Heart failure is the only cardiovascular disease in which prevalence and incidence continue to rise, becoming a tremendous burden for both patients and the healthcare system. The current therapy for heart failure has been focused on the attenuation of the progression of the disease by targeting the neurohumoral factors involved. While successfully improving the prognosis, the morbidity and mortality remains high. Because the loss of functional cardiac muscle cells contributes significantly to the development and progression of heart failure, therapeutic interventions targeted at the regeneration of lost cardiac muscle cells retain enormous medical promise. Towards this goal, cell-based therapy for cardiac regeneration employing various cell types, ranging from skeletal myoblasts to bone marrow derived stem cells to endogenous cardiac stem/progenitor cells, has sparked tremendous interest in recent years. To date, however, true cardiac regeneration has not been achieved, owing largely to the significant loss of cells at the time of implantation and the inability of surviving cells to differentiate into desired cell types in a hostile and diseased myocardium. Maximizing cell engraftment, survival, and differentiation, therefore, remains the greatest hurdle towards therapeutic cardiac regeneration. It is suggested that the impaired survival of implanted cells can be attributed to failure of establishment of contact with the surrounding extracellular matrix (ECM) network in the local microenvironment or niche. Therefore, we hypothesize that establishing contact between implanted stem cells and ECM in a 3D format to mimic a nurturing cellular niche will not only significantly improve engraftment, but also promote functional differentiation. Herein, we aim to employ a system developed using combinatorial approaches to systematically manipulate the local microenvironment encapsulating implanted stem cells, with a goal towards optimizing a transient cellular niche to promote differentiation, to protect stem cells and to augment engraftment during and following implantation. Achieving true cardiac regeneration is a complex and over-arcing goal that any single laboratory would not be able to tackle alone. Therefore, we have assembled a team of investigators and designed an integrated proposal taking advantage of the diverse, yet complementary, expertise from stem cell biology, myocardial biology and physiology, biomaterial science, bioengineering to molecular imaging. Our investigator team has a longstanding and productive track record and will work together to achieve the ultimate goal of therapeutic cardiac regeneration by maximizing stem/progenitor cells engraftment, survival, and differentiation.

Public Health Relevance

Cardiovascular disease remains the single greatest cause of death in developed countries, claiming more lives in the US than the four next leading causes combined. Among cardiovascular disease, the incidence of heart failure continues to rise at a staggering rate. The loss of functional cardiac cells is essential to the development and progression of heart failure. Medical interventions targeted at the repair and/or regeneration of lost cardiac cells, therefore, hold tremendous promise. Towards this goal, cell-based therapy for cardiac regeneration has sparked tremendous interest in recent years. To date, however, true cardiac regeneration has not been achieved, owing largely to the significant loss of cells at the time of implantation and the inability of surviving cells to differentiate into desired cell types in a hostile and diseased microenvironment. The major goal of our proposal is to maximize cell engraftment, survival, and differentiation. The data obtained from our proposal will contribute significantly towards achieving an ultimate goal of therapeutic cardiac regeneration.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL099073-03
Application #
8281574
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2010-08-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$678,207
Indirect Cost
$246,583
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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