Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Lua, Ingrid; Li, Yuchang; Pappoe, Lamioko S.; Asahina, Kinji

doi:10.1016/j.ajpath.2015.08.009

Cited by 57 publications

(86 citation statements)

References 39 publications

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“…In the CG model, we observed GFP + ACTA2 + myofibroblasts in the CF area that are positive for COLI (Fig. C), as we previously reported . One month after recovery from CG‐induced CF, mesothelial cells remained positive for GFP, but no GFP + cells were observed beneath mesothelial cells (Fig.…”

Section: Resultssupporting

confidence: 83%

“…Tamoxifen (Sigma‐Aldrich, St. Louis, MO) was injected intraperitoneally to Wt1 CreERT2 ; Rosa26mTmG flox ( R26TG fl/fl ) and R26TG fl/fl mice at 100 µg/g body weight twice in a 3‐day interval . To induce CF, we injected 0.1% chlorhexidine gluconate (CG) in 15% ethanol/phosphate‐buffered saline to mice at 1.5 mL/100 g body weight into the peritoneum every other day for a total of 10 times . For recovery from CG‐induced CF, mice were kept for 1 month without treatment.…”

Section: Methodsmentioning

confidence: 99%

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Development of Capsular Fibrosis Beneath the Liver Surface in Humans and Mice

Balog

Ogawa

et al. 2019

Hepatology

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Glisson's capsule is the connective tissue present in the portal triad as well as beneath the liver surface. Little is known about how Glisson's capsule changes its structure in capsular fibrosis (CF), which is characterized by fibrogenesis beneath the liver surface. In this study, we found that the human liver surface exhibits multilayered capsular fibroblasts and that the bile duct is present beneath the mesothelium, whereas capsular fibroblasts are scarce and no bile ducts are present beneath the mouse liver surface. Patients with cirrhosis caused by alcohol abuse or hepatitis C virus infection show development of massive CF. To examine the effect of alcohol on CF in mice, we first injected chlorhexidine gluconate (CG) intraperitoneally and then fed alcohol for 1 month. The CG injection induces CF consisting of myofibroblasts beneath the mesothelium. One month after CG injection, the fibrotic area returns to the normal structure. In contrast, additional alcohol feeding sustains the presence of myofibroblasts in CF. Cell lineage tracing revealed that mesothelial cells give rise to myofibroblasts in CF, but these myofibroblasts disappear 1 month after recovery with or without alcohol feeding. Capsular fibroblasts isolated from the mouse liver spontaneously differentiated into myofibroblasts and their differentiation was induced by transforming growth factor beta 1 (TGF‐β1) or acetaldehyde in culture. In alcohol‐fed mice, infiltrating CD11b+Ly‐6CLow/– monocytes had reduced mRNA expression of matrix metalloproteinase 13 and matrix metalloproteinase 9 and increased expression of tissue inhibitor of matrix metalloproteinase 1, Tgfb1, and interleukin‐10 during resolution of CF. Conclusion: The present study revealed that the structure of Glisson's capsule is different between human and mouse livers and that alcohol impairs the resolution of CF by changing the phenotype of Ly‐6CLow/– monocytes.

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Section: Resultssupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Development of Capsular Fibrosis Beneath the Liver Surface in Humans and Mice

Balog

Ogawa

et al. 2019

Hepatology

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“…The cells were treated with 10 ng/ml TGF-β1 (Sigma) or 100 pg/ml PDGF-BB (eBioscience, San Diego, CA). Immunocytochemistry was performed as previously described[16,18]. The cells cultured on a glass cover were fixed with 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

“…MCs express glycoprotein M6A (GPM6A), mesothelin (MSLN), and podoplanin (PDPN)[16–18]. During liver development, mesodermal MCs migrate inward from the liver surface and give rise to both HSCs and PFs[19].…”

Section: Introductionmentioning

confidence: 99%

“…During liver development, mesodermal MCs migrate inward from the liver surface and give rise to both HSCs and PFs[19]. Upon liver injury, MCs give rise to HSCs or myofibroblasts near the liver surface, depending on the etiology[16,18]. Similar to HSC activation, MCs change their phenotype to myofibroblasts in response to transforming growth factor-β (TGF-β)[16].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers

