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

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 delin-eate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships be-tween transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-j3 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 j3 cell maturation and identify sex hormones as drivers of j3 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.

Automated summary

By analyzing the single-cell transcriptomes and accessible chromatin profiles, we compared the differentiation process of pancreatic islet cells derived from human pluripotent stem cells with those from childhood and adult donors. We identified major cell types, defined their regulomes, and described the spatiotemporal gene regulatory relationships between transcription factors. Our study revealed CDX2 as a regulator of enterochromaffin-like cells and provided evidence against the proposed non-pancreatic origin. Additionally, we observed insufficient activation of signal-dependent transcriptional programs during in vitro beta cell maturation and identified sex hormones as drivers of beta cell proliferation in childhood.