Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification

Author:

Augsornworawat PunnORCID,Hogrebe Nathaniel J.ORCID,Ishahak MatthewORCID,Schmidt Mason D.ORCID,Marquez Erica,Maestas Marlie M.,Veronese-Paniagua Daniel A.,Gale Sarah E.,Miller Julia R.,Velazco-Cruz Leonardo,Millman Jeffrey R.ORCID

Abstract

AbstractInsulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.

Funder

JDRF

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Rita Levi-Montalcini Postdoctoral Fellowship in Regenerative Medicine

NSF | BIO | Division of Molecular and Cellular Biosciences

Washington University BioSURF award

WUSTL | Washington University School of Medicine in St. Louis

Children’s Discovery Institute

U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute

U.S. Department of Health & Human Services | NIH | National Center for Research Resources

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology

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