Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis

Aveline Filliol, Yoshinobu Saito, Ajay Nair, Dianne H. Dapito, Le Xing Yu, Aashreya Ravichandra, Sonakshi Bhattacharjee, Silvia Affo, Naoto Fujiwara, Hua Su, Qiuyan Sun, Thomas M. Savage, John R. Wilson-Kanamori, Jorge M. Caviglia, Li Kang Chin, Dongning Chen, Xiaobo Wang, Stefano Caruso, Jin Ku Kang, Amit Dipak AminSebastian Wallace, Ross Dobie, Deqi Yin, Oscar M. Rodriguez-Fiallos, Chuan Yin, Adam Mehal, Benjamin Izar, Richard A. Friedman, Rebecca G. Wells, Utpal B. Pajvani, Yujin Hoshida, Helen E. Remotti, Nicholas Arpaia, Jessica Zucman-Rossi, Michael Karin, Neil C. Henderson, Ira Tabas, Robert F. Schwabe

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts3, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.

Original languageEnglish (US)
Pages (from-to)356-365
Number of pages10
Issue number7931
StatePublished - Oct 13 2022
Externally publishedYes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis'. Together they form a unique fingerprint.

Cite this