Abstract

Heart malfunction or failure after myocardial infarction (Ml) is a leading cause of disability and death. The success of endothelial or cardiac stem cells to improve heart recovery after ischemic damage holds great promise for cell-based therapies to treat myocardial infarction. We recently found that application of embryonic endothelial progenitor cells (eEPCs) after infarction in the mouse or pig increases capillary density and improves heart performance. However, the reasons for heart recovery after cell therapy remain unclear. A broad spectrum of progenitor cells show beneficial effects, but participation of donor cells as functional entities in host tissue is often transient, or relatively low, hardly explaining the substantial improvement in whole organ function. This raises the possibility that endothelial progenitors - besides building new vessels - improve tissue recovery in ways that are poorly understood. Consistent with this notion, we found that the benefits of eEPC application are already evident 24 hours after transplantation suggesting an acute cardioprotective effect mediated by paracrine interactions between eEPCs and host tissue. Using genome-wide expression profiling and bioinformatics, we identified most of the eEPC-secreted factors and we placed them in 7 functional groups. Further comparison with mature endothelial cells revealed that one group, consisting of wnt-pathway modulators, is highly specific to the eEPC population. To determine if wnt-pathway modulation contributes to the stem-cell cardioprotection effects, we will: (1) investigate how wnt-signaling changes in acute or chronic heart ischemia;(2) analyze how transplanted EPCs modulate wnt-signaling in the injured heart;and (3) identify the cellular and molecular mechanisms of the EPC-mediated cardioprotection. These studies focus on the fundamental issue of how stem cells help the heart to recover after myocardial infarction. This knowledge will help shape future therapeutic strategies to treat heart injuries.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083958-04
Application #
7597223
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$372,621
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Sanders, Lehanna N; Schoenhard, John A; Saleh, Mohamed A et al. (2016) BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction. Circ Res 119:434-49
Bylund, Jeffery B; Hatzopoulos, Antonis K (2016) Differentiation of Atrial Cardiomyocytes from Pluripotent Stem Cells Using the BMP Antagonist Grem2. J Vis Exp :
Paik, David T; Rai, Meena; Ryzhov, Sergey et al. (2015) Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis. Circ Res 117:804-16
Tanwar, Vineeta; Bylund, Jeffery B; Hu, Jianyong et al. (2014) Gremlin 2 promotes differentiation of embryonic stem cells to atrial fate by activation of the JNK signaling pathway. Stem Cells 32:1774-88
Fioret, Bryan A; Heimfeld, Jeremy D; Paik, David T et al. (2014) Endothelial cells contribute to generation of adult ventricular myocytes during cardiac homeostasis. Cell Rep 8:229-41
Müller, Iris I; Melville, David B; Tanwar, Vineeta et al. (2013) Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm. Dis Model Mech 6:332-41
Rai, Meena; Walthall, Joel M; Hu, Jianyong et al. (2012) Continuous antagonism by Dkk1 counter activates canonical Wnt signaling and promotes cardiomyocyte differentiation of embryonic stem cells. Stem Cells Dev 21:54-66
Aisagbonhi, Omonigho; Rai, Meena; Ryzhov, Sergey et al. (2011) Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis Model Mech 4:469-83
Safa, Radwan N; Peng, Xu-Yang; Pentassuglia, Laura et al. (2011) Neuregulin-1ýý regulation of embryonic endothelial progenitor cell survival. Am J Physiol Heart Circ Physiol 300:H1311-9
Melville, David B; Montero-Balaguer, Mercedes; Levic, Daniel S et al. (2011) The feelgood mutation in zebrafish dysregulates COPII-dependent secretion of select extracellular matrix proteins in skeletal morphogenesis. Dis Model Mech 4:763-76

Showing the most recent 10 out of 31 publications