Ischemic heart disease continues to have a tremendous impact on public health, shortening lifespan and impairing the quality of life. The inability of the adult human myocardium to undergo regeneration after a myocardial infarction has inspired research using cell therapy for myocardial repair. However, clinical trials to date have shown modest or no benefit, suggesting the need to consider other cell sources and approaches. In large animal models, derivatives of human pluripotent stem cells have provided promising results, but the grafts have generally been small, transient, and of limited functional benefit. In addition, there remain important questions regarding cardiac cells derived from iPSCs, including the optimal delivery strategy, immunogenicity, maturity, and the ability to couple effectively to the native myocardium without causing arrhythmias. In this proposal, three integrated projects will address these challenges and advance toward the long-term goal of utilizing a functional human cardiac tissue patch (hCTP) for repair of ischemic myocardium. The first project aims to generate novel cell populations, including induced cardiac progenitor cells and genetically engineered cell lines that will be evaluated for their immunogenicity in a novel humanized mouse model. These and other cell products, including commercially available sources, will be utilized to generate large vascularized hCTPs in the second project. The third project will utilize a porcine post-infarction model to test hCTPs and optimize electrical and vascular integration as assessed by optical mapping technology and MRI/NMR spectroscopy, respectively. These studies will overcome critical barriers to generating large, fully functional human cardiac tissues that can be integrated safely into the native myocardium to provide a powerful new approach for treatment of advanced ischemic heart disease.

Public Health Relevance

The proposed consortium will develop clinical size human myocardial tissue equivalents (?patches?) fabricated from pluripotent stem cells with engineered immunoprivilege. The tissue patches will contain robust capillary bed and standardized cellular composition and will be tested in a pig infarction model for their ability to improve pathological cardiac remodeling, bioenergetics, and electrical and mechanical function. We expect that this pre-clinical research will result in new clinical trials leading to better therapeutic modalities for patients with ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL134764-01
Application #
9221111
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Buxton, Denis B
Project Start
2016-09-15
Project End
2023-05-31
Budget Start
2016-09-15
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$949,976
Indirect Cost
$131,509
Name
University of Alabama Birmingham
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Jackman, Christopher; Li, Hanjun; Bursac, Nenad (2018) Long-term contractile activity and thyroid hormone supplementation produce engineered rat myocardium with adult-like structure and function. Acta Biomater 78:98-110

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