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 

机构地区：[1]Epigenetics in Human Health and Disease Program,Baker Heart and Diabetes Institute,75 Commercial Road,Melbourne 3004 VIC,Australia [2]Department of Diabetes,Central Clinical School,Monash University,Melbourne 3004 VIC,Australia [3]Epigenetics in Human Health and Disease Laboratory,Central Clinical School,Monash University,Melbourne 3004 VIC,Australia [4]School of Science,STEM College,RMIT University,Melbourne 3001 VIC,Australia [5]Immunology and Diabetes Unit,St Vincent’s Institute of Medical Research,Fitzroy 3065 VIC,Australia [6]Department of Medicine and Therapeutics,The Chinese University of Hong Kong,Sha Tin,Hong Kong SAR [7]Hong Kong Institute of Diabetes and Obesity,Prince of Wales Hospital,The Chinese University of Hong Kong,3/F Lui Che Woo Clinical Sciences Building,30-32-Ngan Shing Street,Sha Tin,Hong Kong SAR [8]Li Ka Shing Institute of Health Sciences,The Chinese University of Hong Kong,Sha Tin,Hong Kong SAR [9]Biomedical Laboratory Science,Department of Technology,Faculty of Health,University College Copenhagen,Copenhagen,Denmark

出　　处：《Signal Transduction and Targeted Therapy》2024年第2期679-692,共14页信号转导与靶向治疗（英文）

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.

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.

关 键 词：EZH2 struction INHIBITORS 

分 类 号：R587.1[医药卫生—内分泌]