Aged-senescent cells contribute to impaired heart regeneration
Aged-senescent cells contribute to impaired heart regeneration
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DOI：
10.1111/acel.12931
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发表时间：
2019-06-01
期刊：
影响因子：
7.8
通讯作者：
Ellison-Hughes, Georgina M.
中科院分区：
文献类型：
--
作者：
Lewis-McDougall, Fiona C.;Ruchaya, Prashant J.;Ellison-Hughes, Georgina M.
衰老导致细胞衰老增加，并与组织特异性干/祖细胞的效力下降有关。在这里，我们对从 32-86 岁患有心血管疾病的人类受试者中分离出的心脏祖细胞 (CPC) 进行了广泛的分析。在老年受试者（>70 岁）中，超过一半的 CPC 出现衰老（p16(INK4A)、SA-beta-gal、DNA 损伤 γ H2AX、端粒长度、衰老相关分泌表型 [SASP]），移植到梗塞心脏后无法复制、分化、再生或恢复心脏功能。衰老 CPC 分泌的 SASP 因子使原本健康的 CPC 衰老。使用 senolytics 消除衰老的 CPC 可消除 SASP 及其在体外的衰弱作用。体内衰老细胞的全面消除（INK-ATTAC 或用 D + Q senolytics 处理的野生型小鼠）可激活驻留的 CPC，并增加小 Ki67、EdU 阳性心肌细胞的数量。消除衰老细胞的治疗方法可以减轻心脏随年龄增长而恶化的情况，并恢复心脏的再生能力。
Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32-86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16(INK4A), SA-beta-gal, DNA damage gamma H2AX, telomere length, senescence-associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wild-type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67-, EdU-positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.