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.Destruc...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.展开更多
Type 1 diabetes(T1D)is an autoimmune disease that selectively destroys insulin-producingβ-cells in the pancreas.An unmet need in diabetes management,current therapy is focussed on transplantation.While the reprogramm...Type 1 diabetes(T1D)is an autoimmune disease that selectively destroys insulin-producingβ-cells in the pancreas.An unmet need in diabetes management,current therapy is focussed on transplantation.While the reprogramming of progenitor cells into functional insulin-producingβ-cells has also been proposed this remains controversial and poorly understood.The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation.After the death of a 13-year-old girl with established insulin-dependent T1D,pancreatic cells were harvested in an effort to restore and understand exocrine competence.The pancreas showed classic silencing ofβ-cell progenitor genes with barely detectable insulin(Ins)transcript.GSK126,a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of coreβ-cell markers and ductal progenitor genes.GSK126 also reinstated Ins gene expression despite absoluteβ-cell destruction.These studies show the refractory nature of chromatin characterises exocrine suppression influencingβ-cell plasticity.Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.展开更多
Dear Editor,Takotsubo syndrome(TS)is a stress-induced non-ischaemic cardiomyopathy that is more common in women,but is associated with higher morbidity and mortality in males.Also known as broken-heart syndrome,TS is ...Dear Editor,Takotsubo syndrome(TS)is a stress-induced non-ischaemic cardiomyopathy that is more common in women,but is associated with higher morbidity and mortality in males.Also known as broken-heart syndrome,TS is characterised by transient left ventricular(LV)dysfunction independent of obstructive coronary artery disease.TS is a polygenic condition and nowhere is this more evident than the use of positive inotropes,such as isoprenaline(ISO)in pre-clinical models.1 There is no standard therapy for broken-heart syndrome because the mechanisms underlying the condition remain unknown.Furthermore,there is no consensus on predisposition for Takotsubo2 and our goal was to better understand the regulatory mechanism as a first step towards improved treatment plans.Suberanilohydroxamic acid or SAHA,a drug approved for cancer treatment by the US Food and Drug Administration has previously been shown to improve cardiopulmonary function.3 We tested the hypothesis that the cardioprotective benefit of SAHA in a pre-clinical model of Takotsubo is conferred by an epigenetic acetylation/deacetylation(Ac/Dc)axis.展开更多
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)+1 种基金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.
文摘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.
基金A.E-O.is a National Health and Medical Research Council(NHMRC)Senior Research Fellow(1154650)acknowledges grant funding(2003401,1113188)+1 种基金M.E.C.acknowledges NHMRC(1175760)supported by an Innovation Grant from JDRF International(Grant#1-INO-2022-1123-A-N)。
文摘Type 1 diabetes(T1D)is an autoimmune disease that selectively destroys insulin-producingβ-cells in the pancreas.An unmet need in diabetes management,current therapy is focussed on transplantation.While the reprogramming of progenitor cells into functional insulin-producingβ-cells has also been proposed this remains controversial and poorly understood.The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation.After the death of a 13-year-old girl with established insulin-dependent T1D,pancreatic cells were harvested in an effort to restore and understand exocrine competence.The pancreas showed classic silencing ofβ-cell progenitor genes with barely detectable insulin(Ins)transcript.GSK126,a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of coreβ-cell markers and ductal progenitor genes.GSK126 also reinstated Ins gene expression despite absoluteβ-cell destruction.These studies show the refractory nature of chromatin characterises exocrine suppression influencingβ-cell plasticity.Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.
基金A.E-O.dedicates this article to his late grandmother.Professor Sam El-Osta is a National Health and Medical Research Council(NHMRC)Senior Research Fellow(1154650)Funded by NSFC(81561128017)and NHMRC(1113188)International Joint Programme.
文摘Dear Editor,Takotsubo syndrome(TS)is a stress-induced non-ischaemic cardiomyopathy that is more common in women,but is associated with higher morbidity and mortality in males.Also known as broken-heart syndrome,TS is characterised by transient left ventricular(LV)dysfunction independent of obstructive coronary artery disease.TS is a polygenic condition and nowhere is this more evident than the use of positive inotropes,such as isoprenaline(ISO)in pre-clinical models.1 There is no standard therapy for broken-heart syndrome because the mechanisms underlying the condition remain unknown.Furthermore,there is no consensus on predisposition for Takotsubo2 and our goal was to better understand the regulatory mechanism as a first step towards improved treatment plans.Suberanilohydroxamic acid or SAHA,a drug approved for cancer treatment by the US Food and Drug Administration has previously been shown to improve cardiopulmonary function.3 We tested the hypothesis that the cardioprotective benefit of SAHA in a pre-clinical model of Takotsubo is conferred by an epigenetic acetylation/deacetylation(Ac/Dc)axis.