Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes

Zengrong Zhu, Qing V. Li, Kihyun Lee, Bess P. Rosen, Federico González, Chew Li Soh, Danwei Huangfu

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

Summary Directed differentiation of human pluripotent stem cells (hPSCs) into somatic counterparts is a valuable tool for studying disease. However, examination of developmental mechanisms in hPSCs remains challenging given complex multi-factorial actions at different stages. Here, we used TALEN and CRISPR/Cas-mediated gene editing and hPSC-directed differentiation for a systematic analysis of the roles of eight pancreatic transcription factors (PDX1, RFX6, PTF1A, GLIS3, MNX1, NGN3, HES1, and ARX). Our analysis not only verified conserved gene requirements between mice and humans but also revealed a number of previously unsuspected developmental mechanisms with implications for type 2 diabetes. These include a role of RFX6 in regulating the number of pancreatic progenitors, a haploinsufficient requirement for PDX1 in pancreatic β cell differentiation, and a potentially divergent role of NGN3 in humans and mice. Our findings support use of systematic genome editing in hPSCs as a strategy for understanding mechanisms underlying congenital disorders.

Original languageEnglish
Pages (from-to)755-768
Number of pages14
JournalCell Stem Cell
Volume18
Issue number6
DOIs
StatePublished - 2 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Fingerprint

Dive into the research topics of 'Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes'. Together they form a unique fingerprint.

Cite this