Sexual Dimorphism in Hepatocyte Xenograft Models

Gulce Sari, Gertine W. van Oord, Martijn D.B. van de Garde, Jolanda J.C. Voermans, Andre Boonstra, Thomas Vanwolleghem*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
29 Downloads (Pure)

Abstract

Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.

Original languageEnglish
Pages (from-to)1-12
JournalCell Transplantation
Volume30
Early online date2 May 2021
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
The authors thank Dr Zongdi Feng (Nationswide Children Hospital, Columbus, Ohio) for providing the HEV Kernow strain; Claudia E. Mulders (Erasmus University Medical Center, Department of Viroscience, Rotterdam, Netherlands) and Anthonie Z.M.A. Groothuismink (Erasmus University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands) for excellent technical assistance in HEV studies and microscopy imaging. Authors also thank Juan Rodríguez-Coira Villanueva who was involved in the initial parts of the study. TV is a Senior Clinical Investigator of the Research Foundation—Flanders (Belgium) (FWO). The author(s) received no financial support for the research, authorship, and/or publication of this article.

Publisher Copyright:
© The Author(s) 2021.

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