Regenerative capacity of the heart is mediated through multiple distinct populations of stem cell types that are the subject of ongoing intense study. In the past decade, isolation and characterization of cardiac progenitor cells (CPCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) has provided substantial insight to the capabilities of stem cells to rebuild the damaged heart and advance clinical therapy. Clinical trials have proven the efficacy and safety of autologous and allogeneic CPC and MSC delivery to human patients, yet improvements in cardiac function and reduction in scar tissue remain modest and far below that needed for restoration of normal functional output. This proposal overcomes these current cell- based limitations with two novel methods for improving myocardial repair: 1) CardioClusters, a three- dimensional microenvironment consisting of CPCs, MSCs and EPCs, and 2) CardioChimeras, the product of cellular fusion between two stem cell populations. The innovation of this proposal is the creation of CardioClusters and CardioChimeras with the ability to capitalize upon beneficial attributes of multiple human stem cells from a single patient providing a clinically relevant translational strategy. The short-term goal of this proposal will determine the enhanced proliferation, growth, survival and commitment potential of CardioChimeras and stem cells in CardioClusters, which are optimized for improving cell-based therapy. Accomplishing the stated aims of this proposal will yield the construction and comprehensive characterization of CardioClusters and CardioChimeras.
Specific Aims are: 1) CardioClusters exhibit enhanced proliferation, survival and cardiac commitment relative to cardiospheres, single or combinatorial cell populations, 2) CardioChimeras display improved characteristics of growth, survival, secretion of paracrine factors and cardiac commitment relative to non-fused cell populations and 3) CardioClusters as well as CardioChimeras restore myocardial structure and function after intramyocardial injection better than cardiospheres or single / multiple cell suspensions. The significance of these studies is to create novel cell-based strategies engineered to improve current cellular therapy to mitigate ischemic disease. Collectively, studies in this proposal will pave the way for interventional approaches to selectively adapt stem cell behavior and merge beneficial attributes of stem cell populations found within the human heart for prevention of heart failure after cardiomyopathic injury.

Public Health Relevance

Heart disease leading to cardiovascular failure is a major public health issue in the United States with a considerable burden for the health care system. Despite recent progress to advance stem cell based therapy for patients, heart failure carries a five-year mortality that rivals most cancers. This proposal describes two approaches to control and pattern stem cells derived from the human heart to promote superior repair and regeneration after myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122525-01
Application #
8675146
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
2014-05-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92182
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Kubli, Dieter A; Sussman, Mark A (2017) Eat, breathe, ROS: controlling stem cell fate through metabolism. Expert Rev Cardiovasc Ther 15:345-356
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Sussman, Mark A (2017) A Matter of Opinion. Circ Res 120:36-38
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Samse, Kaitlen; Hariharan, Nirmala; Sussman, Mark A (2016) Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase. Pharmacol Res 103:13-6
Kulandavelu, Shathiyah; Karantalis, Vasileios; Fritsch, Julia et al. (2016) Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. J Am Coll Cardiol 68:2454-2464
Broughton, Kathleen M; Sussman, Mark A (2016) Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps. Circ Res 118:867-80
Quijada, Pearl; Sussman, Mark A (2015) Circulating around the tissue: hematopoietic cell-based fusion versus transdifferentiation. Circ Res 116:563-5

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