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

Abstract

Summary: Differentiation 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. : In this article, Blelloch, Hebrok, and colleagues show that in vitro hESC-derived islet β cells express elevated LIN28 and reduced let-7 levels relative to their in vivo matured counterparts. Reduction of LIN28, but not increase in let-7, promotes suppression of a juvenile-specific β cell transcriptional program, implicating LIN28 as a barrier to β cell maturation in vitro. Keywords: hESC-derived human pancreatic beta cells, LIN28, let-7, microRNAs, beta cell maturation