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Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells

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  • Christian Freise
  • Hyunho Lee
  • Christopher Chronowski
  • Doug Chan
  • Jessica Cziomer
  • Martin Rühl
  • Tarkan Dagdelen
  • Maik Lösekann
  • Ulrike Erben
  • Andre Catic
  • Werner Tegge
  • Detlef Schuppan
  • Rajan Somasundaram
  • Ergun Sahin

Abstract

The interaction of extracellular matrix (ECM) components with hepatic stellate cells (HSCs) is thought to perpetuate fibrosis by stimulating signaling pathways that drive HSC activation, survival and proliferation. Consequently, disrupting the interaction between ECM and HSCs is considered a therapeutical avenue although respective targets and underlying mechanisms remain to be established. Here we have interrogated the interaction between type VI collagen (CVI) and HSCs based on the observation that CVI is 10-fold upregulated during fibrosis, closely associates with HSCs in vivo and promotes cell proliferation and cell survival in cancer cell lines. We exposed primary rat HSCs and a rat hepatic stellate cell line (CFSC) to soluble CVI and determined the rate of proliferation, apoptosis and fibrogenesis in the absence of any additional growth factors. We find that CVI in nanomolar concentrations prevents serum starvation-induced apoptosis. This potent anti-apoptotic effect is accompanied by induction of proliferation and acquisition of a pronounced pro-fibrogenic phenotype characterized by increased α-smooth muscle actin, TGF-β, collagen type I and TIMP-1 expression and diminished proteolytic MMP-13 expression. The CVI-HSC interaction can be disrupted with the monomeric α2(VI) and α3(VI) chains and abrogates the activating CVI effects. Further, functional relevant α3(VI)—derived 30 amino acid peptides lead to near-complete inhibition of the CVI effect. In conclusion, CVI serves as a potent mitogen and activating factor for HSCs. The antagonistic effects of the CVI monomeric chains and peptides point to linear peptide sequences that prevent activation of CVI receptors which may allow a targeted antifibrotic therapy.

Suggested Citation

  • Christian Freise & Hyunho Lee & Christopher Chronowski & Doug Chan & Jessica Cziomer & Martin Rühl & Tarkan Dagdelen & Maik Lösekann & Ulrike Erben & Andre Catic & Werner Tegge & Detlef Schuppan & Raj, 2021. "Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells," PLOS ONE, Public Library of Science, vol. 16(9), pages 1-18, September.
  • Handle: RePEc:plo:pone00:0254557
    DOI: 10.1371/journal.pone.0254557
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    References listed on IDEAS

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    1. Ingmar Mederacke & Christine C. Hsu & Juliane S. Troeger & Peter Huebener & Xueru Mu & Dianne H. Dapito & Jean-Philippe Pradere & Robert F. Schwabe, 2013. "Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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