Single-Cell Multi-Omic Roadmap of Human Fetal Pancreatic Development

de la O, S.; Liu, Z.; Sun, H.; Yu, S. K.; Wong, D. M.; Chu, E.; Rao, S. A.; Eng, N.; Peixoto, G.; Bouza, J.; Shen, Y.; Knox, S. M.; Tward, A. D.; Gloyn, A. L.; Sneddon, J. B.

doi:10.1101/2022.02.17.480942

bioRxiv · 10.1101/2022.02.17.480942

Single-Cell Multi-Omic Roadmap of Human Fetal Pancreatic Development

de la O, S.·Liu, Z.·Sun, H.·Yu, S. K.·Wong, D. M.·Chu, E.·Rao, S. A.·Eng, N.·Peixoto, G.·Bouza, J.·Shen, Y.·Knox, S. M.·Tward, A. D.·Gloyn, A. L.·Sneddon, J. B.

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Abstract

The critical cellular transitions that govern human pancreas development are largely unknown. We performed large-scale single-cell RNA-sequencing (scRNA-Seq) to interrogate human fetal pancreas development from 8-20 weeks post conception. We identified 103 distinct cell types, including four novel endocrine progenitor subtypes displaying unique transcriptional features and differentiation potency. Integration with single-nucleus Assay for Transposase Accessible Chromatin Sequencing (snATAC-Seq) identified candidate regulators of human endocrine cell fate and revealed development-specific regulatory annotation at diabetes risk loci. Comparison of in vitro stem cell-derived and endogenous endocrine cells predicted aberrant genetic programs leading to the generation of off-target cells. Finally, knock-out studies revealed that the gene FEV regulates human endocrine differentiation. This work establishes a roadmap of human pancreatic development, highlights previously unappreciated cellular diversity and lineage dynamics, and provides a blueprint for understanding pancreatic disease and physiology, as well as generating human stem cell-derived islet cells in vitro for regenerative medicine purposes.

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de la O, S., Liu, Z., Sun, H., Yu, S. K., Wong, D. M., Chu, E., Rao, S. A., Eng, N., Peixoto, G., Bouza, J., Shen, Y., Knox, S. M., Tward, A. D., Gloyn, A. L., Sneddon, J. B.. 2022-02-18. Single-Cell Multi-Omic Roadmap of Human Fetal Pancreatic Development. https://doi.org/10.1101/2022.02.17.480942

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