Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3763914

Documents

In Collections

This item can be found in the following collections:

Helden, R.W.J. van (2024)

Organs-on-chip: towards therapies for cardiovascular disease using human stem cells

Doctoral Thesis
Central to this thesis was the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model a rare form of mitochondrial cardiomyopathy. To model this disease required the design of new methodologies, improving upon the current limitations of hiPSC-CMs as model systems, notably the variability and the immature state of the resulting cardiomyocytes. The diseases we were interested in manifest soon after birth. At the outset of the studies, it was unclear whether a phenotype would be evident in our standard immature 2D cultures, or whether more complex models would be required to capture more salient features of the condition. Our focus was on the rare mitochondrial disease Combined Oxidative Phosphorylation Deficiency, caused by mutations in the gene alanyl-tRNA synthetase 2. We refined our emerging 3D cardiac microtissue protocol to improve robustness and reproducibility and reduce cost by basing differentiation on small molecules rather than growth...Show moreCentral to this thesis was the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model a rare form of mitochondrial cardiomyopathy. To model this disease required the design of new methodologies, improving upon the current limitations of hiPSC-CMs as model systems, notably the variability and the immature state of the resulting cardiomyocytes. The diseases we were interested in manifest soon after birth. At the outset of the studies, it was unclear whether a phenotype would be evident in our standard immature 2D cultures, or whether more complex models would be required to capture more salient features of the condition. Our focus was on the rare mitochondrial disease Combined Oxidative Phosphorylation Deficiency, caused by mutations in the gene alanyl-tRNA synthetase 2. We refined our emerging 3D cardiac microtissue protocol to improve robustness and reproducibility and reduce cost by basing differentiation on small molecules rather than growth factors without altering the functionality of hiPSC-CMs. We also demonstrated that integrating pH and O2 sensors in a micro-physiological chip was possible for the assessment of metabolic parameters under microfluidic flow. The overall goal of this thesis was to provide additional tools that would have utility in studying mitochondrial and other cardiac diseases.
Show less
hiPSC
Cardiomyocytes
Organ-on-Chip
Cardiomyopathy
Mitochondrial disease
Organoids
Cardiac metabolism
In vitro disease modeling
All authors
Helden, R.W.J. van
Supervisor
Mummery, C.L.
Co-supervisor
Bellin, M.; Orlova, V.V.
Committee
Jongbloed, M.R.M.; Quax, P.H.A.; Passier, P.C.J.J.; Velden, J. van der
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2024-06-19
ISBN (print)
9789465061108

Funding

Sponsorship
nCardia, Dutch Heart Foundation, Willy van Heumenfonds, Proefdier vrij