Epicardial injection of Ad-HGF activates endogenous

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Epicardial injection of Ad-HGF activates endogenous c-kit+ cardiac stem cells and fosters survival and regeneration of the infarcted aged heart Jiabao Liu, PhD E-mail: 610860661@qq.com Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Background [1] Stem Cells. 2014 Jul;32(7):1701-12. [2] Nature 2011; 473: 326–335. [3] J Am Coll Cardiol. 2011 Aug 23;58(9):977-86. [4] Lancet 2012; 379: 895–904.

Background Hepatocyte growth factor (HGF) is a multifunctional cytokine that exerts considerable biological effects including cell growth, anti-fibrogenic, wound repair, tissue homeostasis etc.. [1] Eur J Vasc Endovasc Surg. 2014 Oct;48(4):430-7. [2] Cell Mol Life Sci. 2011 May;68(10):1703-17.

Our previous studies Our precious studies have demonstrated adenovirus carrying the HGF gene (Ad-HGF) plays an indispensable role in the neovascularization and heart function preservation after MI. However whether Ad-HGF could promote the proliferation and differentiation of endogenous c-kit positive CSCs is still largely unknown. [1] PLoS One. 2013;8(1):e53007. [2] Curr Gene Ther. 2014 Feb;14(1):63-73.

Objective of this study This study aims to determine whether injection of Ad-HGF into the infarction border zone of aged rat following MI can promote the proliferation and differentiation of endogenous c-kit positive CSCs and thus improve cardiac remodeling.

A positive correlation between the expression levels of HGF and c-kit+ CSCs in rat heart of different age stages

Ad-HGF treatment increased the protein expression of HGF and p-Met in aged infarcted heart N, normal zone; P, peri-infarct zone; I, infarct zone.

Ad-HGF increased the number of c-kit+ CSCs in aged infarcted heart

Ad-HGF promotes proliferation and differentiation of c-kit+ CSCs in aged infarcted heart

Ad-HGF promotes the cardiomyocyte regeneration and angiogenesis in aged infarcted heart

Ad-HGF activates the Akt-p21/p27-cell cycle pathway

Ad-HGF reduces apoptosis in 28th day’s heart

Ad-HGF improves the cardiac remodeling of 28th day’s heart following MI

Summary Notably, we discovered the expression levels of HGF/p-Met and c-kit+ CSCs gradually decreased with age increasing and showed a positive correlation between them. Ad-HGF treatment activated endogenous c-kit+ CSCs and promoted cardiomyocyte proliferation and angiogenesis, thus improved the cardiac remodeling of the aged rat following MI.

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