Lua

Zagory

et al. 2016

Journal of Hepatology

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125

115

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Background & Aims Contribution of hepatic stellate cells (HSCs), portal fibroblasts (PFs), and mesothelial cells (MCs) to myofibroblasts is not fully understood due to insufficient availability of markers and isolation methods. The present study aimed to isolate these cells, characterize their phenotypes, and examine their contribution to myofibroblasts in liver fibrosis. Methods Liver fibrosis was induced in Collagen1a1-green fluorescent protein (Col1a1GFP) mice by bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, or CCl4 injections. Combining vitamin A (VitA) lipid autofluorescence and expression of GFP and glycoprotein M6a (GPM6A), we separated HSCs, PFs, and MCs from normal and fibrotic livers by fluorescence-activated cell sorting (FACS). Results Normal Col1a1GFP livers broadly expressed GFP in HSCs, PFs, and MCs. Isolated VitA+ HSCs expressed reelin, whereas VitA−GFP+GPM6A− PFs expressed ectonucleoside triphosphate diphosphohydrolase-2 and elastin. VitA−GFP+GPM6A+ MCs expressed keratin 19, mesothelin, and uroplakin 1b. Transforming growth factor (TGF)-β1 treatment induced the transformation of HSCs, PFs, and MCs into myofibroblasts in culture. TGF-β1 suppressed cyclin D1 mRNA expression in PFs but not in HSCs and MCs. In biliary fibrosis, PFs adjacent to the bile duct expressed α-smooth muscle actin. FACS analysis revealed that HSCs are the major source of GFP+ myofibroblasts in the injured Col1a1GFP mice after DDC or CCl4 treatment. Although PFs partly contributed to GFP+ myofibroblasts in the BDL model, HSCs were still dominant source of myofibroblasts. Conclusion HSCs, PFs, and MCs have distinct phenotypes, and PFs partly contribute to myofibroblasts in the portal triad in biliary fibrosis.

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Single‐cell RNA sequencing captures patient‐level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions

Whitfield,

Berthelet,

Mangiola

et al. 2023

Clinical & Translational Med

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BackgroundMalignant pleural effusions (MPEs) are a common complication of advanced cancers, particularly those adjacent to the pleura, such as lung and breast cancer. The pathophysiology of MPE formation remains poorly understood, and although MPEs are routinely used for the diagnosis of breast cancer patients, their composition and biology are poorly understood. It is difficult to distinguish invading malignant cells from resident mesothelial cells and to identify the directionality of interactions between these populations in the pleura. There is a need to characterize the phenotypic diversity of breast cancer cell populations in the pleural microenvironment, and investigate how this varies across patients.MethodsHere, we used single‐cell RNA‐sequencing to study the heterogeneity of 10 MPEs from seven metastatic breast cancer patients, including three Miltenyi‐enriched samples using a negative selection approach. This dataset of almost 65 000 cells was analysed using integrative approaches to compare heterogeneous cell populations and phenotypes.ResultsWe identified substantial inter‐patient heterogeneity in the composition of cell types (including malignant, mesothelial and immune cell populations), in expression of subtype‐specific gene signatures and in copy number aberration patterns, that captured variability across breast cancer cell populations. Within individual MPEs, we distinguished mesothelial cell populations from malignant cells using key markers, the presence of breast cancer subtype expression patterns and copy number aberration patterns. We also identified pleural mesothelial cells expressing a cancer‐associated fibroblast‐like transcriptomic program that may support cancer growth.ConclusionsOur dataset presents the first unbiased assessment of breast cancer‐associated MPEs at a single cell resolution, providing the community with a valuable resource for the study of MPEs. Our work highlights the molecular and cellular diversity captured in MPEs and motivates the potential use of these clinically relevant biopsies in the development of targeted therapeutics for patients with advanced breast cancer.

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Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Cited by 57 publications

References 39 publications

Development of Capsular Fibrosis Beneath the Liver Surface in Humans and Mice

Development of Capsular Fibrosis Beneath the Liver Surface in Humans and Mice

Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers

Single‐cell RNA sequencing captures patient‐level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions

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