Wnt11 signaling in stem cell survival and cardiac regeneration The potential of mesenchymal stem cells (MSC) to adopt cardiac multilineage differentiation has been shown in vitro. However, several recent studies question the potential of in vivo differentiation, with low rates of cell survival and engraftment being the suggested causes. Several lines of evidence demonstrate that noncanonical Wnt signaling is sufficient to induce cardiomyocytic commitment in both embryonic and adult stem cell populations. Wnt11, one member of the non-canonical Wnts, enhances cardiac differentiation of circulating progenitor cells upon co-culture with neonatal cardiomyocytes (CM) and promotes cardiac differentiation in noncardiogenic tissue. We propose the following two hypotheses: Hypothesis 1. Wnt11 increases MSC survival and engraftment in ischemic microenvironment via regulation of GATA-4 and anti- apoptotic miRNAs;Hypothesis 2. Overexpression of Wnt11 in MSC enhances protection, regeneration and repair of ischemic myocardium. The hypothesis that Wnt11 signaling is a key regulator of multiple aspects of MSC-dependent cardiac repair is based on our convincing preliminary findings: (1) upregulation of Wnt11 increased the viability of MSC in an ischemic environment;(2) Wnt11 promoted MSC transdifferentiation into a cardiac phenotype, (3) Wnt11 augmented release of MSC-mediated paracrine factors which facilitated the protection of native cardiomyocytes and regeneration of damaged myocardium. We will systematically explore the role of Wnt11 on MSC-mediated repair of infracted heart by examining its effect on myoangiogenesis and MSC protection at the molecular, cellular and in vivo organ levels. We will use gene transduction, laser micro-dissection, "suicide gene", and series electrophysiologic techniques to study the action of Wnt11 on MSC mediated regeneration of infarcted myocardium. The results of these studies should (i) clarify the role of GATA-4 and anti-apoptotic miRNA in Wnt11 mediated MSC survival, and (ii) elucidate the molecular mechanisms which may regulate MSCWnt11 induced myoangiogenesis. Engineering cells with Wnt11 is quite exciting idea. The resultant secretory factors and miRNAs will allow directed differentiation and survival. These data will have far- reaching impact upon understanding of Wnt11 mediated signaling pathway in cardiac repair.

Public Health Relevance

Coronary artery disease is the most common cause of heart infarction. The cell based therapy using stem cells to cure the infarcted heart appears to be a promising approach. However, several recent studies question the potential of in vivo effect of cell therapy, with low rates of implanted cell survival and engraftment being the suggested causes. The proposed research will attempt myocardial repair by genetic manipulation of stem cells prior to transplantation into infarcted heart in order to increase stem cell survival and engraftment in ischemic microenvironment, and enhances regeneration of infarcted myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105176-03
Application #
8279226
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (02))
Program Officer
Adhikari, Bishow B
Project Start
2010-09-10
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Yu, Bin; Yang, Yueting; Liu, Huan et al. (2016) Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. PLoS One 11:e0151542
Okada, Motoi; Kim, Ha Won; Matsu-ura, Kaoru et al. (2016) Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 34:148-59
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
Kang, Kai; Ma, Ruilian; Cai, Wenfeng et al. (2015) Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction. Stem Cells Int 2015:659890
Yu, Bin; Kim, Ha Won; Gong, Min et al. (2015) Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 182:349-60
Liu, Honghai; Chen, Ruikai; Yang, Huaxiao et al. (2014) Enzyme-etching technique to fabricate micropatterns of aligned collagen fibrils. Biotechnol Lett 36:1245-52
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
Yu, Bin; Gong, Min; Wang, Yigang et al. (2013) Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS One 8:e73304
Yu, Bin; Gong, Min; He, Zhisong et al. (2013) Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family. Int J Biochem Cell Biol 45:2724-35
Ma, Zhen; Liu, Qiuying; Yang, Huaxiao et al. (2013) Laser patterning for the study of MSC cardiogenic differentiation at the single-cell level. Light Sci Appl 2:

Showing the most recent 10 out of 16 publications