1. Aged-senescent cells contribute to impaired heart regeneration
- Author
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Wael Awad, Prashant J Ruchaya, James Clark, Larissa G.P. Langhi Prata, Beverley J. Cottle, Eva Domenjo-Vila, Georgina M. Ellison-Hughes, Fiona C Lewis-McDougall, Tamara Tchkonia, Daniele Torella, Prakash P Punjabi, Tze Shin Teoh, and James L. Kirkland
- Subjects
EXPRESSION ,Cardiac function curve ,Senescence ,Geriatrics & Gerontology ,senescence ,DNA damage ,SECRETORY PHENOTYPE ,SUFFICIENT ,030204 cardiovascular system & hematology ,MOUSE ,CARDIOMYOCYTES ,Andrology ,03 medical and health sciences ,p16INK4a ,0302 clinical medicine ,In vivo ,FAILURE ,Medicine ,Progenitor cell ,11 Medical and Health Sciences ,030304 developmental biology ,0303 health sciences ,Science & Technology ,REJUVENATION ,business.industry ,Regeneration (biology) ,CELLULAR SENESCENCE ,aging ,cardiac regeneration ,CARDIAC STEM-CELLS ,Cell Biology ,progenitor cells ,06 Biological Sciences ,3. Good health ,Telomere ,Transplantation ,myocardial infarction ,senolytics ,senescence-associated secretory phenotype ,cardiac repair ,business ,Life Sciences & Biomedicine ,Developmental Biology - Abstract
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 (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-β-gal, DNA damage γH2AX, 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 effectin vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics)in vivoactivates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p
- Published
- 2018
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