Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age
Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age
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DOI：
10.2337/db21-0536
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发表时间：
2022-05-01
期刊：
影响因子：
7.7
通讯作者：
Cianflone, Eleonora
中科院分区：
文献类型：
--
作者：
Marino, Fabiola;Scalise, Mariangela;Cianflone, Eleonora
糖尿病（DM）影响多能心脏干/祖细胞（CSCs）和成体心肌再生的生物学。我们评估了衰老和衰老相关分泌表型（SASP）是糖尿病心脏退行性缺损的主要机制的假设。因此，我们测试了衰老CSC的消融是否会挽救由DM造成的心脏再生/修复缺陷。我们从接受心脏手术的非老年（50- 64岁）2型糖尿病（T2 DM）和非糖尿病（NDM）及梗死后心肌病患者中获得心脏组织。T2 DM中较高的活性氧产生与衰老/功能失调的T2 DM-人CSC（hCSC）数量增加相关，与NDM-hCSC相比，体外增殖、克隆形成/球体形成和肌源性分化减少。T2 DM-hCSC显示出确定的病理性SASP。两种衰老清除剂达沙替尼（D）和槲皮素（Q）的组合在体外清除衰老的T2 DM-hCSC，恢复它们的扩增和肌源性分化能力。在幼龄小鼠的T2 DM模型中，糖尿病状态本身（与缺血和年龄无关）导致CSC衰老，伴心肌病理性重塑和心功能不全。D + Q治疗有效地消除衰老细胞，挽救CSC功能，导致功能性心肌修复/再生，改善小鼠DM的心脏功能。总之，DM阻碍CSC生物学，通过诱导细胞衰老和SASP抑制CSC的再生潜力，与衰老无关。在T2 DM中，衰老清除剂清除衰老，废除SASP并恢复具有完全增殖/分化能力的hCSC池，使心脏功能正常化。
Diabetes mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared senescent T2DM-hCSCs in vitro, restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs' regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function.