Bone marrow stromal cells (BMSC) have a great potential in the treatment of myocardial disorders. Due to their malleable nature, BMSC possess multi-lineage potential and can overcome lineage restrictions to form non-hematopoietic tissues including myocardium. There is unflinching evidence that mononuclear cells emigrate from their bone marrow niches in response to tissue ischemia and become blood borne. These cells show tropism for the ischemic myocardium where they undergo milieu dependent transformation and develop into functioning cardiomyocytes. Our long term goal is to exploit BMSC as a therapeutic modality to regenerate the infarcted myocardium and revamp the injured heart function. The proposed study addresses some fundamental issues pertaining to both in vitro as well as in vivo fusion and transdifferentiation potential of ischemically mobilized BMSC to form cardiac myocytes. We postulate that ischemically stressed myocardium provides a strong trigger to initiate mobilization of specific sub- populations of BMSC into peripheral circulation. The blood-borne cells home onto the injured myocardium to adopt cardiac phenotvpes and improve cardiac function. Characterization of BMSC committed to cardiac lineage will help to understand the basic mechanisms underlying BMSC mobilization and differentiation both in vitro and in vivo conditions. Three main hypotheses fundamental to the proposed project include: 1) ischemic stress mobilizes specific population of BMSC cells into peripheral circulation: 2) Mobilized BMSC undergo milieu dependent differentiation into cardiomvocvtes and endothelial cells to promote cardiomyogenesis and angiogenesis: 3) Mobilized BMSC protect myocvtes against ischemia by secreting specific factors. The experimental design involves the use of BMSC from transgenic mice expressing enhanced green fluorescent protein. Co-culture cell model will be used to study the biology of BMSC in vitro. Their potential to differentiate into cardiac phenotypes in a cardiac microenvironment using murine heart model of myocardial infarction will be examined. The effect of ischemia on BMSC mobilization in peripheral circulation and finally their engraftment in the ischemic area will be studied. The mechanism by which BMSC survive in the ischemic environment and protect myocytes will be investigated by examining the molecular mediators, such as growth factors, cytokines, paracrine factors, secreted by the BMSC. A broad multidisciplinary approach that will encompass diverse techniques including histochemistry, immunocytochemistry, pathology, flow cytometric analysis, confocal microscopy and molecular biology will be used to investigate the specific aims. A complete understanding of the ongoing molecular processes in stem cell mediated regeneration is central to the success of cell derived-therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083236-05
Application #
7753616
Study Section
Special Emphasis Panel (ZRG1-CVS-D (91))
Program Officer
Adhikari, Bishow B
Project Start
2005-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$372,621
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Zuo, Shi; Jones, W Keith; Li, Hongxia et al. (2012) Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury. Stem Cells Dev 21:598-608
Ma, Zhen; Liu, Qiuying; Liu, Honghai et al. (2012) Laser-patterned stem-cell bridges in a cardiac muscle model for on-chip electrical conductivity analyses. Lab Chip 12:566-73
He, Zhisong; Li, Hongxia; Zuo, Shi et al. (2011) Transduction of Wnt11 promotes mesenchymal stem cell transdifferentiation into cardiac phenotypes. Stem Cells Dev 20:1771-8
Dai, Bo; Huang, Wei; Xu, Meifeng et al. (2011) Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 58:2118-27
Li, Hongxia; Zuo, Shi; Pasha, Zeeshan et al. (2011) GATA-4 promotes myocardial transdifferentiation of mesenchymal stromal cells via up-regulating IGFBP-4. Cytotherapy 13:1057-65
Li, Hongxia; Zuo, Shi; He, Zhisong et al. (2010) Paracrine factors released by GATA-4 overexpressed mesenchymal stem cells increase angiogenesis and cell survival. Am J Physiol Heart Circ Physiol 299:H1772-81
Wang, Xiaohong; Zhao, Tiemin; Huang, Wei et al. (2009) Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors. Stem Cells 27:3021-31
Dai, Ying; Ashraf, Muhammad; Zuo, Shi et al. (2008) Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair. J Mol Cell Cardiol 44:607-17
Zhang, Dongsheng; Fan, Guo-Chang; Zhou, Xiaoyang et al. (2008) Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol 44:281-92
Xu, Meifeng; Uemura, Ryota; Dai, Ying et al. (2007) In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol 42:441-8

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