Coronary artery disease is the leading cause of death in persons over 65. Myocyte loss and endothelial dysfunction contributes to the increased severity of cardiovascular disease in the aging population. Approaches specifically aimed at replacing the necrotic myocardium with adult derived bone marrow stem (BMS) cells for transdifferentiation into cell lineages of the myocardium could provide a basis for effective treatment of age-related diseases. The major hypotheses to be tested are: 1) BMS cells become scarce in aging animals but have the potential to acquire cardiac phenotypes; 2) BMS cells transdifferentiate in old myocardium and improve cardiac function; 3) Mobilization of BMS cells in aging myocardium promotes neoangiogenesis and myocyte repair; 4) Mild cellular stress stimulates growth factors resulting in neoangiogenesis as well as proliferation of BMS cells into cardiac phenotypes. We will utilize young adult and old mice to characterize age related changes in BMS cells and their potential to grow in the old myocardium into cardiac phenotypes. Where feasible, BMS cells from transgenic mice expressing enhanced green fluorescent protein (GFP) will be used. The origin of cells in the regenerating myocardium following BMS cell transplantation will be determined by the expression of GFP. The coculture cell model will be used to study the biology of BMS cells and their differentiation potential into cardiac phenotypes after exposure to different cardiac microenvironment. Both isolated perfused myocardium and left anterior descending coronary artery ligation model will be used to determine the effects of BMS cell engraftment and differentiation in cardiac function and pathology. The regenerating myocardium will be determined by GFP, BrdU and Ki67 immunocytochemistry. Both latter markers label cells in S phase indicative of cell proliferation. Myocyte proteins, nestin and desmin will be localized. The maturing myocytes will be determined by expression of myocyte enhancer factor 2, transcription factor (GATA-4) and early marker of myocyte development, CSX/NKx2.5 ; vascular endothelial cells involved in angiogenesis will be recognized by factor VIII, cadherin and CD34 antibodies ; and smooth muscle will be identified by anti alpha smooth muscle actin. The coupling between myocytes will be assessed with connexin 43 antibodies and carboxyfluorescein dye. The proposed studies will provide a comprehensive information about the biology of BMS cells in the aging myocardium and their potential to transdifferentiate into cell lineages of the host organ for stem cell-based strategies in the treatment of aging-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL074272-04
Application #
7080424
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Liang, Isabella Y
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$510,337
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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
Matsu-ura, Toru; Sasaki, Hiroshi; Okada, Motoi et al. (2016) Attenuation of teratoma formation by p27 overexpression in induced pluripotent stem cells. Stem Cell Res Ther 7:30
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
Feng, Yuliang; Huang, Wei; Meng, Wei et al. (2014) Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells 32:462-72
Feng, Yuliang; Huang, Wei; Wani, Mashhood et al. (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9:e88685
Konoplyannikov, Mikhail; Haider, Khawaja Husnain; Lai, Vien Khach et al. (2013) Activation of diverse signaling pathways by ex-vivo delivery of multiple cytokines for myocardial repair. Stem Cells Dev 22:204-15
Igura, Koichi; Okada, Motoi; Kim, Ha Won et al. (2013) Identification of small juvenile stem cells in aged bone marrow and their therapeutic potential for repair of the ischemic heart. Am J Physiol Heart Circ Physiol 305:H1354-62
Kim, Sun Wook; Kim, Ha Won; Huang, Wei et al. (2013) Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378. Cardiovasc Res 100:241-51
Buccini, Stephanie; Haider, Khawaja Husnain; Ahmed, Rafeeq P H et al. (2012) Cardiac progenitors derived from reprogrammed mesenchymal stem cells contribute to angiomyogenic repair of the infarcted heart. Basic Res Cardiol 107:301
Lu, Gang; Jiang, Shujia; Ashraf, Muhammad et al. (2012) Subcellular preconditioning of stem cells: mito-Cx43 gene targeting is cytoprotective via shift of mitochondrial Bak and Bcl-xL balance. Regen Med 7:323-34

Showing the most recent 10 out of 65 publications