The overall aim of this Award was to test the central hypothesis that bone marrow derived stem cells have the ability to differentiate and adopt cardiac phenotype when transplanted in young as well as aging hearts with experimental myocardial infarction. To support this hypothesis, the initial studies were designed and conducted to understand the basic properties of BMSCs and compare them in vitro from young and aging donor animals. Furthermore, we have elucidated that cardiac transdifferentiation of BMSCs can be achieved in vitro under specific set of cell culture conditions. The second phase of experiments was performed in vivo in experimental animal models to extrapolate our in vitro findings and observe that the transplanted BMSCs are able to achieve cardiomyocytes phenotype and integrate with the host myocardium. To accomplish these aims, state of the art integrated approaches including our well-established co-culture conditions, in vivo experimental animal model, histological studies combined with confocal microscopy and ultra-structure analysis by transmission electron microscopy, molecular studies by western blotting, fluorescent in situ hybridization, real time and classical PCR, siRNA techniques, and heart function studies using Pressure- volume loops and echocardiography were employed. Aging significantly affected the stem cells which were slower in their proliferation and propagation ability in vitro. Similarly when subjected to anoxia, younger MSCs showed more resistance and survived better as indicated by low level LDH release (an indicator of cellular injury) and reduced TUNEL positivity. Genetic modulation of the cells with AKT and angiopoietinl or their pharmacological preconditioning prior to transplantation promoted their survival as well as angiogenic and myogenic potential in young and aging animal hearts

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 #
5R37HL074272-10
Application #
8502187
Study Section
Special Emphasis Panel (NSS)
Program Officer
Schwartz, Lisa
Project Start
2003-07-01
Project End
2013-07-31
Budget Start
2013-06-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$137,036
Indirect Cost
$62,902
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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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
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
Lai, Vien Khach; Ashraf, Muhammad; Jiang, Shujia et al. (2012) MicroRNA-143 is a critical regulator of cell cycle activity in stem cells with co-overexpression of Akt and angiopoietin-1 via transcriptional regulation of Erk5/cyclin D1 signaling. Cell Cycle 11:767-77
Higuchi, Sayaka; Ii, Masaaki; Zhu, Ping et al. (2012) Delta-opioid receptor activation promotes mesenchymal stem cell survival via PKC/STAT3 signaling pathway. Circ J 76:204-12
Li, Longhu; Haider, Husnain Kh; Wang, Linlin et al. (2012) Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol 302:H2112-21
Idris, Niagara Muhammad; Ashraf, Muhammad; Ahmed, Rafeeq P H et al. (2012) Activation of IL-11/STAT3 pathway in preconditioned human skeletal myoblasts blocks apoptotic cascade under oxidant stress. Regen Med 7:47-57
Lu, Gang; Ashraf, Muhammad; Haider, Khawaja Husnain (2012) Insulin-like growth factor-1 preconditioning accentuates intrinsic survival mechanism in stem cells to resist ischemic injury by orchestrating protein kinase cýý-erk1/2 activation. Antioxid Redox Signal 16:217-27

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