiangchen Li; Weijun Guan; Yuhua Gao

doi:10.3389/fcell.2021.673231

miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells

Front Cell Dev Biol. 2021 May 13:9:673231. doi: 10.3389/fcell.2021.673231. eCollection 2021.

Authors

Chunyu Bai^{1

2}, Qiwei Ren³, Haifeng Liu⁴, Xiangchen Li⁵, Weijun Guan², Yuhua Gao^{1

2}

Affiliations

¹ Institute of Precision Medicine, Jining Medical University, Jining, China.
² Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing China.
³ College of Basic Medicine, Jining Medical University, Jining, China.
⁴ Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining, China.
⁵ College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A&F University, Lin'an, China.

Abstract

Pancreatic beta cell transplantation is the ideal method for treatment of type 1 diabetes mellitus (T1DM), and the generation of beta cells from induced pluripotent stem cells (iPSCs) of patients is a promising strategy. In this study, we improved a previous strategy to produce beta cells using extracellular vesicles (EVs) derived from mature beta cells and differentiated beta cells from iPSCs (i-Beta cells), which secreted insulin under glucose stimulation in vitro and ameliorated hyperglycemia in vivo. Mechanistic analyses revealed that EV-carried microRNA (miR)-212/132 (EV-miR-212/132) directly bound to the 3' UTR of FBW7 to prevent its translation and FBW7 combined with NGN3 to accelerate its proteasomal degradation. EV-miR-212/132 stabilized NGN3 expression to promote differentiation of endocrine cells from induced iPSCs. Moreover, NGN3 bound to PDX1 to enhance transcription of endogenous miR-212/132 and formed a positive regulatory circuit that maintained the functions of mature pancreatic beta cells.

Conclusion: This study describes a novel approach for beta cell production and supports the use of iPSCs for cell replacement therapy of T1DM.

Keywords: beta cells; differentiation; extracellular vesicles; iPSCs; miRNAs.