ENUMATH 2023, September 4 – 8, Lisbon, Portugal

Mathematical and numerical modeling of cardiac derived stem

cells and isogeometric simulation of an engineered tissue

Sofia Botti1,2 , Chiara Bartolucci4 , Alessandro Reali5 , Stefano Severi4 , Michele Torre5 ,
Luca F. Pavarino2 , and Rolf Krause1,3
1
Euler Institute, Università della Svizzera Italiana, Lugano, Switzerland
2
Department of Mathematics “Felice Casorati”, University of Pavia, Pavia, Italy
3
Faculty of Mathematics and Informatics, FernUni, Brig
4
Department of Electrical, Electronic, and Information Engineering “Guglielmo
Marconi”, University of Bologna, Cesena, Italy
5
Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy
sofia.botti@usi.ch

Abstract
Regenerative cardiology recently advanced in patient-specific medicine by employing somatic cells to
derive Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), [1].
These cells arise from differentiation protocols, that result in heterogeneous populations of immature
CMs consisting predominantly of ventricular-like cells with a small percentage of atrial-like cells and
nodal-like cells. The Dynamic Clamp (DC) technique is a popular experimental manipulation to induce
electronic maturation towards an adult phenotype. To overcome the lack of inward rectifier potassium
current (IK1 ), a closed-loop paradigm uses the acquired transmembrane potential to compute the voltage-
dependent IK1 , finally injected into the cell, [2]. The first presented mathematical model for hiPSC-CMs
is a fully virtual framework to study this DC technique, taking into account six different IK1 formulations.
The hiPSC–CMs’ maturation is analyzed by comparing three specific biomarkers at different injected
current percentages with human adult ventricular-like cardiomyocytes experimental data. The results of
this quantitative analysis suggest that atrial–like potassium current formulations allow the cell to reach
action potential features comparable with the ones of mature cells, [4]
The possibility to engineer hiPSC-derived cardiac cell cultures being as similar as possible to undis-
eased and diseased regions of the human heart is the first step to improving the translation of hiPSC-CMs
to humans. Re-creating in-vitro a reliable 3D tissue is undoubtedly more complex and this study based
on a bioengineered three-dimensional model of a human left heart ventricle, built by Harvard University
researchers, [3]. The challenge is to couple cardiac Monodomain model with stem cell ionic models
to simulate the action potential propagation in the engineered ventricle. The cardiac model is then
discretized by means of Isogoemetric Analysis in space and finite differences in time, carrying out nu-
merical experiments to assess the accuracy of such approach. Thus, the presented framework is used to
investigate the propagation of an action potential on the calibrated model of the engineered ventricle.
Our results demonstrate the increasing accuracy of the virtual representation of innovative hiPSC-CMs
ventricle, suggesting an in silico low-cost approach to stem cells tissue investigations, [5].
Keywords: Human Induced Pluripotent Cells-derived Cardiomyocytes, Monodomain model, Dynamic Clamp
tecnique, Engineered tissue
References
[1] K. Takahashi, S. Yamanaka (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic
and Adult Fibroblast Cultures by Defined Factors. Cell 126.4, 663–676.
[2] A. O. Verkerk, C. C. Veerman, R. Wilders et al. (2017). Patch-clamp recording from human induced
pluripotent stem cell-derived cardiomyocytes: Improving action potential characteristics through dy-
namic clamp. Journal of Molec. Sc. 18(9).
[3] L. MacQueen et al (2018). A tissue-engineered scale model of the heart ventricle. Nat. Biomed. Eng.
2.1, 930–941.
[4] S. Botti, C. Bartolucci, R. Krause, L.F. Pavarino, S. Severi (accepted paper). An in silico Study
of Cardiac hiPSC Electronic Maturation by Dynamic Clamp. In Functional Imaging and Modeling
of the Heart - FIMH 2023, eds.: Olivier Bernard, Patrick Clarysse, Nicolas Duchateau, Jacques
Ohayon, Magalie Viallon. FIMH, Lyon, FR
[5] S. Botti, M. Torre (submitted paper). Isogeometric simulation of a derived stem cell engineered
ventricle.