Wnt11 signaling in stem cell survival and cardiac regeneration

Summary

Principal Investigator: Meifeng Xu
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2010-09-10 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Transduction of Wnt11 promotes mesenchymal stem cell transdifferentiation into cardiac phenotypes
    Zhisong He
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA
    Stem Cells Dev 20:1771-8. 2011
  2. pmc Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury
    Shi Zuo
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA
    Stem Cells Dev 21:598-608. 2012
  3. pmc GATA-4 promotes myocardial transdifferentiation of mesenchymal stromal cells via up-regulating IGFBP-4
    Hongxia Li
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45867, USA
    Cytotherapy 13:1057-65. 2011
  4. pmc Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function
    Bo Dai
    Liuhua Qiao Hospital, Guangzhou, Guangdong, China
    J Am Coll Cardiol 58:2118-27. 2011
  5. pmc Laser-patterned stem-cell bridges in a cardiac muscle model for on-chip electrical conductivity analyses
    Zhen Ma
    Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
    Lab Chip 12:566-73. 2012
  6. pmc Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles
    Bin Yu
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
    PLoS ONE 8:e73304. 2013
  7. pmc Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family
    Bin Yu
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
    Int J Biochem Cell Biol 45:2724-35. 2013
  8. pmc Enzyme-etching technique to fabricate micropatterns of aligned collagen fibrils
    Honghai Liu
    Department of Bioengineering, Clemson University, Clemson, SC, 29634, USA
    Biotechnol Lett 36:1245-52. 2014

Research Grants

  1. CHRONIC ADAPTATIONS TO MYOCARDIAL ISCHEMIA
    John M Canty; Fiscal Year: 2013
  2. PDE5A Inhibition Stimulates Stem Cell Survival &Differentiation
    Muhammad Ashraf; Fiscal Year: 2013
  3. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
  4. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
  5. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  6. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  7. Cell-Based Cardiac Repair
    Charles E Murry; Fiscal Year: 2013
  8. Amplification of Cardiosphere-Derived Cell Therapy
    BRIAN RAYMOND WEIL; Fiscal Year: 2013
  9. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
  10. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013

Detail Information

Publications8

  1. pmc Transduction of Wnt11 promotes mesenchymal stem cell transdifferentiation into cardiac phenotypes
    Zhisong He
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA
    Stem Cells Dev 20:1771-8. 2011
    ..Functional studies indicated that the differentiation of MSC(Wnt11) was diminished by knockdown of GATA-4 with GATA-4-siRNA. Transduction of Wnt11 into MSCs increases their differentiation into CMs by upregulating GATA-4...
  2. pmc Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury
    Shi Zuo
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA
    Stem Cells Dev 21:598-608. 2012
    ..Transplantation of MSC(Wnt11) improved cardiac function. The release of Wnt11 and other factors from transplanted MSC(Wnt11) is more likely responsible for protection of native CM at risk...
  3. pmc GATA-4 promotes myocardial transdifferentiation of mesenchymal stromal cells via up-regulating IGFBP-4
    Hongxia Li
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45867, USA
    Cytotherapy 13:1057-65. 2011
    ..We investigated whether overexpression of GATA-4 increases adult mesenchymal stromal cell (MSC) transdifferentiation into a cardiac phenotype in vitro...
  4. pmc Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function
    Bo Dai
    Liuhua Qiao Hospital, Guangzhou, Guangdong, China
    J Am Coll Cardiol 58:2118-27. 2011
    ..The purpose of this study was to assess the effect of scar tissue composition on engraftment of progenitor cells into infarcted myocardium...
  5. pmc Laser-patterned stem-cell bridges in a cardiac muscle model for on-chip electrical conductivity analyses
    Zhen Ma
    Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
    Lab Chip 12:566-73. 2012
    ....
  6. pmc Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles
    Bin Yu
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
    PLoS ONE 8:e73304. 2013
    ..In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC)...
  7. pmc Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family
    Bin Yu
    Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
    Int J Biochem Cell Biol 45:2724-35. 2013
    ..In this study, we tested whether regulation of microRNAs and their target proteins was associated with the cytoprotective effects of GATA-4...
  8. pmc Enzyme-etching technique to fabricate micropatterns of aligned collagen fibrils
    Honghai Liu
    Department of Bioengineering, Clemson University, Clemson, SC, 29634, USA
    Biotechnol Lett 36:1245-52. 2014
    ..Using this technique, collagen patterns with designated orientations and with clear pattern boundaries and defined shapes were fabricated. ..

Research Grants30

  1. CHRONIC ADAPTATIONS TO MYOCARDIAL ISCHEMIA
    John M Canty; Fiscal Year: 2013
    ..The results will identify the stem cell and pathological sub- strate most likely to benefit patients with asymptomatic LVSD before clinical heart failure develops. ..
  2. PDE5A Inhibition Stimulates Stem Cell Survival &Differentiation
    Muhammad Ashraf; Fiscal Year: 2013
    ..The proposed study using the PDE5A inhibitors may identify a potential therapeutic role for these compounds for stem cell based de novo myocardial regeneration. ..
  3. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  4. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  5. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  6. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Cell-Based Cardiac Repair
    Charles E Murry; Fiscal Year: 2013
    ..These experiments will advance our understanding of human heart development and make clinical trials of heart regeneration more feasible. ..
  8. Amplification of Cardiosphere-Derived Cell Therapy
    BRIAN RAYMOND WEIL; Fiscal Year: 2013
    ....
  9. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  10. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  11. Infarct Repair with Mesenchymal Stem Cell Subpopulation
    Buddhadeb Dawn; Fiscal Year: 2013
    ....
  12. NF-kB-dependent miRNAs in Cardioprotection and Regeneration
    W Keith Jones; Fiscal Year: 2013
    ..Other novel aspects are, investigation of the role played by miRNA transfer from cell-to-cell, and use of an innovative non-viral in vivo transfection technology for small RNAs. ..
  13. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..