RT Journal Article
SR Electronic
T1 Aged-senescent cells contribute to impaired heart regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 397216
DO 10.1101/397216
A1 Fiona C. Lewis-McDougall
A1 Prashant J. Ruchaya
A1 Eva Domenjo-Vila
A1 Tze Shin Teoh
A1 Larissa Prata
A1 Beverley J. Cottle
A1 James E. Clark
A1 Prakash P. Punjabi
A1 Wael Awad
A1 Daniele Torella
A1 Tamara Tchkonia
A1 James L. Kirkland
A1 Georgina M. Ellison-Hughes
YR 2018
UL http://biorxiv.org/content/early/2018/10/01/397216.abstract
AB 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 effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25±0.07% vs. 0.03±0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.