Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age

Diabetes Mellitus(DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs)and adult myocardial regeneration. We assessed the hypothesis that senescenceand senescence-associated secretory phenotype (SASP) are a main mechanism ofcardiac degenerative defect in DM. Accordingly, we tested whether that ablationof senescent CSCs would rescue the cardiac regenerative/reparative defectimposed by DM. We obtained cardiac tissue from non-aged (50-64 years old) DMtype 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathyundergoing cardiac surgery. A higher ROS production in T2DM associated with anincreased number of senescent/dysfunctional T2DM-human(h)CSCs with reducedproliferation, clonogenesis/spherogenesis and myogenic differentiation vs.NDM-hCSCs in vitro. T2DM-hCSCs show a defined pathologic SASP. Acombination of two senolytics, Dasatinib (D) and Quercetin (Q), clearssenescent T2DM-hCSCs in vitro restoring their expansion and myogenicdifferentiation capacities. In a T2DM model in young mice, diabetic status perse (independently of ischemia and age) causes CSC senescence coupled withmyocardial pathologic remodeling and cardiac dysfunction. D+Q treatmentefficiently eliminates senescent cells, rescuing CSC function, which results infunctional myocardial repair/regeneration improving cardiac function in murineDM. In conclusions, DM hampers CSC biology inhibiting their regenerativepotential through the induction of cellular senescence and SASP independentlyfrom aging. Senolytics clear senescence abrogating the SASP restoring a fullyproliferative-/differentiation- competent hCSC pool in T2DM with normalizationof cardiac function.