Open AccessAged‐senescent cells contribute to impaired heart regeneration
Author(s) -
LewisMcDougall Fiona C.,
Ruchaya Prashant J.,
DomenjoVila Eva,
Shin Teoh Tze,
Prata Larissa,
Cottle Beverley J.,
Clark James E.,
Punjabi Prakash P.,
Awad Wael,
Torella Daniele,
Tchkonia Tamara,
Kirkland James L.,
EllisonHughes Georgina M.
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12931
Subject(s) - telomere , senescence , biology , regeneration (biology) , progenitor cell , microbiology and biotechnology , stem cell , transplantation , phenotype , in vivo , in vitro , cardiac function curve , dna damage , immunology , cancer research , medicine , heart failure , dna , genetics , gene
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‐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 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.