Adverse remodeling of the myocardium after myocardial infarction speeds progression to heart failure. Some of the major shortcomings in cell therapy are the growth and differentiation of implanted cells. In patients, cells are injectedto an area comprised mostly of noncontractile collagen, far different from their native microenvironment. This study aims to determine whether a biodegradable, modular hydrogel can be used to implant cells and direct their behavior. Dr. Andres Garcia has developed a biocompatible, injectable, smart delivery system based on polyethylene glycol. This material forms a stable hydrogel and degrades as matrix metalloproteases are released. Our preliminary data suggest that adult c-kit positive cardiac progenitor cells (CPCs) currently in human clinical trials, migrate into hydrogels containing growth factors, but the numbers of these cells in vivo is not known. Preliminary data from that Davis laboratory suggests that these cells express the Notch receptor and respond to Jagged- induced activation by increasing differentiation. In a separate system, a Notch-activating peptide termed JAG-1 has been immobilized and CPCs cultured within demonstrate increased expression of cardiac, endothelial, and smooth muscle genes. Completion of the proposed studies will demonstrate a potential role for PEG hydrogel- mediated delivery of CPCs to the post-infarct myocardium for the purpose of enhancing implanted progenitor cell therapy.
Cardiovascular disease is a leading cause of morbidity and mortality worldwide and effective diagnostic and treatment options are greatly needed. Cell therapy trials show promise, but still require new strategies to improve efficacy. We propose that delivery of cells within a modular, biodegradable hydrogel with cardiac ligands will improve transplanted cell therapy efficacy leading to improved function.
|Zhou, Dennis W; Lee, Ted T; Weng, Shinuo et al. (2017) Effects of substrate stiffness and actomyosin contractility on coupling between force transmission and vinculin-paxillin recruitment at single focal adhesions. Mol Biol Cell 28:1901-1911|