Discovery of cardiac progenitor cells (CPCs) in the adult heart has led to heightened expectations for novel treatments of cardiac disease. However, adoptive transfer of CPCs results only in transient improvement of cardiac performance because most of the donated cells fail to persist in the hostile milieu of the ischemic scar. Whereas most approaches focus upon enhancing capabilities of stem cells, engineering of the damaged myocardium is a valid alternative strategy to enhance myocardial repair and regeneration. Extracellular matrix (ECM) proteins are pivotal components of the myocardial environment important in maintenance of cellular function. Therefore, the overall goal of this proposal is to improve the survival, proliferation, recruitment, and persistence of CPC in the damaged myocardium by modification of fibronectin (Fn) expression, an ECM protein which correlates highly with spatio-temporal appearance of CPCs in the heart. Our preliminary data delineate a Fn-?5?1-FAK-Pim-1 signaling cascade that regulates CPC growth and survival. The relevance of Fn, ?5?1, FAK and Pim-1 in cardiomyocyte biology are well accepted, however, nothing is known so far about this pathway in CPCs. Therefore, the short term goal is to understand the significance of the Fn-?5? 1-FAK-Pim-1 pathway in CPCs under pathological conditions and extrapolate an innovative therapeutic approach to engineer the extracellular environment of the damaged myocardium to enhance regeneration and repair. Translational potential of these findings will be explored using an adeno-associated virus type 9 (AAV9) vector to express a functional collagen-tethered Fn fragment designed to enhance CPC survival, proliferation, recruitment, and engraftment.
Our specific aims are: 1) The Fn-?5?1-FAK-Pim-1 signaling axis is triggered following cardiomyopathic injury in vivo, 2) ?5?1-integrin receptor activation by Fn induces immediate early stress responses, survival, and proliferation via FAK-Pim-1 signaling in CPCs, 3) Robust and persistent CPC- dependent regeneration is mediated by overexpression of a collagen binding Fn fragment delivered by cardiotropic AAV9 vector. The significance of these studies is to define beneficial aspects of the endogenous repair to injury response. The long term goal will be to transfer the Fn fragment expressing AAV9 regimen into human disease establishing an innovative therapeutic concept for regenerative medicine.

Public Health Relevance

Heart disease, especially heart failure is a major public health issue in the United States with a considerable burden for the health care system. Despite recent progress in understanding the pathophysiology, heart failure still carries a 5-year mortality that rivals most cancers. This proposal focuses upon understanding how the environment of the damaged heart can impact upon repair and regeneration on a cellular and molecular level. Defining these issues on a mechanistic level will lead to novel approaches to enhance treatment of heart disease and aging.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
San Diego State University
Schools of Arts and Sciences
San Diego
United States
Zip Code
Monsanto, Megan M; Wang, Bingyan J; Sussman, Mark A (2017) Synthetic MSC? Nothing Beats the Real Thing. Circ Res 120:1694-1695
Khalafalla, Farid G; Greene, Steven; Khan, Hashim et al. (2017) P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling. Circ Res 121:1224-1236
Quijada, Pearl; Salunga, Hazel T; Hariharan, Nirmala et al. (2015) Cardiac Stem Cell Hybrids Enhance Myocardial Repair. Circ Res 117:695-706
Quijada, Pearl; Sussman, Mark A (2015) Circulating around the tissue: hematopoietic cell-based fusion versus transdifferentiation. Circ Res 116:563-5
Samse, Kaitlen; Emathinger, Jacqueline; Hariharan, Nirmala et al. (2015) Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells. J Biol Chem 290:13935-47
Doroudgar, Shirin; Völkers, Mirko; Thuerauf, Donna J et al. (2015) Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes. Circ Res 117:536-46
Hariharan, Nirmala; Quijada, Pearl; Mohsin, Sadia et al. (2015) Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J Am Coll Cardiol 65:133-47
Orogo, Amabel M; Gonzalez, Eileen R; Kubli, Dieter A et al. (2015) Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival. J Biol Chem 290:22061-75
McGregor, Michael; Hariharan, Nirmala; Joyo, Anya Y et al. (2014) CENP-A is essential for cardiac progenitor cell proliferation. Cell Cycle 13:739-48
Toko, Haruhiro; Hariharan, Nirmala; Konstandin, Mathias H et al. (2014) Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. J Biol Chem 289:5348-56

Showing the most recent 10 out of 33 publications