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

作     者：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 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

作者机构：Epigenetics in Human Health and Disease ProgramBaker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of DiabetesCentral Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease LaboratoryCentral Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of ScienceSTEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes UnitSt Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and TherapeuticsThe Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and ObesityPrince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory ScienceDepartment of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2024年第9卷第2期

页      面：679-692页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 10[医学] 

基　　金：National Health and Medical Research Council(NHMRC)Senior Research Fellow(grant 1154650) acknowledges grant support from NHMRC Clinical Trials and Cohort Studies(grant 2014763) supported by a strategic research agreement by JDRF International grant(2-SRA-2024-1442-S-B) a research grant from the Danish Diabetes Academy to A.E.O.,which is funded by the Novo Nordisk Foundation,grant NNF17SA0031406. 

主　　题：EZH2 struction inhibitors 

摘      要：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-producingβ-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 stimulateβ-cell growth and induceβ-cell function.We and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-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 FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell identity.The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification.Targeting EZH2 is fundamental toβ-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 ofβ-like cell function.