Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition

Background: To improve the regenerative capacity of aged individuals, we reconstituted bone marrow (BM) of aged mice with young Sca-1 cells, which repopulated cardiac progenitors and prevented cardiac dysfunction after a myocardial infarction (MI). However, the mechanisms involved were incompletely elucidated. This study aimed to investigate whether young, highly regenerative BM Sca-1 cells exert their cardio-protective effects on the aged heart through reactivation of the epithelial-to-mesenchymal transition (EMT) process. Methods: In vitro, BM Sca-1 cells were co-cultured with epicardial-derived cells (EPDCs) under hypoxia condition; mRNA and protein levels of EMT genes were measured along with cellular proliferation and migration. In vivo, BM Sca-1(+) or Sca-1(-) cells from young mice (2-3 months) were transplanted into lethally-irradiated old mice (20-22 months) to generate chimeras. In addition, Sca-1 knockout (KO) mice were reconstituted with wild type (WT) BM Sca-1(+) cells. The effects of BM Sca-1 cell on EMT reactivation and improvement of cardiac function after MI were evaluated. Results: In vitro, BM Sca-1(+) cells increased EPDC proliferation, migration, and EMT relative to Sca-1(-) cells and these effects were inhibited by a TGF-β blocker. In vivo, more young BM Sca-1(+) than Sca-1(-) cells homed to the epicardium and induced greater host EPDC proliferation, migration, and EMT after MI. Furthermore, reconstitution of Sca-1 KO mice with WT Sca-1(+) cells was associated with the reactivation of EMT and improved cardiac function after MI. Conclusions: Young BM Sca-1(+) cells improved cardiac regeneration through promoting EPDC proliferation, migration and reactivation of EMT via the TGF-β signaling pathway.