4 research outputs found
Aged-senescent cells contribute to impaired heart regeneration
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 (p16INK4A , SA-Ī²-gal, DNA damage Ī³H2AX, 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
Aged-senescent cells contribute to impaired heart regeneration
Aging leads to increased cellular senescence and is associated with decreased potency of tissueāspecific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32ā86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A, SAāĪ²āgal, DNA damage Ī³H2AX, telomere length, senescenceāassociated 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 (INKāATTAC or wildātype mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67ā, EdUāpositive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.This work was supported by British Heart Foundation project grant PG/14/11/30657 (GMEāH and J.E.C.), NIH grant AG13925 (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), Robert and Arlene Kogod (JLK), the Noaber Foundation (JLK), Glenn/American Federation for Aging Research (AFAR) BIG Award (J.L.K.) and Italian Ministry of Health grant GRā2010ā2318945