Abstract 16576: Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition
Introduction: Reconstitution of aged bone marrow (BM) with young stem cells repopulates cardiac-resident BM-derived progenitor cells and prevents progressive cardiac dysfunction after an MI. However, the identity of the BM cells and mechanisms involved are unknown.
Hypothesis: Young, highly regenerative BM Sca-1 cells will home to the aged heart and improve cardiac repair after an MI by epicardial-derived cells (EPDCs) and epithelial-to-mesenchymal transition (EMT).
Methods/Results: In vitro, BM Sca-1 cells were co-cultured with EPDCs under hypoxia conditions and Sca-1+ cells significantly increased EPDC proliferation, migration, and EMT relative to Sca-1- cells (n=6). Sca-1+ cells stimulated an increase in mesenchymal and decrease in epithelial gene expression in EPDCs and increased the mesenchymal protein expression of calponin, vimentin, and smooth muscle actin in EPDCs, indicating activation of EMT (n=6). Sca-1+ cells secreted significantly more transforming growth factor beta (TGF-β) homodimer compared to Sca-1- cells under hypoxia conditions (219.9±19.3 pg/mg for Sca-1+ vs. 138.6±14.3 pg/mg for Sca-1-, p<0.01). The effects of BM Sca-1+ cells on EPDCs were inhibited by a TGF-β blocker. In vivo, BM Sca-1+ or Sca-1- cells from young mice (2 mos) were transplanted into lethally-irradiated aged mice (22 mos) to generate chimeras. More young BM Sca-1+ cells (n=6) homed to the epicardium than young BM Sca-1- cells (16.7±1.1% vs. 5.2±0.5%, day 3 and 10.3±1.4% vs. 4.3±0.8%, day 7, p<0.01), though both cell types homed more to the epicardium than the mid-myocardium or endocardium post-MI. Young BM Sca-1+ cells induced significantly greater host epicardial cell proliferation, migration, and EMT after MI than young BM Sca-1- cells. Furthermore, transplantation of BM Sca-1+ cells was associated with improved cardiac function after MI (fractional shortening: 28.9±1.8% vs. 25.2±0.7%, p<0.01: ejection fraction: 62.67±2.8% vs. 57.6±1.3%, p<0.01 for Sca-1+ vs. Sca-1-, respectively, day 28 post-MI).
Conclusions: Reconstitution of aged BM with young Sca-1+ cells improved cardiac regeneration through reactivation of the EMT process, promoting EPDC proliferation, migration and EMT through activation of the TGF-β signaling pathway.
Author Disclosures: J. Li: None. S. Li: None. R.D. Weisel: None. S. Liu: None. R. Li: Research Grant; Significant; Canadian Institutes of Health Research Foundation grant (332652).
- © 2016 by American Heart Association, Inc.