Angiocrine Hepatocyte Growth Factor Signaling Controls Physiological Organ and Body Size and Dynamic Hepatocyte Proliferation to Prevent Liver Damage during Regeneration

Xue-Jun Zhang; Victor Olsavszky; Yuhan Yin; Baocai Wang; Thomas Engleitner; Rupert Öllinger; Kai Schledzewski; Philipp-Sebastian Koch; Roland Rad; Roland M Schmid; Helmut Friess; Sergij Goerdt; Norbert Hüser; Cyrill Géraud; Guido von Figura; Daniel Hartmann

doi:10.1016/j.ajpath.2019.10.009

Angiocrine Hepatocyte Growth Factor Signaling Controls Physiological Organ and Body Size and Dynamic Hepatocyte Proliferation to Prevent Liver Damage during Regeneration

Am J Pathol. 2020 Feb;190(2):358-371. doi: 10.1016/j.ajpath.2019.10.009. Epub 2019 Nov 27.

Authors

Xue-Jun Zhang¹, Victor Olsavszky², Yuhan Yin³, Baocai Wang³, Thomas Engleitner⁴, Rupert Öllinger⁴, Kai Schledzewski², Philipp-Sebastian Koch², Roland Rad⁴, Roland M Schmid⁵, Helmut Friess³, Sergij Goerdt², Norbert Hüser³, Cyrill Géraud⁶, Guido von Figura⁵, Daniel Hartmann⁷

Affiliations

¹ Department of Surgery, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany; Department of Orthopedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
² Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Center of Excellence in Dermatology, Mannheim, Germany.
³ Department of Surgery, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany.
⁴ Translatum Cancer Center, and Department of Medicine II, Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany.
⁵ II: Medical Clinic and Policlinic, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany.
⁶ Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Center of Excellence in Dermatology, Mannheim, Germany; Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: [email protected].
⁷ Department of Surgery, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany. Electronic address: [email protected].

PMID: 31783007
DOI: 10.1016/j.ajpath.2019.10.009

Abstract

Liver sinusoidal endothelial cells (LSECs) control organ functions, metabolism, and development through the secretion of angiokines. LSECs express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiological homeostasis and liver regeneration. Stab2-iCre^tg/wt;Hgf^fl/fl (Hgf^ΔLSEC) mice were generated to abrogate Hgf expression selectively in LSECs from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver/body weight ratios were not altered, total body weight and total liver weight were reduced in Hgf^ΔLSEC. Necrotic organ damage was more marked in Hgf^ΔLSEC mice, and regeneration was delayed 72 hours after PH. This was associated with decreased hepatocyte proliferation at 48 hours after PH. Molecularly, Hgf^ΔLSEC mice showed down-regulation of Hgf/c-Met signaling and decreased expression of Deptor in hepatocytes. In vitro knockdown of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis after partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Size*
Cell Adhesion Molecules, Neuronal / physiology
Cell Proliferation*
Endothelium / cytology
Endothelium / metabolism
Female
Hepatectomy
Hepatocyte Growth Factor / physiology*
Hepatocytes / cytology*
Hepatocytes / physiology
Homeostasis
Liver Diseases / metabolism
Liver Diseases / pathology
Liver Diseases / prevention & control*
Liver Regeneration*
Male
Mice
Mice, Knockout
Organogenesis / physiology*
Paracrine Communication
Signal Transduction

Substances

Cell Adhesion Molecules, Neuronal
HGF protein, mouse
Stab2 protein, mouse
Hepatocyte Growth Factor