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

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Public Summary:
This paper presents an in-depth analysis of how pancreatic islets, derived from stem cells, develop at the genetic level. Using single-cell multiome techniques, the researchers examined the gene regulation processes during islet differentiation. They discovered a novel cell type in the fetal pancreas and identified weaknesses in the maturation of artificial β cells. The study also suggests that sex hormones influence β cell proliferation in childhood. These insights provide a detailed understanding of the genetic mechanisms in stem-cell-derived pancreatic islets, offering new avenues for diabetes research and treatment.
Scientific 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-beta 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 beta cell maturation and identify sex hormones as drivers of beta 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.