Growth differentiation factor 7 autocrine signaling promotes hepatic progenitor cell expansion in liver fibrosis

Defu Kong; Apostolos Mourtzinos; Janette Heegsma; Hans Blokzijl; Vincent E de Meijer; Klaas Nico Faber

doi:10.1186/s13287-023-03493-3

Growth differentiation factor 7 autocrine signaling promotes hepatic progenitor cell expansion in liver fibrosis

Stem Cell Res Ther. 2023 Oct 5;14(1):288. doi: 10.1186/s13287-023-03493-3.

Authors

Defu Kong¹, Apostolos Mourtzinos¹, Janette Heegsma¹, Hans Blokzijl¹, Vincent E de Meijer², Klaas Nico Faber³

Affiliations

¹ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
² Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. k.n.faber@umcg.nl.

Abstract

Background and aim: Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver.

Methods: GDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids.

Results: GDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids.

Conclusions: Collectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease.

Keywords: GDF7; LGR5; Liver fibrosis; Organoids; Progenitor cell.

Publication types

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

MeSH terms

Autocrine Communication*
Hepatic Stellate Cells / metabolism
Humans
Liver / metabolism
Liver Cirrhosis / pathology
Liver Diseases* / pathology
Stem Cells / metabolism
Transforming Growth Factor beta1 / metabolism

Substances

growth differentiation factor 7
Transforming Growth Factor beta1
GDF7 protein, human