Graduate Seminar Series: Molecular Stream
Graduate Seminar Series for the Institute of Biomedical Engineering (BME). This day is for molecular stream presenters.
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Presentation Title: modRNA as a Modular Tool for Improving Outcomes with Human Pluripotent Stem Cell-Derived Cardiomyocyte Transplantation
Following myocardial infarction (MI), necrotic cardiomyocytes are replaced by non-contractile scar tissue, often leading to progressive heart failure requiring heart transplantation. The scarcity of donor hearts prompted the Laflamme team to use human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to remuscularize the scar tissue, and they have successfully demonstrated partial remuscularization and improved contractile function in multiple animal models of MI. However, the resultant grafts are often relatively small with limited host-graft integration. To improve engraftment outcomes, pro-survival, mitogenic, or pro-migratory proteins can be used but they diffuse away rapidly, limiting the benefit. Moreover, to avoid negative effects of prolonged signaling, such proteins should only be present for a few days post-transplantation. Modified mRNA (modRNA) delivery to hPSC-CMs prior to transplantation facilitates short-term protein translation. modRNA is also not immunogenic and there is no risk of aberrant mutations since the genome is not altered.
Hence, my objective is to demonstrate that modRNA can be used as a tunable protein translation tool to improve the survival and migration of hPSC-CMs post-transplantation using a cryoinjury in guinea pigs as a model of MI. First, I will show that graft size and function can be improved by treating hPSC-CMs with modRNA encoding for the known cytoprotective and mitogenic factor, insulin growth factor 1 (IGF-1). Second, I will show that graft distribution can be modulated by treating cells with the cardiomyocyte chemokinetic factor (Wnt family member 5A) Wnt5a. Finally, I will engineer a cell-specific protein expression tool to enable expression of the protein of interest in graft cells at any time post-transplant. My project will demonstrate the utility of modRNA to improve outcomes post-hPSC-CM transplant in the guinea pig MI model. Replenishing the cardiomyocytes lost after MI will ultimately benefit patients suffering from post-MI heart failure.
Supervisor Name: Michael Laflamme
Year of Study: 2
Program of Study: PhD
Zoom link: https://us02web.zoom.us/j/89610372821?pwd=azd4SCtYVWtreVovaGNPV1c2NGY2Zz09
Meeting ID: 896 1037 2821
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