TY - JOUR
T1 - EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors
AU - Al-Hasani, Keith
AU - Marikar, Safiya Naina
AU - Kaipananickal, Harikrishnan
AU - Maxwell, Scott
AU - Okabe, Jun
AU - Khurana, Ishant
AU - Karagiannis, Thomas
AU - Liang, Julia J.
AU - Mariana, Lina
AU - Loudovaris, Thomas
AU - Kay, Thomas
AU - El-Osta, Assam
N1 - Funding Information:
A.E.O. is a National Health and Medical Research Council (NHMRC) Senior Research Fellow (grant 1154650) and acknowledges grant support from NHMRC Clinical Trials and Cohort Studies (grant 2014763). This study was supported by a strategic research agreement by JDRF International grant (2-SRA-2024-1442-S-B) and a research grant from the Danish Diabetes Academy to A.E.O., which is funded by the Novo Nordisk Foundation, grant NNF17SA0031406. We also thank Dr H.E. Thomas for expert guidance and support. The authors would like to acknowledge the donor’s consent for translational research.
Publisher Copyright:
© 2023, The Author(s).
PY - 2024/1/1
Y1 - 2024/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85180864456&partnerID=8YFLogxK
U2 - 10.1038/s41392-023-01707-x
DO - 10.1038/s41392-023-01707-x
M3 - Article
C2 - 38161208
AN - SCOPUS:85180864456
SN - 2095-9907
VL - 9
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
IS - 1
M1 - 2
ER -