Ischemic heart disease is the leading cause of congestive heart failure. The ultimate therapy would pursue stem cell-based regeneration. Bone marrow (BM) can be regarded as the major reservoir of stem cells. Stromal-derived factor-11 (SDF-11) induced by myocardial ischemia plays a critical role for recruiting circulating BM-derived stem cells (BMSC) to ischemia myocardium for heart repair via binding of SDF-1 to CXC chemokine receptor 4 (CXCR4). Besides exogenous stem cells, compelling evidence has accumulated suggesting that the heart has endogenous regenerative potential. Resident cardiac stem cells (CSCs) are potentially available for self-renewing of adult heart. However, myocardial damage from ischemia is usually irreversible. Proposed mechanisms for the failure of endogenous heart repair include: acute depletion of resident CSCs after myocardial infarction (MI), inadequate proliferation and self-renewal of CSCs to rapidly reconstitute CSC population in heart, and limited and transient endogenous homing signals (e.g. SDF-11) induced by myocardial ischemia. We propose to replenish the stem cell pool for heart repair, by isolating and expanding CSCs from heart in vitro, infusing them systemically back in vivo post MI, and recruiting them to the ischemic myocardium using SDF-11/CXCR4 signal pathway. However, major challenges remain, including low level of CXCR4 expression of CSCs under normal conditions, the poor survival of grafted cells, which has limited the reparative capacity of stem cells in vivo. We propose a series of in vitro experiments and in vivo experiments to verify that hypoxia preconditioning can be utilized to increase CSC homing via regulation of CXCR4 expression and enhance survival of homed cells via cytoprotection in acute ischemic myocardium. In addition, recombinant adeno-associated virus (rAAV) mediated SDF-1 gene therapy may permit us to conduct CSC transplantation for patients with chronic myocardial ischemia. To test these hypotheses, we propose the following Specific Aims: (1) To evaluate hypoxia induced cardiac stem cell homing: role of CXCR4 and HIF-11 in cell recruitment and retention. (2) To determine whether hypoxia-preconditioning can enhance homed CSC survival and characterize the mechanism. (3) To investigate the possibility of homing CSC to chronic ischemia myocardium via rAAV virus mediated SDF-11 gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086555-06
Application #
8230796
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2008-03-01
Project End
2013-07-31
Budget Start
2012-03-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$120,562
Indirect Cost
$43,771
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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
Wang, Zi; Su, Xuan; Ashraf, Muhammad et al. (2018) Regenerative Therapy for Cardiomyopathies. J Cardiovasc Transl Res :
Ruan, Xiao-Fen; Ju, Cheng-Wei; Shen, Yan et al. (2018) Suxiao Jiuxin pill promotes exosome secretion from mouse cardiac mesenchymal stem cells in vitro. Acta Pharmacol Sin 39:569-578
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

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