Heart cell therapy using stem cells with myogenic and angiogenic potential or cytokine induced mobilization of bone marrow cells (BMCs) to the site of injury has shown promise. Similarly, ischemic and pharmacological preconditioning has cardioprotective effects. These therapeutic modalities have been adopted to promote de novo myocardial regeneration and reversal of deleterious hemodynamic effects after myocardial infarction (MI). In order to achieve these effects the present study involves transplantation of BMCs together with skeletal myoblasts (SkMs) which will serve mainly as carries of therapeutic genes. Our main hypothesis is that preconditioning and re-programming of cells prior to transplantation would enhance their survival, engraftment and efficacy for cardiac repair. The main aims of our study are;
Aim -1) Preconditioning of donor cells for their enhanced survival after transplantation. We posit that treatment of cells by preconditioning mimetics may enhance their tolerance to ischemia via stimulation of cell survival signaling. The preconditioned (PC) cells will also exhibit paracrine effects which will give enhanced host myocyte survival in the infarcted heart.
Aim -2) Intramyocardial delivery of non-virally transfected SkMs overexpressing SDF-11 along with transient cytokine therapy for BMCs mobilization for improved heart function. We hypothesized that the elevated SDF-11 levels in the heart will attract circulating CXCR4+ BMCs, egress of which from BM will be distinctly increased after cytokine therapy, to participate in the repair process by angiomyogenesis in the ischemic heart.
Aim -3: To activate cytoprotective regulatory pathways in donor SkMs before transplantation. Considering a critical role for Akt and Bcl-2 in cell survival and angiogenesis downstream of angiopoietin-1 (Ang-1)/Tie-2 signaling pathway, we hypothesize that transplantation of SkMs co-overexpressing Ang-1 and Akt or Bcl-2 will give increased cell survival, enhanced angiogenesis, and improved cardiac function.
Aim -4 will focus on in vitro re-programming of donor cells for directed differentiation via co-culture with cardiomyocytes to adopt cardiac phenotype after transplantation. The co-culture derived cells will show better engraftment and transdifferentiation after transplantation. Put together, our combined therapeutic approach for preconditioning and re-programming of donor cells before transplantation is expected to give better prognosis in the treatment of ischemically injured myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087288-05
Application #
8206537
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Adhikari, Bishow B
Project Start
2008-01-18
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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
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
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
Pasha, Zeeshan; Haider, Husnain Kh; Ashraf, Muhammad (2011) Efficient non-viral reprogramming of myoblasts to stemness with a single small molecule to generate cardiac progenitor cells. PLoS One 6:e23667
Takamiya, Michitaka; Haider, Khawaja H; Ashraf, Muhammad (2011) Identification and characterization of a novel multipotent sub-population of Sca-1? cardiac progenitor cells for myocardial regeneration. PLoS One 6:e25265
Igura, Koichi; Haider, Husnain Kh; Ahmed, Rafeeq P H et al. (2011) Neuropeptide y and neuropeptide y y5 receptor interaction restores impaired growth potential of aging bone marrow stromal cells. Rejuvenation Res 14:393-403
Haider, Husnain Kh; Mustafa, Anique; Feng, Yuliang et al. (2011) Genetic modification of stem cells for improved therapy of the infarcted myocardium. Mol Pharm 8:1446-57
Ahmed, Rafeeq P H; Ashraf, Muhammad; Buccini, Stephanie et al. (2011) Cardiac tumorigenic potential of induced pluripotent stem cells in an immunocompetent host with myocardial infarction. Regen Med 6:171-8

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