Heart failure is the leading cause of death and disability in the western world. According to the American Heart Association, nearly 5 million people are in heart failure and about 550,000 new cases are diagnosed each year in the United States alone. The definitive treatment is heart transplantation;yet, donor organ shortage and the need for immunosuppression limit clinical impact and outcomes. As a result, each year 25-50,000 patients in the US die while waiting for a donor heart. Autologous tissue-engineered hearts stemming from a patient's own cells could potentially overcome all these hurdles by providing viable tissue grafts needing no immunosuppressive therapy. In preliminary studies, we developed a novel technique to isolate acellular whole heart extracellular matrix (ECM) scaffolds from rat and porcine hearts by perfusion decellularization. These ECM scaffolds supported engraftment of fetal heart cells to form contractile tissue. Other groups have provided novel cardiac cell populations derived from adult human cells. We therefore propose to test the hypothesis that (1) the human heart's ECM can be isolated via perfusion decellularization from hearts that were found unsuitable for transplantation, and that (2) the resulting acellular scaffolds can be repopulated with adult stem cell derived cardiomyocytes to form viable tissue. Completion of the proposed research is expected to provide us with two basic milestones towards regeneration of functional human myocardium from patient derived cells: human ECM scaffolds and human cardiomyocytes. Further we will examine the ECM's role in supporting engraftment, differentiation and formation of functional tissue. Aside of the promise to regenerate viable human myocardium, the proposed experiments will provide a unique and novel in vitro system to evaluate the regenerative potential of different cell types, genes and small molecules in an isolated human heart model.

Public Health Relevance

Heart failure is the leading cause of death and disability in the western world. According to the American Heart Association, nearly 5 million people are in heart failure and about 550,000 new cases are diagnosed each year in the United States alone. The definitive treatment is heart transplantation;yet, donor organ shortage and the need for immunosuppression limit clinical impact and outcomes. As a result, each year 25-50,000 patients in the US die while waiting for a donor heart. Autologous tissue-engineered hearts stemming from a patient's own cells could potentially overcome all these hurdles by providing viable tissue grafts needing no immunosuppressive therapy. We propose to provide two basic milestones towards regeneration of functional human heart grafts from patient derived cells: human heart matrix scaffolds and human cardiomyocytes. We will attempt to combine the two to study their interaction and to develop techniques to regenerate viable human heart muscle.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL108663-02
Application #
8330276
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M2))
Program Officer
Lundberg, Martha
Project Start
2011-09-09
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$238,972
Indirect Cost
$102,676
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Guyette, Jacques P; Gilpin, Sarah E; Charest, Jonathan M et al. (2014) Perfusion decellularization of whole organs. Nat Protoc 9:1451-68