Additive Therapeutic Efficacy Of Pluripotent Stem Cell-Derived Cardiovascular Cells Engrafted In Hydrogels To Treat Ischemia-Reperfusion Injury After Myocardial Infarction - PROJECT SUMMARY / ABSTRACT Limited therapies are available for the preservation of long-term cardiac function following myocardial infarction (MI), a leading cause of death worldwide. The long-term goal is to develop an independent research career as a cardiac surgeon-scientist focused on accelerating the design of novel cell-based therapies for the treatment of MI and ischemia-reperfusion injury (IRI), minimizing infarction-related morbidity and mortality. The overall objective of this proposal is to determine the in-vivo efficacy of myocardial injected human-induced pluripotent stem cell-derived cardiomyocytes and vascular endothelial cells (hiPSC-CMs/vECs) engrafted in retention scaffolds in a post-MI rat model. The central hypothesis is that hiPSC-CMs and hiPSC-vECs in gelatin methacryloyl hydrogel (GelMA-H) engrafted into infarcted cardiac tissue will enhance cell retention, optimizing reestablishment of myocardium and perfused vasculature, leading to reduced fibrosis and preserved cardiac function. The rationale for this research is that rigorous preclinical evidence supporting the therapeutic efficacy of engrafted hiPSC-derived cells would offer a strong scientific framework to guide new strategies to address IRI, enhancing length and quality of life post-infarction. The central hypothesis will be tested via the research aim: Determine the (a) tissue and (b) organ therapeutic efficacy of hiPSC-CMs and hiPSC-vECs engrafted in GelMA-H in an immunodeficient rat model of MI. Under this aim, hiPSC-derived cells will be engrafted in GelMA-H scaffolds and myocardially delivered post-MI. Cell retention will be quantified via bioluminescence. After 4-week survival, immunohistochemical techniques will be employed to elucidate extent of ventricular fibrosis, remuscularization, and angiogenesis and arrhythmogenicity and cardiac function will be assessed. This aim will be accomplished via training goals: 1) Develop proficiency in design and implementation of cell- based translational models and acquire enhanced knowledge in cell differentiation and immunohistochemical techniques; and 2) Attain advanced skills in data collection, analytic strategies, research dissemination, and grantsmanship. Courses, seminars, and conferences will be attended, each purposely selected to accomplish the overall objective and advance the applicant towards an independent basic/translational cardiovascular research career. The research proposed is innovative because it incorporates the use of two cell types derived from hiPSCs engrafted in a hydrogel retention scaffold to maximize the therapeutic effect of stem cell therapy based on the demonstrated benefits of each of these individual components. The proposed work is significant because it is expected to: 1) Provide a strong potential to guide new strategies to address IRI; 2) Mitigate healthcare disparity and burden of a pervasive, preventable public health issue; and 3) Provide necessary training required to submit a competitive K08 focused on development of preclinical interventions to treat MI or IRI as an important step toward future use in humans. Ultimately, such knowledge will have positive impacts on the development of novel cell-based therapies that improve outcomes of patients experiencing MI or IRI.
