Stem cell transplantation and therapeutic gene delivery have shown promise in cardiovascular therapeutics. We hypothesized that concomitant mobilization of the resident cardiac stem cells (CSCs) and bone marrow stem cells (BMSCs) and their homing into the infarcted myocardium will be an effective strategy for myocardial regeneration. The rationale for this study is to exploit the diverse properties of CSCs and BMSCs, and varying mechanisms of action of different cytokines in myocardial regeneration following infarction. We anticipate that transplantation of Sca-1+ cells genetically modified to overexpress hepatocyte growth factor (HGF), stromal cell derived factor-11 (SDF-11) and insulin-like growth factor (IGF-1) will develop favorable chemotactic gradient in the heart. The locally developed gradient of HGF and SDF-11 will favor mobilization and homing-in of CSCs and BMSCs. Additionally, SDF-11 will provide retention signals for the chemokine receptor CXCR4 positive BMSCs for long enough time duration to ensure their participation and commitment to the repair process. IGF-1 overexpression will stimulate IGF-1/IGF-1R ligand-receptor system to activate PI3K/Akt signaling to promote proliferation and differentiation of these cells. The mobilized and transplanted stem cells will further contribute to the repair process by the release of trophic factors to exert paracrine effects. The main hypothesis will be studied in three specific Aims.
Aim -1 is intended to develop chemotactic gradient of cytokines to favor simultaneous mobilization and recruitment of CSCs and BMSCs in the infarcted heart.
Aim -2 will elucidate the angiogenic and myogenic fate and functional benefits of the mobilized cells.
Aim -3 will determine the role of cytokine priming of stem cells by preconditioning or by gene modification for protracted cytokines expression to promote their survival after transplantation. We anticipate that simultaneous mobilization of CSCs and BMSCs together with cytokine priming will augment their engraftment and upregulate survival factors thus preventing apoptosis and necrosis in the infarcted myocardium. Based on the anticipated beneficial effects of our multimodal therapeutic approach, the proposed study will show the significance of simultaneous mobilization of BMSCs and resident CSCs. The information thus obtained from these studies will likely lead to new therapeutic approaches for management of cardiovascular pathologies. NARRATIVE: Bone marrow derived stem cells and resident cardiac stem cells have shown promise in myocardial repair. Our proposal is based on concomitant mobilization of both these stem cell populations by multiple cytokine therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089535-05
Application #
8235813
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2008-04-10
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
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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