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Theranostics 2018; 8(7):1766-1781. doi:10.7150/thno.22788 This issue Cite

Research Paper

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

Jiao Li^1,2,3, Shu-Hong Li², Jun Wu², Richard D. Weisel^2,3, Alina Yao², William L. Stanford⁴, Shi-Ming Liu^1✉, Ren-Ke Li^2,3✉

1. Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
2. Toronto General Research Institute, Division of Cardiovascular Surgery, University Health Network, Toronto, Canada
3. Division of Cardiac Surgery, Department of Surgery, University of Toronto; Toronto, Canada
4. Regenerative Medicine Program, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa

✉ Corresponding author: Shi-Ming Liu, MD, Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Tel: 86-020-34153522; Fax: 86-20-3415-3709; gzliushimingcom and Ren-Ke Li, MD, PhD, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, Canada M5G 1L7. Tel: 1-416-581-7492; Fax: 1-416-581-7493; renkelica More

Abstract

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.

Keywords: stem cells, aging, rejuvenation, heart

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