LIN28B Impairs the Transition of hESC-Derived β Cells from the Juvenile to Adult State.

Xin Zhou,Mayya Shveygert,Matthias Hebrok,Holger A Russ,Cassandra D Belair,Gopika G Nair,Robert Blelloch,Mei-Lan Li

doi:10.1016/j.stemcr.2019.11.009

Xin Zhou, Mayya Shveygert + Show 6 more

Open Access

https://doi.org/10.1016/j.stemcr.2019.11.009

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Abstract

SummaryDifferentiation of human embryonic stem cells into pancreatic β cells holds great promise for the treatment of diabetes. Recent advances have led to the production of glucose-responsive insulin-secreting cells in vitro, but resulting cells remain less mature than their adult primary β cell counterparts. The barrier(s) to in vitro β cell maturation are unclear. Here, we evaluated a potential role for microRNAs. MicroRNA profiling showed high expression of let-7 family microRNAs in vivo, but not in in vitro differentiated β cells. Reduced levels of let-7 in vitro were associated with increased levels of the RNA binding protein LIN28B, a negative regulator of let-7 biogenesis. Ablation of LIN28B during human embryonic stem cell (hESC) differentiation toward β cells led to a more mature glucose-stimulated insulin secretion profile and the suppression of juvenile-specific genes. However, let-7 overexpression had little effect. These results uncover LIN28B as a modulator of β cell maturation in vitro.

Highlights

A growing number of people are suffering from diabetes worldwide (Roglic and World Health Organization, 2016)
Transplantation of cadaveric islet cells provides an alternative option resulting in effective glycemic control, but these cells are in limited supply making it unfeasible for broad implementation (Sneddon et al, 2018). b cells produced by the differentiation of pluripotent stem cells, both human embryonic stem cells and induced pluripotent stem cells hold great promise in filling this gap
Let-7 Expression Increases with b Cell Maturation To determine a potential role for miRNAs in the maturation of pancreatic b cells, we performed small RNA sequencing (RNA-seq) of in vitro stem cell-derived, in vivo matured, and human cadaveric islet cells

Summary

Introduction

A growing number of people are suffering from diabetes worldwide (Roglic and World Health Organization, 2016). Type 1 diabetic (T1D) and end-stage type 2 diabetic (T2D) patients rely on exogenous injection of insulin to control blood glucose. While life sustaining, this therapy is arduous and prone to complications as it is virtually impossible to mimic the dynamic changes in insulin production and secretion performed by endogenous b cells. There remain differences between in vitro produced cells and endogenous adult b cells in their gene expression profile and secretory capacity. It is important both conceptually and practically to understand the barriers to in vitro differentiation toward mature adult b cells. Since euglycemia can be restored in diabetic mice by transplantation of stem cell-derived pancreatic progenitors or b cell populations, it is speculated that the in vivo environment supports further maturation of generated b cells, the changes that occur in b cells upon transplantation have not been elucidated

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