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

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Insulin-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.

Original languageEnglish
Pages (from-to)904-916
Number of pages13
JournalNature Cell Biology
Volume25
Issue number6
DOIs
StatePublished - Jun 2023

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