Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy

Stefan Hoehme; Seddik Hammad; Jan Boettger; Brigitte Begher-Tibbe; Petru Bucur; Eric Vibert; Rolf Gebhardt; Jan G Hengstler; Dirk Drasdo

doi:10.1016/j.isci.2022.105714

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy

iScience. 2022 Dec 5;26(1):105714. doi: 10.1016/j.isci.2022.105714. eCollection 2023 Jan 20.

Authors

Stefan Hoehme^{1

2

3}, Seddik Hammad^{4

5

6}, Jan Boettger⁷, Brigitte Begher-Tibbe⁵, Petru Bucur^{8

9}, Eric Vibert⁸, Rolf Gebhardt⁷, Jan G Hengstler⁵, Dirk Drasdo^{1

5

10}

Affiliations

¹ Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany.
² Institute of Computer Science, University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany.
³ Saxonian Incubator for Clinical Research (SIKT), Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany.
⁴ Section Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany.
⁵ Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139 Dortmund, Germany.
⁶ Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
⁷ Faculty of Medicine, Rudolf-Schoenheimer-Institute of Biochemistry, Leipzig University, 04103 Leipzig, Germany.
⁸ Unité INSERM 1193, Centre Hépato-Biliaire, Villejuif, France.
⁹ Service de Chirurgie Digestive, CHU Trousseau, Tours, France.
¹⁰ Inria Paris & Sorbonne Université LJLL, 75012 Paris, France.

Abstract

Partial liver removal is an important therapy option for liver cancer. In most patients within a few weeks, the liver is able to fully regenerate. In some patients, however, regeneration fails with often severe consequences. To better understand the control mechanisms of liver regeneration, experiments in mice were performed, guiding the creation of a spatiotemporal 3D model of the regenerating liver. The model represents cells and blood vessels within an entire liver lobe, a macroscopic liver subunit. The model could reproduce the experimental data only if a biomechanical growth control (BGC)-mechanism, inhibiting cell cycle entrance at high compression, was taken into account and predicted that BGC may act as a short-range growth inhibitor minimizing the number of proliferating neighbor cells of a proliferating cell, generating a checkerboard-like proliferation pattern. Model-predicted cell proliferation patterns in pigs and mice were found experimentally. The results underpin the importance of biomechanical aspects in liver growth control.

Keywords: Tissue engineering; mathematical biosciences; systems biology.