Aged-senescent cells contribute to impaired heart regeneration

TY - JOUR

T1 - Aged-senescent cells contribute to impaired heart regeneration

AU - Lewis-McDougall, Fiona C

AU - Ruchaya, Prashant J

AU - Domenjo-Vila, Eva

AU - Teoh, Tze Shin

AU - Prata, Larissa

AU - Cottle, Beverley J

AU - Clark, James E

AU - Punjabi, Prakash P

AU - Awad, Wael

AU - Torella, Daniele

AU - Tchkonia, Tamara

AU - Kirkland, James L

AU - Ellison-Hughes, Georgina M

N1 - © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

PY - 2019/6

Y1 - 2019/6

N2 - 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-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 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.

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, aged 32-86 years. In aged subjects (>70 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 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.

KW - aging

KW - cardiac regeneration

KW - cardiac repair

KW - myocardial infarction

KW - p16INK4a

KW - progenitor cells

KW - senescence

KW - senescence-associated secretory phenotype

KW - senolytics

UR - http://www.scopus.com/inward/record.url?scp=85065871555&partnerID=8YFLogxK

U2 - 10.1111/acel.12931

DO - 10.1111/acel.12931

M3 - Article

C2 - 30854802

SN - 1474-9718

VL - 18

JO - AGING CELL

JF - AGING CELL

IS - 3

M1 - e12931

ER -