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Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Item Type:Article
Title:Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes
Creators Name:Zhu, H. and Wang, G. and Nguyen-Ngoc, K.V. and Kim, D. and Miller, M. and Goss, G. and Kovsky, J. and Harrington, A.R. and Saunders, D.C. and Hopkirk, A.L. and Melton, R. and Powers, A.C. and Preissl, S. and Spagnoli, F.M. and Gaulton, K.J. and Sander, M.
Abstract:Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.
Keywords:Human Pluripotent Stem Cells, Islets, ß Cell, Pancreas, CDX2, Serotonin, Development, Fetal Pancreas, Single-Cell Genomics, Gene Regulatory Network, Signals, Transcription Factors, ATAC-Seq, RNA-Seq
Source:Developmental Cell
Publisher:Cell Press
Page Range:727-743
Date:8 May 2023
Official Publication:https://doi.org/10.1016/j.devcel.2023.03.011
PubMed:View item in PubMed

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