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EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

Authors :
Keith Al-Hasani
Safiya Naina Marikar
Harikrishnan Kaipananickal
Scott Maxwell
Jun Okabe
Ishant Khurana
Thomas Karagiannis
Julia J. Liang
Lina Mariana
Thomas Loudovaris
Thomas Kay
Assam El-Osta
Source :
Signal Transduction and Targeted Therapy, Vol 9, Iss 1, Pp 1-14 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

Abstract β-cells are a type of endocrine cell found in pancreatic islets that synthesize, store and release insulin. In type 1 diabetes (T1D), T-cells of the immune system selectively destroy the insulin-producing β-cells. Destruction of these cells leads to a lifelong dependence on exogenous insulin administration for survival. Consequently, there is an urgent need to identify novel therapies that stimulate β-cell growth and induce β-cell function. We and others have shown that pancreatic ductal progenitor cells are a promising source for regenerating β-cells for T1D owing to their inherent differentiation capacity. Default transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 methyltransferase. In the present study, we show that transient stimulation of exocrine cells, derived from juvenile and adult T1D donors to the FDA-approved EZH2 inhibitors GSK126 and Tazemetostat (Taz) influence a phenotypic shift towards a β-like cell identity. The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification. Targeting EZH2 is fundamental to β-cell regenerative potential. Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo. These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration of β-like cell function.

Details

Language :
English
ISSN :
20593635
Volume :
9
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Signal Transduction and Targeted Therapy
Publication Type :
Academic Journal
Accession number :
edsdoj.14c0d5910f4469ba3b5e5607fe3fe80
Document Type :
article
Full Text :
https://doi.org/10.1038/s41392-023-01707-x