Cellular cardiomyoplasty (CCM), which involves the transplantation of exogenous cells into the heart, is a promising approach to repair injured myocardium and improve cardiac function. We have isolated a population of muscle-derived stem cells (MDSCs) from the skeletal muscle of mice and humans, that when compared with myoblasts, display a significantly improved capacity for cardiac regeneration in a mouse model of acute myocardial infarction (AMI). Transplanted MDSCs survive significantly better than skeletal myoblasts due to their high expression of cellular antioxidants, which confers the cells with an increased resistance to stress, and through a paracrine effect which reduces myocardial fibrosis, promotes angiogenesis, and ameliorates left ventricular (LV) remodeling. We have successfully expanded human MDSCs, to clinically relevant numbers in culture and more importantly, human MDSCs have already entered the clinical arena for the treatment of bladder dysfunction &myocardial infarction, confirming that MDSCs represent a viable therapeutic cell source for CCM. However, several limitations, such as a poor delivery approach of the cells (direct intramyocardial injection in PBS) that leads to limited cell retention and survival as well as the low cardiomyogenic potential of the MDSCs, may still limit the cardiac regenerative potential of the MDSCs (Primary focus of the application). The use of FGF2-coacervate, as a novel delivery vehicle for the MDSCs, represents a new area of research that could not only promote cell retention, survival, and the cardiac regenerative potential of the MDSCs, but also synergistically enhance angiogenesis through the release of FGF2. We have shown that coacervate loaded with FGF2 was capable of enhancing cardiac repair and regeneration through the promotion of angiogenesis and supporting the survival of residual cardiomyocytes (preliminary data). Therefore, the focus of Aim 1 of this proposal will be to combine the new FGF2-coacervate technology with MDSCs to further improve cardiac repair. We will compare this combinatorial therapy to MDSCs and FGF2- coacervate therapies separately. Moreover, we have observed that the viral transduction of MDSCs with Wnt- 11, a molecule required for cardiogenesis, enhances the cardiomyogenic differentiation of the MDSCs in vitro and cardiac repair in vivo when injected directly into injured myocardium. In a second set of experiments (Aim 2), we will determine whether the intramyocardial injection of Wnt-11 transduced MDSCs (Wnt-11 MDSCs) in combination with FGF2 coacervate, can further enhance the cardiac regenerative potential of the Wnt-11 MDSCs when compared to non-transduced MDSCs and Inducible Pluripotent Stem Cell (iPSC)- derived cardiomyocytes delivered with FGF2-coacervate. The successful completion of these aims will increase our understanding of the basic biology of muscle-derived progenitor cell populations with enhanced cardiomyogenic potential for cardiac repair and facilitate the development of new therapeutic technologies that merge the merits of stem cell therapy with biomimetic coacervate to improve cardiac repair and regeneration.

Public Health Relevance

Cellular cardiomyoplasty, which involves the transplantation of exogenous cells into the heart, is a promising approach to repair injured myocardium and improve cardiac function. Muscle-derived Stem Cells (MDSCs) represent a potential therapeutic cell source for treating patients with acute myocardial infarction (AMI);however, several limitations, such as a poor delivery approach of the cells (direct intramyocardial injection in PBS that leads to limited cell retention and survival as well as the low cardiomyogenic potential of th MDSCs, may limit the cardiac repair/regenerative potential of the MDSCs, which is the primary focus of the application. Therefore, the focus of this proposal will be to combine a new coacervate technology (using fibroblast growth factor 2 to promote angiogenesis) with MDSCs to further improve cardiac repair;moreover, we will utilize Wnt- 11, a molecule required for cardiogenesis, to enhance the cardiomyogenic differentiation of the MDSCs and potentially further improve cardiac repair in vivo when injected directly into injured myocardium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB016774-01A1
Application #
8636750
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2014-03-15
Project End
2016-02-29
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$194,330
Indirect Cost
$67,022
Name
University of Pittsburgh
Department
Orthopedics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213