Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age
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posted on 2022-02-02, 19:40 authored by Fabiola Marino, Mariangela Scalise, Nadia Salerno, Luca Salerno, Claudia Molinaro, Donato Cappetta, Michele Torella, Marta Greco, Daniela Foti, Ferdinando C. Sasso, Pasquale Mastroroberto, Antonella De Angelis, Georgina M. Ellison-Hughes, Maurilio Sampaolesi, Marcello Rota, Francesco Rossi, Konrad Urbanek, Bernardo Nadal-Ginard, Daniele Torella, Eleonora CianfloneDiabetes Mellitus
(DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs)
and adult myocardial regeneration. We assessed the hypothesis that senescence
and senescence-associated secretory phenotype (SASP) are a main mechanism of
cardiac degenerative defect in DM. Accordingly, we tested whether that ablation
of senescent CSCs would rescue the cardiac regenerative/reparative defect
imposed by DM. We obtained cardiac tissue from non-aged (50-64 years old) DM
type 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathy
undergoing cardiac surgery. A higher ROS production in T2DM associated with an
increased number of senescent/dysfunctional T2DM-human(h)CSCs with reduced
proliferation, clonogenesis/spherogenesis and myogenic differentiation vs.
NDM-hCSCs in vitro. T2DM-hCSCs show a defined pathologic SASP. A
combination of two senolytics, Dasatinib (D) and Quercetin (Q), clears
senescent T2DM-hCSCs in vitro restoring their expansion and myogenic
differentiation capacities. In a T2DM model in young mice, diabetic status per
se (independently of ischemia and age) causes CSC senescence coupled with
myocardial pathologic remodeling and cardiac dysfunction. D+Q treatment
efficiently eliminates senescent cells, rescuing CSC function, which results in
functional myocardial repair/regeneration improving cardiac function in murine
DM. In conclusions, DM hampers CSC biology inhibiting their regenerative
potential through the induction of cellular senescence and SASP independently
from aging. Senolytics clear senescence abrogating the SASP restoring a fully
proliferative-/differentiation- competent hCSC pool in T2DM with normalization
of cardiac function.