PIs: Bradley Keller, MD
Co-PIs: William Wagner, PhD
Title: Engineered Early Embryonic Cardiac Tissue
Description: We have developed an Engineered Early Embryonic Cardiac Tissue, termed EEECT, using embryonic cardiac cells isolated during the period of primary morphogenesis in order to investigate the regulation of embryonic CM proliferation and differentiation and to generate tissues with optimal properties for cardiac repair. Our EEECT construct uses a simple cylindrical geometry which is reproducible, scalable, and preserves the unique proliferative and contractile properties of developing myocardium. Using EEECT we can investigate the regulation of CM proliferation and maturation within a functioning in vitro 3D environment. EEECT proliferation and force production increases in response to cyclic mechanical stretch. With prolonged culture EEECT acquires a post-natal myocardial phenotype (reduced proliferation, increased calcium and β-adrenergic sensitivity, and increased force production). Preliminary data show that cylindrical EEECT can be implanted onto recipient injured adult myocardium as part of a cardiac repair/recovery strategy. Implanted EEECT survive, proliferate, and functionally contribute to recipient cardiac functional recovery.
Specific Aim 1: Define molecular pathways that regulate the EEECT CM proliferation. We hypothesize that (1) EEECT CM proliferation is regulated by interactions between integrin-linked kinase (ILK), p38 mitogen-activated protein kinase (p38 MAPK), and Akt; (2) cyclic mechanical strain stimulates cell proliferation via ILK, p38MAPK, and Akt; and (3) Thyroid hormone triggers CM within EEECT to shift from an immature proliferative to a post-natal hypertrophic growth phenotype.
Specific Aim 2: Determine the fate of EGFP+ EEECT following implantation onto injured adult rat EGFP- myocardium and the contribution of EEECT to recipient myocardial function and remodeling. We hypothesize that following implantation (1) EEECT undergo limited cell death followed by significant CM proliferation; (2), become vascularized by vessels composed predominantly of recipient endothelial cells; (3) positively contribute to the diastolic and systolic functional recovery of recipient infarcted myocardium.
Significance. Our experimental strategy translates insights gained from investigating in vivo embryonic myocardium and in vitro Engineered Early Embryonic Cardiac Tissue (EEECT) towards the long term goal of developing a functioning engineered cardiac graft that optimizes post-implantation cell survival, proliferation, and sustainable functional recovery of injured myocardium.
Term: 07/01/08 – 05/31/12
Amount: $1, 515,000