Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis
by
Oliver Krenkel 1,2, Jana Hundertmark 1,3, Thomas P. Ritz 1, Ralf Weiskirchen 4
and Frank Tacke 3,*
Oliver Krenkel 1,2, Jana Hundertmark 1,3, Thomas P. Ritz 1, Ralf Weiskirchen 4 and Frank Tacke 3,*
1
Department of Medicine III, University Hospital Aachen, D-52074 Aachen, Germany
2
Boehringer-Ingelheim Pharma GmbH & Co. KG, D-88397 Biberach an der Riss, Germany
3
Department of Hepatology/Gastroenterology, Charité University Medical Center, D-13353 Berlin, Germany
4
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital Aachen, D-52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 503; https://doi.org/10.3390/cells8050503
Received: 1 May 2019 / Revised: 20 May 2019 / Accepted: 22 May 2019 / Published: 24 May 2019
(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)
Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis.
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Keywords:
hepatic stellate cells; myofibroblasts; liver fibrosis; scRNASeq
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MDPI and ACS Style
Krenkel, O.; Hundertmark, J.; Ritz, T.P.; Weiskirchen, R.; Tacke, F. Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis. Cells 2019, 8, 503.
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