Cellular senescence and senescence-associated secretory phenotype drive multipotent cardiac stem/progenitor cell dysfunction in human diabetic cardiomyopathy independently of age

Background: Aging and Diabetes Mellitus (DM) independently and additively increase cardiovascular risk and a pathophysiological basis for this epidemiological link is currently the subject of intense investigations. Both aging and DM affect the biology and regenerative potential of tissue specific cardiac adult stem/progenitor cells (CSCs). In aged subjects over half of the CSCs are senescent with a senescence-associated secretory phenotype (SASP) that renders otherwise healthy CSCs to senescence, impairing their proliferative and differentiation potential. Although a link to organismal aging is clear, cells can undergo senescence, regardless of age. Yet, it is unclear whether the SASP is induced by Diabetes per se in CSCs and whether targeting senescent cells within the diabetic CSC compartment rescues their regenerative biology. Methods: In order to investigate the effects of DM on CSC senescence and to try separate those of aging from Diabetes on senescence events, we obtained peri-infarct/border zone biopsies from non-aged patients (50-64 years old) with DM type 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathy undergoing surgical coronary revascularization. Results: Ischemic injury in DM is associated with a higher ROS production, as revealed by the exacerbated expression of 8-OH-deoxyguanosine, nitrotyrosine, and 4-hydroxinonenal targeting both cardiomyocytes as well as CSCs. The latter associated with an increased number of senescent and dysfunctional T2DM-hCSCs (isolated from atrial samples of T2DM and NDM patients with ischemic cardiomyopathy) identified by increased p16INK4a positive cells, reduced telomerase activity and telomere length, reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation when compared to NDM-hCSCs in vitro. Importantly, T2DM-hCSCs show a defined SASP, as demonstrated by the increased secretion of MMP-3, PAI1, IL-6, IL-8, IL-1β and GM-CSF. A combination of two senolytics, Dasatinib and Quercetin, clears senescent T2DM-hCSCs in vitro restoring expansion and myogenic differentiation capacities of the diabetic hCSC pool. Conclusions: DM hampers human CSC biology, inducing a variety of hallmarks of senescence in non-aged subjects that contribute to the deficit of their regenerative potential. Clearance of senescent cells by senolytics abrogates the SASP and restores a fully proliferative- and differentiation- competent hCSC pool in T2DM.