NYMC Faculty Publications

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

Fabiola Marino, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.Follow
Mariangela Scalise, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Nadia Salerno, Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy.
Luca Salerno, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Claudia Molinaro, Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy.
Donato Cappetta, Department of Experimental Medicine, Section of Pharmacology, University of Campania "L. Vanvitelli," Naples, Italy.
Michele Torella, Department of Translational Medicine, University of Campania "L. Vanvitelli," Naples, Italy.
Marta Greco, Department of Health Sciences, Magna Græcia University, Catanzaro, Italy.
Daniela Foti, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Ferdinando C. Sasso, Department of Translational Medicine, University of Campania "L. Vanvitelli," Naples, Italy.
Pasquale Mastroroberto, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Antonella De Angelis, Department of Experimental Medicine, Section of Pharmacology, University of Campania "L. Vanvitelli," Naples, Italy.
Georgina M. Ellison-Hughes, Centre for Human and Applied Physiological Sciences and Centre for Stem Cells and Regenerative Medicine, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, U.K.
Maurilio Sampaolesi, Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Marcello Rota, Department of Physiology, New York Medical College, Valhalla, NY.Follow
Francesco Rossi, Department of Experimental Medicine, Section of Pharmacology, University of Campania "L. Vanvitelli," Naples, Italy.
Konrad Urbanek, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Bernardo Nadal-Ginard, Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy.
Daniele Torella, Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.
Eleonora Cianflone, Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy.

Author Type(s)

Faculty

DOI

10.2337/db21-0536

Journal Title

Diabetes

First Page

1081

Last Page

1098

Document Type

Article

Publication Date

5-1-2022

Department

Physiology

Abstract

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.

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