Depolymerizing F-actin accelerates the exit from pluripotency to enhance stem cell-derived islet differentiation.

Autor:	Hogrebe NJ; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue St. Louis, MO 63110 USA., Schmidt MD; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue St. Louis, MO 63110 USA., Augsornworawat P; Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand., Gale SE; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue St. Louis, MO 63110 USA., Shunkarova M; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue St. Louis, MO 63110 USA., Millman JR; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue St. Louis, MO 63110 USA.; Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 21. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1101/2024.10.21.618465
Abstrakt:	Improving generation of insulin-producing islets from human pluripotent stem cells (hPSCs) would enhance their clinical relevance for treating diabetes. Here, we demonstrate that cytoskeletal state at the onset of differentiation is critical for definitive endoderm formation. Depolymerizing F-actin with latrunculin A (latA) during the first 24 hours of differentiation facilitates rapid exit from pluripotency and alters Activin/Nodal, BMP, JNK-JUN, and WNT pathway signaling dynamics during definitive endoderm formation. These signaling changes influence downstream patterning of the gut tube, leading to improved pancreatic progenitor identity and decreased expression of markers for other endodermal lineages. Continued differentiation generates islets containing a higher percentage of β cells that exhibit improved maturation, insulin secretion, and ability to reverse hyperglycemia. Furthermore, this latA treatment reduces enterochromaffin cells in the final cell population and corrects differentiations from hPSC lines that otherwise fail to consistently produce pancreatic islets, highlighting the importance of cytoskeletal signaling during differentiation onset. Competing Interests: Competing Interests. N.J.H., P.A., and J.R.M. are inventors on patents and patent applications related to SC-islets. J.R.M. was employed at and has stock at Sana Biotechnology. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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