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

TY - JOUR

T1 - Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age

AU - Marino, Fabiola

AU - Scalise, Mariangela

AU - Salerno, Nadia

AU - Salerno, Luca

AU - Molinaro, Claudia

AU - Cappetta, Donato

AU - Torella, Michele

AU - Greco, Marta

AU - Foti, Daniela

AU - Sasso, Ferdinando C.

AU - Mastroroberto, Pasquale

AU - De Angelis, Antonella

AU - Ellison-Hughes, Georgina M.

AU - Sampaolesi, Maurilio

AU - Rota, Marcello

AU - Rossi, Francesco

AU - Urbanek, Konrad

AU - Nadal-Ginard, Bernardo

AU - Torella, Daniele

AU - Cianflone, Eleonora

N1 - Funding Information: Funding. This research was funded by Ministero dell’Instruzione, dell’Uni-versitàe della Ricerca grants PRIN2015ZTT5KB_004, PRIN2017NKB2N4_005, and PON-AIM–1829805-2. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. F.M., M.Sc., N.S., L.S., C.M., D.C., and M.G. contributed to the data acquisition and analysis. M.T., D.F., F.C.S, P.M., A.D.A., K.U., D.T., and E.C. contributed to the data interpretation. A.D.A., G.M.E.-H., K.U., D.T., and E.C. designed the study. G.M.E.-H., M.Sa., M.R., and F.R. provided critical feedback and helped to shape the research, analysis, and manuscript. K.U., B.N-G., D.T., and E.C. wrote the original draft and edited the manuscript. K.U., D.T., and E.C. contributed to the conceptualization. All the authors approved the final version of this manuscript. D.T. and E.C. are the guarantors of this work and, as such, had full access to all the Publisher Copyright: © 2022, American Diabetes Association Inc. All rights reserved.

PY - 2022/5/1

Y1 - 2022/5/1

N2 - Diabetes 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 main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared 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) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs' regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function.

AB - Diabetes 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 main mechanisms of cardiac degenerative defect in DM. Accordingly, we tested whether ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from nonaged (50- to 64-year-old) patients with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy undergoing cardiac surgery. A higher reactive oxygen species production in T2DM was associated with an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with reduced proliferation, clonogenesis/spherogenesis, and myogenic differentiation versus NDM-hCSCs in vitro. T2DM-hCSCs showed a defined pathologic SASP. A combination of two senolytics, dasatinib (D) and quercetin (Q), cleared 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) caused CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D + Q treatment efficiently eliminated senescent cells, rescuing CSC function, which resulted in functional myocardial repair/regeneration, improving cardiac function in murine DM. In conclusion, DM hampers CSC biology, inhibiting CSCs' regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence, abrogating the SASP and restoring a fully proliferative/differentiation-competent hCSC pool in T2DM with normalization of cardiac function.

UR - http://www.scopus.com/inward/record.url?scp=85128801264&partnerID=8YFLogxK

U2 - 10.2337/db21-0536

DO - 10.2337/db21-0536

M3 - Article

C2 - 35108360

AN - SCOPUS:85128801264

SN - 1939-327X

VL - 71

SP - 1081

EP - 1098

JO - Diabetes

JF - Diabetes

IS - 5

ER -