Various tissue engineering strategies have been adopted to treat damaged heart muscle as a result of myocardial infarction. However, the rebuilt myocardium must include a vascular network able to nourish it under diverse metabolic demands. Recently we demonstrated the efficacy of such an approach using cardiac tissue grafts developed from genetically modified mesenchymal stem cells. While demonstrating the value of such an approach, a better source of cells for tissue engineering would be induced pluripotent stem cells (iPSCs) derived from the patient's own tissues. Our objective is to develop a novel approach to treatment of myocardial infarction (MI), using a rodent model, that involves tissue engineering using iPSCs. Such an approach could eventually be used in humans and would allow autologous transplantation, thereby eliminating the problem of host rejection. The use of iPSCs will allow efficient differentiation into endothelial cells and other cardiac lineage cells, immune compatibility between donor and recipient tissues, and rapid transport of nutrients and waste products to new and developing tissue (via blood vessel formation). We hypothesize that a tri-cell patch composed of a network of iPSC-derived endothelial cells and other cardiac lineage cells will be effective for regrowth of neovasculature and myocardial tissue, which in turn could lead to improved cardiac function.
In Aim 1, we will perform in vitro studies to characterize iPSC differentiation and define the optimal conditions for their directed differentiation into endothelial and cardiomyocyte cell lineages that will be suitable for development of a tri-cell patch to be used in cardiac repair. We will further enhance the angiogenic or myogenic potential of cardiac precursor cells, and determine whether preconditioning promotes differentiation of iPSCs into cardiac lineage cells.
In Aim 2 we will determine whether a prevascularized cell patch will increase the retention and survival of iPSC-derived cardiac phenotypes after implantation leading to significant improvements in vascularity, perfusion, and cardiac function. Studies in Aim 3 will determine whether downregulation of fibrosis by manipulating subcellular pathways by over expression of adenylyl cyclases or specific fibrosis repressive microRNAs will influence the engraftment of a cardiac progenitor cell patch after myocardial infarction. These studies will provide new insights into the development of engineered iPSC-derived cardiac tissue patches as a viable therapy for cardiac muscle regeneration.

Public Health Relevance

This project will investigate the effectiveness of prevascularized tri-cell patch composed of endothelial cells, myocytes, and other cardiac lineage cells derived from induced pluripotent stem cells (iPSCs) for their survival and engraftment after in vivo application on infarcted hearts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110740-02
Application #
8325050
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Lundberg, Martha
Project Start
2011-09-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$286,122
Indirect Cost
$103,879
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Cai, Wen-Feng; Liu, Guan-Sheng; Wang, Lei et al. (2016) Repair Injured Heart by Regulating Cardiac Regenerative Signals. Stem Cells Int 2016:6193419
Li, Longhu; Zhao, Dong; Jin, Zhe et al. (2015) Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines. PLoS One 10:e0145766
Cai, Wen-Feng; Kang, Kai; Huang, Wei et al. (2015) CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia-reperfusion injury. J Cell Mol Med 19:1825-35
Wen, Zhili; Huang, Wei; Feng, Yuliang et al. (2014) MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF. PLoS One 9:e104666
Wang, Yuhua; Huang, Wei; Liang, Jialiang et al. (2014) Suicide gene-mediated sequencing ablation revealed the potential therapeutic mechanism of induced pluripotent stem cell-derived cardiovascular cell patch post-myocardial infarction. Antioxid Redox Signal 21:2177-91
Huang, Wei; Xiao, Ding-Zhang; Wang, Yigang et al. (2014) Fn14 promotes differentiation of human mesenchymal stem cells into heart valvular interstitial cells by phenotypic characterization. J Cell Physiol 229:580-7
Chang, Dehua; Wen, Zhili; Wang, Yuhua et al. (2014) Ultrastructural features of ischemic tissue following application of a bio-membrane based progenitor cardiomyocyte patch for myocardial infarction repair. PLoS One 9:e107296
Huang, Wei; Dai, Bo; Wen, Zhili et al. (2013) Molecular strategy to reduce in vivo collagen barrier promotes entry of NCX1 positive inducible pluripotent stem cells (iPSC(NCX¹⁺)) into ischemic (or injured) myocardium. PLoS One 8:e70023
Feng, Yuliang; Wang, Yuhua; Cao, Nan et al. (2012) Progenitor/stem cell transplantation for repair of myocardial infarction: Hype or hope? Ann Palliat Med 1:65-77

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