A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells

Daniel Benten, Johannes Kluwe, Jan W. Wirth, Nina D. Thiele, Antonia Follenzi, Kuldeep K. Bhargava, Christopher J. Palestro, Michael Koepke, Reni Tjandra, Tassilo Volz, Marc Lutgehetmann, Sanjeev Gupta

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo. To investigate whether HSCs could engraft and repopulate the liver, we transplanted GFP-transduced immortalized hHSCs into immunodeficient NOD/SCID mice. Biodistribution analysis with radiolabeled hHSCs showed that after intrasplenic injection, the majority of transplanted cells rapidly translocated to the liver. GFP-immunohistochemistry demonstrated that transplanted hHSCs engrafted alongside hepatic sinusoids. Prior permeabilization of the sinusoidal endothelial layer with monocrotaline enhanced engraftment of hHSCs. Transplanted hHSCs remained engrafted without relevant proliferation in the healthy liver. However, after CCl4 or bile duct ligation-induced liver damage, transplanted hHSCs expanded and contributed to extracellular matrix production, formation of bridging cell-septae and cirrhosis-like hepatic pseudolobules. CCl4-induced injury recruited hHSCs mainly to zone 3, whereas after bile duct ligation, hHSCs were mainly in zone 1 of the liver lobule. Transplanted hHSCs neither transdifferentiated into other cell types nor formed tumors in these settings. In conclusion, a humanized mouse model was generated by transplanting hHSCs, which proliferated during hepatic injury and inflammation, and contributed to liver fibrosis. The ability to repopulate the liver with transplanted hHSCs will be particularly significant for mechanistic studies of cell-cell interactions and fibrogenesis within the liver.

Original languageEnglish (US)
Pages (from-to)525-536
Number of pages12
JournalLaboratory Investigation
Volume98
Issue number4
DOIs
StatePublished - Apr 1 2018

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Hepatic Stellate Cells
Liver Cirrhosis
Liver
Bile Ducts
Ligation
Wounds and Injuries
Monocrotaline
Inbred NOD Mouse
Liver Regeneration
SCID Mice
Myofibroblasts
Extracellular Matrix Proteins
Cell Communication
Extracellular Matrix
Hepatocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells. / Benten, Daniel; Kluwe, Johannes; Wirth, Jan W.; Thiele, Nina D.; Follenzi, Antonia; Bhargava, Kuldeep K.; Palestro, Christopher J.; Koepke, Michael; Tjandra, Reni; Volz, Tassilo; Lutgehetmann, Marc; Gupta, Sanjeev.

In: Laboratory Investigation, Vol. 98, No. 4, 01.04.2018, p. 525-536.

Research output: Contribution to journalArticle

Benten, D, Kluwe, J, Wirth, JW, Thiele, ND, Follenzi, A, Bhargava, KK, Palestro, CJ, Koepke, M, Tjandra, R, Volz, T, Lutgehetmann, M & Gupta, S 2018, 'A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells', Laboratory Investigation, vol. 98, no. 4, pp. 525-536. https://doi.org/10.1038/s41374-017-0010-7
Benten, Daniel ; Kluwe, Johannes ; Wirth, Jan W. ; Thiele, Nina D. ; Follenzi, Antonia ; Bhargava, Kuldeep K. ; Palestro, Christopher J. ; Koepke, Michael ; Tjandra, Reni ; Volz, Tassilo ; Lutgehetmann, Marc ; Gupta, Sanjeev. / A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells. In: Laboratory Investigation. 2018 ; Vol. 98, No. 4. pp. 525-536.
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abstract = "Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo. To investigate whether HSCs could engraft and repopulate the liver, we transplanted GFP-transduced immortalized hHSCs into immunodeficient NOD/SCID mice. Biodistribution analysis with radiolabeled hHSCs showed that after intrasplenic injection, the majority of transplanted cells rapidly translocated to the liver. GFP-immunohistochemistry demonstrated that transplanted hHSCs engrafted alongside hepatic sinusoids. Prior permeabilization of the sinusoidal endothelial layer with monocrotaline enhanced engraftment of hHSCs. Transplanted hHSCs remained engrafted without relevant proliferation in the healthy liver. However, after CCl4 or bile duct ligation-induced liver damage, transplanted hHSCs expanded and contributed to extracellular matrix production, formation of bridging cell-septae and cirrhosis-like hepatic pseudolobules. CCl4-induced injury recruited hHSCs mainly to zone 3, whereas after bile duct ligation, hHSCs were mainly in zone 1 of the liver lobule. Transplanted hHSCs neither transdifferentiated into other cell types nor formed tumors in these settings. In conclusion, a humanized mouse model was generated by transplanting hHSCs, which proliferated during hepatic injury and inflammation, and contributed to liver fibrosis. The ability to repopulate the liver with transplanted hHSCs will be particularly significant for mechanistic studies of cell-cell interactions and fibrogenesis within the liver.",
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AU - Follenzi, Antonia

AU - Bhargava, Kuldeep K.

AU - Palestro, Christopher J.

AU - Koepke, Michael

AU - Tjandra, Reni

AU - Volz, Tassilo

AU - Lutgehetmann, Marc

AU - Gupta, Sanjeev

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