Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors

Esra Karakose; Xuedi Wang; Peng Wang; Saul Carcamo; Deniz Demircioglu; Luca Lambertini; Olivia Wood; Randy Kang; Geming Lu; Donald K Scott; Adolfo Garcia-Ocaña; Carmen Argmann; Robert P Sebra; Dan Hasson; Andrew F Stewart

doi:10.1016/j.xcrm.2024.101832

Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors

Cell Rep Med. 2024 Nov 25:101832. doi: 10.1016/j.xcrm.2024.101832. Online ahead of print.

Authors

Affiliations

¹ Diabetes, Obesity, Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: esra.karakose@mssm.edu.
² Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Diabetes, Obesity, Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

PMID: 39626675
DOI: 10.1016/j.xcrm.2024.101832

Abstract

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.

Keywords: alpha cells; beta cells; diabetes; harmine; pancreatic islets; regeneration; transdifferentiation.