Retinoic acid signaling is critical for generation of pancreatic progenitors from human embryonic stem cells

Abstract

Retinoic acid (RA) is essential for gut endoderm development and has been extensively used for in vitro pancreatic differentiation from human pluripotent stem cells. However, the gene regulatory network triggered by RA signaling remains poorly addressed. Also, whether RA signals control histone modifiers such as the Polycomb group proteins during pancreatic specification remains to be explored. Here, we assess the role of RA on pancreas-specific genes during the differentiation of human embryonic stem cells (hESCs). We demonstrate that RA helps cells exit the definitive endoderm stage and proceed toward a pancreatic fate. Inhibition of the RA pathway using the pharmacological inhibitor LE135 impairs the induction of pancreatic endoderm (PE) markers FOXA2, HNF4α, HNF1β, HHEX, and PDX1. We further determine that RA signals alter the expression of epigenetic-associated genes BMI1 and RING1B in the hESC-derived pancreatic progenitors. These findings broaden our understanding of the mechanisms that drive early PE specification.

Keywords:

• BMI1
• human embryonic stem cells
• pancreas development
• PDX1
• PRC1
• retinoic acid signaling

Acknowledgments

The authors would like to thank Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis International University for supporting P.P.

Author contributions

Conceptualization & funding acquisition: P.P. and A.K.; methodology, data analysis, and investigation: N.D.; supervision: P.P.; writing – original draft: N.D.; writing – review and editing: P.P. and N.D.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Science and Engineering Research Board, Department of Science and Technology (DST-SERB), Government of India [Grant number: ECR/2016/000510]; Sunandan Divatia School of Science, SVKM’s NMIMS (deemed-to be) University, Mumbai, India.