MATURATION OF HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES PROJECT SUMMARY Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide a novel and physiologically relevant source of cells that have the potential to be used for in vitro cardiotoxicity testing and disease modeling as well as for the study of in vivo heart development and regenerative medicine. However, compared with primary human CMs, hPSC-CMs are structurally and functionally less mature, which limits their ability to accurately predict cardiotoxicity and model human development and diseases, and may result in adverse events such as arrhythmias upon transplantation. Therefore, improving hPSC-CM maturation is paramount in order to improve applications of these cells. We and other groups have previously demonstrated that efficient CM differentiation from hPSCs can be achieved via mimicking molecular signaling of cardiac induction during in vivo cardiogenesis. In our recent publications, we have also shown that microscale tissue engineering enables reliable generation of 3D cardiac spheres that contain highly enriched hPSC-CMs with enhanced sarcomeric structural maturation. We hypothesize that a multipronged, synergistic approach combining tissue engineering with modulation of multiple molecular signaling pathways can efficiently improve hPSC-CM maturation within short culture durations. With this hypothesis, we aim to enable metabolic and functional maturation of hPSC-CMs by providing the cells with (1) appropriate chemical signals to modulate metabolic maturation and (2) suitable environmental cues to mimic the transition from fetal CMs to postnatal CMs. We expect that this study will lead to the establishment of hPSC-CMs with cardiophysiology closer to human hearts, which will facilitate their applications in preclinical and clinical studies, and provide novel insights into molecular regulation of CM maturation.

Public Health Relevance

We aim to examine stem cell-derived cardiomyocytes in response to a multipronged approach for promotion of cardiomyocyte maturation. Findings from this study will help to address key issues facing applications of cardiomyocytes derived from human pluripotent stem cells in cardiotoxicity testing, disease modeling, developmental biology and regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136345-02
Application #
9636605
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Lundberg, Martha
Project Start
2018-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Rampoldi, Antonio; Crooke, Stephen N; Preininger, Marcela K et al. (2018) Targeted Elimination of Tumorigenic Human Pluripotent Stem Cells Using Suicide-Inducing Virus-like Particles. ACS Chem Biol 13:2329-2338