Stem cell therapy is emerging as a beneficial strategy to treat patients with advanced heart disease. However, limited homing and survival of transplanted stem cells in the myocardium represents a barrier to therapeutic efficacy. During the initial term of funding, we focused on hypoxia preconditioning (HP) as a means to enhance homing and survival of cardiac stem cells by activating CXC chemokine receptor-4 (CXCR4) in HIF- 1?-dependent manner, which led to improved outcomes following cell transplantation in young mice. Unfortunately, aged C-MSC respond poorly to HP, suggesting that research into the molecular mechanisms that regulate HP in aged cells is needed to optimize this novel therapeutic strategy. Age-related impairments in tissue repair are associated with decreased neovascularization, a process that is regulated by HIF-1?- dependent signaling. Our preliminary data suggest that chromatin modifications in aged sca-1+ cardiac mesenchymal stem cells (C-MSC) may underlie impaired HIF-1? responses and compromise their function. Specifically, aged cells exhibit significantly greater histone 3 lysine 27 trimethylation (H3K27me3, a repressive chromatin modification) at the promoters of the HIF-1? target genes CXCR4 and IL-10, which are crucial regulators of stem/progenitor cell homing and survival. Moreover, aged cells exhibit increased expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb Repressor Complex 2 (PRC2). EZH2 is the only known enzyme capable of inducing H3K27me3 in mammalian cells. EZH2 may also cooperate with histone deacetylases (HDAC), which repress transcription by removing specific acetyl groups from histones. We hypothesize that in aged C-MSC, aberrant expression of EZH2 leads to repression of key HIF-1?-dependent genes through H3k27me3-induced gene silencing and by interacting with HDAC11, thus impairing HP responses and compromising therapeutic efficacy. We propose three aims to test our hypothesis.
In Aim 1, we will determine the mechanisms whereby EZH2 is regulated by the transcription factor E2F1 in C-MSC, and we will target E2F1 in aged C-MSC to determine whether it is mechanistically linked to changes in EZH2 expression and function.
In Aim 2, we will carry out genetic and biochemical experiments to determine whether HDAC11 functions as a part of the multi-protein EZH2-PRC2 complex that associates with the IL-10 promoter and represses HIF-1?-induced IL-10 gene expression in aged C-MSC.
In Aim 3, we will ablate EZH2 in aged C-MSC to investigate functional responses to cell transplantation (i.e., cell homing, angiogenesis, cardiac repair). This will be the first i-depth study to investigate the role of epigenetic remodeling in regulating the function of aged stem cells. Our findings may lead to enhanced efficacy of cardiac stem cell therapy and identify new molecular targets that could improve cardiac repair in the elderly.

Public Health Relevance

Most patients with ischemic heart disease are old, and impaired hypoxic signaling is a barrier to effective autologous stem cell therapy. The proposed experiments will address critical gaps in our understanding of the roles of chromatin accessibility in stem cell responses to hypoxia, and key stem cell functions in angiogenesis and tissue repair in the elderly, a population at high risk of ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL086555-08A1
Application #
9106367
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2008-03-01
Project End
2020-03-31
Budget Start
2016-05-01
Budget End
2017-03-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Murphy, Cameron; Withrow, Joseph; Hunter, Monte et al. (2018) Emerging role of extracellular vesicles in musculoskeletal diseases. Mol Aspects Med 60:123-128
Tang, Yaoliang; Lei, Wei; Chen, Yanfang et al. (2018) Noncoding RNAs and Stem Cell Function and Therapy. Stem Cells Int 2018:7306034
Su, Xuan; Jin, Yue; Shen, Yan et al. (2018) Exosome-Derived Dystrophin from Allograft Myogenic Progenitors Improves Cardiac Function in Duchenne Muscular Dystrophic Mice. J Cardiovasc Transl Res 11:412-419
Bayoumi, Ahmed S; Park, Kyoung-Mi; Wang, Yongchao et al. (2018) A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol 114:72-82
Hagan, Mackenzie; Ashraf, Muhammad; Kim, Il-Man et al. (2018) Effective regeneration of dystrophic muscle using autologous iPSC-derived progenitors with CRISPR-Cas9 mediated precise correction. Med Hypotheses 110:97-100
Zhu, Jinyun; Lu, Kai; Zhang, Ning et al. (2018) Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol 46:1659-1670
Teoh, Jian-Peng; Bayoumi, Ahmed S; Aonuma, Tatsuya et al. (2018) ?-arrestin-biased agonism of ?-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225-236
Ruan, Xiao-Fen; Li, Yong-Jun; Ju, Cheng-Wei et al. (2018) Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. Acta Pharmacol Sin 39:579-586
Benson, Tyler W; Weintraub, Daniel S; Crowe, Matthew et al. (2018) Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol 473:79-88
Ju, Chengwei; Shen, Yan; Ma, Gengshan et al. (2018) Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium. J Cardiovasc Transl Res 11:420-428

Showing the most recent 10 out of 37 publications