Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction

Abstract

The study was designed to evaluate the mechanisms of cardiac regeneration after injury and to determine how to restore that capacity in aged individuals. The adult heart retains a small population of nascent cells that have myeloid, mesenchymal, and mesodermal capabilities, which play an essential role in the recovery of ventricular function after injury. In aged individuals, these cells are diminished and dysfunctional. We evaluated the derivation of some of these cardiac progenitors and a method to restore their number and function. We first demonstrated that aged mice have fewer progenitors in both the bone marrow (BM) and the myocardium, which correlated with the extent of cardiac dysfunction after injury. Bone marrow chimerism established in aged mice with young BM donors restored both myocardial progenitors and cardiac function, but neither was restored with aged BM donors. Cardiac micro-chimerism in aged mice was established with young BM cells, which restored cardiac function after injury, even with old peripheral BM cells. The young cardiac-resident BM-derived progenitor cells in the aged myocardium persisted for at least a year, and after myocardial infarction they actively proliferated and enhanced cardiac repair through paracrine mechanisms. Bone marrow reconstitution with young BM cells in aged recipients restored progenitors in both the BM and, most importantly, the myocardium. The number and function of cardiac-resident BM-derived progenitor cells in the aged myocardium prior to injury was the major determinant for successful recovery of cardiac function. The aged heart was rejuvenated with young BM cells.