Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis
Background and Aims In liver fibrosis, myofibroblasts derive from HSCs and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts. Approach and Results Portal mesenchymal cells were isolated from mouse bilio‐vascular tree and analyzed by single‐cell...
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Published in | Hepatology (Baltimore, Md.) Vol. 76; no. 5; pp. 1360 - 1375 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Wiley Subscription Services, Inc
01.11.2022
Wiley-Blackwell |
Subjects | |
Online Access | Get full text |
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Summary: | Background and Aims
In liver fibrosis, myofibroblasts derive from HSCs and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts.
Approach and Results
Portal mesenchymal cells were isolated from mouse bilio‐vascular tree and analyzed by single‐cell RNA‐sequencing. 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 trilineage differentiation potential, that generated proliferative myofibroblasts, contrasting with nonproliferative HSC‐derived myofibroblasts (‐MF). Using bulk RNA‐sequencing, 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 profibrotic and angiogenic effects of these cells, which conditioned medium promoted HSC survival and endothelial cell tubulogenesis. Using PMSC/PMSC‐MF 7‐gene signature and slit guidance ligand 2 fluorescent in situ hybridization, 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 neovessels, in murine and human liver disorders, irrespective of etiology. 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.
Conclusions
PMSCs form a small reservoir of expansive myofibroblasts, which, in interaction with neovessels and HSC‐MFs that mainly arise through differentiation from a preexisting pool, underlie the formation of fibrotic septa in all types of liver diseases. |
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Bibliography: | Funding information SEE ARTICLE ON PAGE 1240 Axelle Cadoret and Chantal Housset share senior authorship. This work was supported by funding from Agence nationale de recherches sur le sida et les hépatites virales (ECTZ35217), Fondation pour la Recherche Médicale (EQU202003010517), and the Microbiome Foundation. Lin Lei received a fellowship from the China Scholarship Council ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0270-9139 1527-3350 |
DOI: | 10.1002/hep.32456 |