Diabetes influences the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. Therefore, the idea was tested that senescence and senescence-associated secretory phenotype (SASP) are the key causes of cardiac degeneration in DM. As a result, researchers investigated whether removing senescent CSCs may repair the heart regenerative/reparative deficit caused by diabetes.
They acquired cardiac tissue from nonaged (50-64-year-old) patients having cardiac surgery with type 2 diabetes mellitus (T2DM) and without DM (NDM) and postinfarct cardiomyopathy. In vitro, increased reactive oxygen species generation in T2DM was related to an increased number of senescent/dysfunctional T2DM-human CSCs (hCSCs) with decreased proliferation, cladogenesis/sporogenesis, and myogenic differentiation compared to NDM-hCSCs. T2DM-hCSCs exhibited a distinct pathogenic SASP. Dasatinib (D) and quercetin (Q) were used to remove senescent T2DM-hCSCs in vitro, restoring their growth and myogenic differentiation capacity. In a T2DM paradigm, diabetes conditions triggered CSC senescence irrespective of ischemia and age, as well as myocardial pathologic remodeling and cardiac failure.
D + Q therapy effectively removed senescent cells, restoring CSC activity, resulting in functional myocardial repair/regeneration and improved heart function in diabetes. Finally, DM impairs CSC biology by decreasing their regenerative capacity by inducing cellular senescence and SASP independently of aging. Conversely, senolytics reverse senescence by inhibiting the SASP and restoring a proliferative/differentiation-competent hCSC pool in T2DM patients with normalized cardiac function.
