Acute myocardial infarction (Ml) remains a leading cause of morbidity and mortality. Novel therapeutic strategies involving autologous cell transplantation are being studied, and recently, elegant studies have shown significant regeneration of myocardial tissue by transplantation of autologous stem cells during the peri-infarct period (days following Ml). We have recently shown that the stem cell homing molecule stromal-cell derived factor-1 (SDF-1) is transiently expressed following Ml, and that re-establishment of SDF-1 expression in myocardial tissue months after Ml via the delivery of cells engineered to express SDF-1 is sufficient to induce stem cell homing of hematopoietic stem cells (HSC), vasculogenesis and recovery of myocardial function without the generation of new cardiac myocytes (Lancet 362:697-703, 2003). These observations have led us to hypothesize that a viable strategy for myocardial regeneration in acute Ml and ischemic cardiomyopathy is the overexpression or re-establishment of signaling for stem cell homing to myocardial tissue. Mesenchymal stem cells (MSCs) do home to injured myocardium within days of an Ml and are believed to be more likely to differentiate into cardiac myocytes than HSCs, but they do not express CXCR4. Since MSCs have been shown to mobilize in experimental models of bone marrow injury, and MSC do home to injured myocardium in the peri-infarct period other homing and mobilization factors must be present. We hypothesize that in order to optimize recovery of myocardial function following Ml or in patients with congestive heart failure we need to reestablish both HSC and MSC homing. The overall objectives of this proposal are to test strategies for expressing stem cell homing factors for myocardial regeneration in a model of ischemic cardiomyopathy (Aim 1), identify molecular triggers that lead to homing of bone marrow derived MSCs (Aim 2), and determine if engineering expression of CXCR4 in MSCs leads to homing in response to SDF-1 and a cell survival advantage in vivo (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL074400-01A2
Application #
6918451
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
2005-04-15
Project End
2009-03-31
Budget Start
2005-04-15
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Costa, Andrea R; Panda, Nikhil C; Yong, Sandro et al. (2012) Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells. Am J Physiol Heart Circ Physiol 302:H270-7
Penn, Marc S; Agarwal, Udit (2010) IGF-1 and mechanisms of myocardial repair. Int J Cardiol 138:1-2
Penn, Marc S (2009) Importance of the SDF-1:CXCR4 axis in myocardial repair. Circ Res 104:1133-5
Mayorga, Maritza; Finan, Amanda; Penn, Marc (2009) Pre-transplantation specification of stem cells to cardiac lineage for regeneration of cardiac tissue. Stem Cell Rev 5:51-60
McConnell, Bradley K; Popovic, Zoran; Mal, Niladri et al. (2009) Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis. J Biol Chem 284:1583-92
Penn, Marc S; Anwaruddin, Saif; Nair, Ravi et al. (2009) From mice to men. Commonalities in physiology for stem cell-based cardiac repair. J Am Coll Cardiol 54:2287-9
Penn, Marc S; Mangi, Abeel A (2008) Genetic enhancement of stem cell engraftment, survival, and efficacy. Circ Res 102:1471-82
Popovic, Zoran B; Benejam, Carlos; Bian, Jing et al. (2007) Speckle-tracking echocardiography correctly identifies segmental left ventricular dysfunction induced by scarring in a rat model of myocardial infarction. Am J Physiol Heart Circ Physiol 292:H2809-16
Bian, Jing; Popovic, Zoran B; Benejam, Carlos et al. (2007) Effect of cell-based intercellular delivery of transcription factor GATA4 on ischemic cardiomyopathy. Circ Res 100:1626-33
Jane-wit, Daniel; Altuntas, Cengiz Z; Johnson, Justin M et al. (2007) Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation 116:399-410

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