Engineering the Microenvironment of the Human Heart to Mature Human Stem Cell-Derived Cardiomyocytes
Author ORCID Identifier
https://orcid.org/0000-0002-1215-095X
Date of Award
Winter 12-3-2025
Document Type
Thesis (Ph.D.)
Department or Program
Engineering Sciences
First Advisor
John Zhang
Abstract
Despite being the leading cause of death globally, cardiovascular diseases are still subject to controversial pharmacological intervention as the majority of cardiac drug failures and post-approval withdrawals are attributed to unforeseen cardiovascular toxicity. The current standard methods of cardiovascular research based on static two-dimensional cell cultures and animal models have significant translational limitations to overcome unsuccessful drug development. To that end, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown to be promising as an alternative personalized cell source. However, a key bottleneck in the current applications of hiPSC-CMs lies in their structural and functional immaturity and thus, to what extent the intact hiPSC-CMs are predictive of clinical drug effects or disease models is unclear.
Understanding the single cell population dynamics and probabilities that a hiPSC-CM cell will evolve towards a mature adult CM structurally, functionally, and genetically is necessary for making predictions and directing decisions to achieve a desired final cell type or population. By employing developmental biology, biochip design, tissue engineering, and machine learning, this thesis builds the foundation for overcoming this obstacle and develops methodologies and design approaches to understand cardiac single cell-cell and cell-matrix interaction dynamics needed in enhancing maturity of hiPSC-CMs and ultimately treating heart diseases. The goal of this thesis is to establish a paired experimental process and guiding computational model using on-chip dynamic cell culture with spatiotemporal image recordings and RNA sequencing measurements to predict both the outcome of hiPSC-CM maturation level and the process parameters that should be adjusted to achieve the desired result.
The research methodology and design approaches developed through the final microphysiological chip will enable a granular understanding of the microenvironmental effects on the developmental biology of fetal to adult human cardiomyocytes - in particular, the mechanical properties of the matrix and cellular network interactions with respect to hiPSC-CM performance. Modular matrix design approaches and insights derived from this study have the potential to extend to other cellular systems to understand the cell-cell and cell-matrix relationships in complex microenvironmental contexts.
Original Citation
1.Wu, Z.*, Park, J.*, Steiner, P., Zhu, B., Zhang, J.X.J. (2024). A generative adversarial network approach for in vitro hiPSC-CMs during maturation. Scientific Reports, 14, 27016.
2. Wu, Z.*, Park, J., Steiner, P., Zhu, B., Zhang, J.X.J. (2024). A graph-based machine learning approach combined with in-vitro calcium sensing for understanding beating dynamics of cardiomyocytes. Journal of Computational Biology, 32, 3.
3. Park, J.*, Wu, Z.*, Steiner, P., Zhu, B., Zhang, J.X.J. (2022). Heart-on-chip with integrated microfluidic cell culture, sensing and computational modeling towards clinical applications. Ann Biomed Eng, 50 (2): 111-137.
4. Park, J.*, Zhang, J.X.J. (2024). Microfluidics in Cardiac Microphysiological Systems. Journal of Micromechanics and Microengineering, 35, 1.
Recommended Citation
Park, Ji Yoon, "Engineering the Microenvironment of the Human Heart to Mature Human Stem Cell-Derived Cardiomyocytes" (2025). Dartmouth College Ph.D Dissertations. 448.
https://digitalcommons.dartmouth.edu/dissertations/448
