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Published on: July 10, 2019
Necroptosis Induced by Ad-HGF Activates Endogenous C-Kit+ Cardiac Stem Cells and Promotes Cardiomyocyte Proliferation
Jiabao Liu1, Peng Wu, Hao Wang
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Insights
Hepatocyte growth factor (HGF) therapy promotes cardiac stem cell (CSC) proliferation and differentiation via necroptosis, aiding aged heart repair after myocardial infarction (MI). This necroptosis mechanism enhances CSCs, offering new therapeutic avenues for ischemic heart disease.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cell Death Mechanisms
Background:
- Cardiac stem cells (CSCs) expressing c-kit are crucial for heart repair, but their function declines with age.
- The role of necroptosis, a regulated form of cell death, in aged cardiac repair and CSC behavior after myocardial infarction (MI) was previously unknown.
Purpose of the Study:
- To investigate the effects of hepatocyte growth factor (HGF) and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI.
- To elucidate the underlying molecular mechanisms, including signaling pathways and cell death pathways involved.
Main Methods:
- Compared c-kit+ CSCs and HGF/p-Met expression in rats of different ages using immunofluorescence and Western blotting.
- Administered adenovirus carrying the HGF gene (Ad-HGF) into aged rat hearts post-MI and assessed CSC proliferation and differentiation.
- Analyzed signaling pathways, necroptosis markers (RIPK1, RIPK3), and HMGB1 levels via Western blotting and ELISA.
Main Results:
- HGF/p-Met expression and c-kit+ CSC abundance decreased with age.
- Ad-HGF treatment promoted CSC differentiation, cardiomyocyte proliferation, and angiogenesis, which were reversed by necroptosis inhibition.
- Ad-HGF induced necroptosis, increasing RIPK1, RIPK3, and HMGB1 levels, and enhanced bone marrow c-kit+ cell abundance.
Conclusions:
- Ad-HGF-induced necroptosis promotes aged heart repair post-MI by enhancing c-kit+ CSC proliferation and differentiation.
- These findings suggest a novel therapeutic strategy targeting necroptosis for treating ischemic heart disease in the elderly.
Background/Aims:
The discovery of c-kit+ cardiac stem cells (CSCs) provided us with new therapeutic targets to repair the damaged heart. However, the precise mechanisms regulating CSC proliferation and differentiation in the aged heart remained elusive. Necroptosis, a type of regulated cell death, has recently been shown to occur following myocardial infarction (MI); however, its effect on c-kit+ CSCs remains unknown. We investigated the effects of hepatocyte growth factor (HGF) and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI.
Methods:
The c-kit+ CSCs and HGF/p-Met expression levels in neonatal, adult and aged rats were compared using immunofluorescence and Western blotting. Immediately after MI, adenovirus carrying the HGF gene (Ad-HGF) was injected into the left ventricular wall surrounding the infarct areas of the aged rat heart. The proliferation and differentiation of the endogenous c-kit+ CSCs were studied using immunofluorescence. The signalling pathways were analysed via Western blotting and ELISA.
Results:
HGF/p-Met expression levels and c-kit+ CSC abundance gradually decreased with age. Ad-HGF promoted c-kit+ CSC differentiation into precursor cells of cardiomyocyte, endothelial and smooth muscle cell lineages and enhanced cardiomyocyte proliferation and angiogenesis in aged rats; these effects were reversed by the inhibition of necroptosis. Ad-HGF administration induced necroptosis by increasing the expression of receptor interacting protein kinase (RIP) 1 and receptor interacting protein kinase (RIP) 3 proteins in the infarcted heart. Moreover, Ad-HGF-induced necroptosis increased high-mobility group box 1 protein (HMGB1) levels and enhanced the abundance of c-kit+ cells in the bone marrow, which may partly account for the beneficial effect of necroptosis on the c-kit+ CSCs.
Conclusion:
Ad-HGF-induced necroptosis facilitated aged heart repair after MI by promoting c-kit+ CSC proliferation and differentiation. These findings may lead to the development of new methods for the treatment of ischaemic heart disease in aged populations.
