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.
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.
|Garg, Priyanka; Garg, Vivek; Shrestha, Rajani et al. (2018) Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. Circ Res 123:224-243|
|Oduk, Yasin; Zhu, Wuqiang; Kannappan, Ramaswamy et al. (2018) VEGF nanoparticles repair the heart after myocardial infarction. Am J Physiol Heart Circ Physiol 314:H278-H284|
|Brown, Matthew E; Zhou, Ying; McIntosh, Brian E et al. (2018) A Humanized Mouse Model Generated Using Surplus Neonatal Tissue. Stem Cell Reports 10:1175-1183|
|Gao, Ling; Gregorich, Zachery R; Zhu, Wuqiang et al. (2018) Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine. Circulation 137:1712-1730|
|Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu et al. (2018) CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle. Circ Res 122:88-96|
|Zhang, Jianyi; Abel, E Dale (2018) Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else? Circ Res 123:329-331|
|Jackman, Christopher P; Ganapathi, Asvin M; Asfour, Huda et al. (2018) Engineered cardiac tissue patch maintains structural and electrical properties after epicardial implantation. Biomaterials 159:48-58|
|Gao, Ling; Yang, Libang; Wang, Lu et al. (2018) Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells. Circ Res 123:1313-1325|
|Zhu, Wuqiang; Zhang, Eric; Zhao, Meng et al. (2018) Regenerative Potential of Neonatal Porcine Hearts. Circulation :|
|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|
Showing the most recent 10 out of 26 publications