Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis (Équipe Housset)

12 - Mars - 2022

Lin Lei, Alix Bruneau, Haquima El Mourabit, Justine Guegan, Trine Folseraas, Sara Lemoinne, Tom Hemming Karlsen, Bénédicte Hoareau, Romain Morichon, Ester Gonzalez-Sanchez, Claire Goumard, Vlad Ratziu, Pierre Charbord, Jérémie Gautheron, Frank Tacke, Thierry Jaffredo, Axelle Cadoret, Chantal Housset

Hepatology 2022

BACKGROUND & AIMS: In liver fibrosis, myofibroblasts derive from hepatic stellate cells (HSCs) and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts.

APPROACH & RESULTS: Portal mesenchymal cells were isolated from mouse bilio-vascular tree and analyzed by scRNAseq. Thereby, we uncovered the landscape of portal mesenchymal cells in homeostatic mouse liver. Trajectory analysis enabled inferring a small cell population further defined by surface markers used to isolate it. This population consisted of portal fibroblasts with mesenchymal stem cell features (PMSCs), i.e., high clonogenicity and tri-lineage differentiation potential, that generated proliferative myofibroblasts, contrasting with non-proliferative HSC-derived myofibroblasts (-MFs). Using bulk RNAseq, we built oligogene signatures of the two cell populations, that remained discriminant across myofibroblastic differentiation. SLIT2, a prototypical gene of PMSC/PMSC-MF signature, mediated pro-fibrotic and angiogenic effects of these cells, whose conditioned medium promoted HSC survival and endothelial cell tubulogenesis. Using PMSC/PMSC-MF 7-gene signature and SLIT2 FISH, we showed that PMSCs display a perivascular portal distribution in homeostatic liver and largely expand with fibrosis progression, contributing to the myofibroblast populations that form fibrotic septa, preferentially along neo-vessels, in murine and human liver disorders, irrespective of aetiology. We also unraveled a 6-gene expression signature of HSCs/HSC-MFs that did not vary in these disorders, consistent with their low proliferation rate.

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Perivascular portal fibroblasts with stem cell features generate expansive myofibroblasts, expressing SLIT2, which promotes angiogenesis and the survival of hepatic stellate cell-derived myofibroblasts, thereby underlying the formation of fibrotic septa (FS).

CONCLUSIONS: PMSCs form a small reservoir of expansive myofibroblasts, which in interaction with neo-vessels and HSC-MFs that mainly arise via differentiation from a preexisting pool, underlie the formation of fibrotic septa in all types of liver diseases.

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