Expression of the ECM proteins fibulin-1 and -2 in acute and chronic liver disease and in cultured rat liver cells

Piscaglia, Fabio; Dudas, J.; Knittel, Thomas; Rocco, P. Di; Saile, Bernhard; Ramadori, Giuliano

doi:10.1055/s-0029-1191795

Cited by 8 publications

(10 citation statements)

References 46 publications

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“…In cirrhotic liver, COL15A1 was expressed together with α‐SMA in cells thus identified as PMFs that were outlining capillaries within large fibrotic septa. Likewise, fibulin‐2, previously used as a marker of PMFs, has been shown to colocalize with vWF along vessels running in the large septa of fibrotic livers . We also found a perivascular distribution of fibulin‐2 in cirrhotic livers, although the area of fibulin‐2 staining in these tissues was largely extracellular and more extensive than that of COL15A1.…”

Section: Discussionsupporting

confidence: 67%

“…F and http://onlinelibrary.wiley.com/doi/10.1002/hep.27318/suppinfo, right‐upper panel). We also performed experiments to determine how COL15A1 compared with fibulin‐2, a previously used marker of PMFs . We confirmed, by RT‐PCR analyses, that Col15a1 was more discriminant than fibulin‐2 to distinguish PMFs from HSC‐MFs (http://onlinelibrary.wiley.com/doi/10.1002/hep.27318/suppinfo).…”

Section: Resultssupporting

confidence: 52%

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Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

et al. 2015

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Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC‐derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1‐immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1‐expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF‐conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A‐containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA‐laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)

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Section: Discussionsupporting

confidence: 67%

Section: Resultssupporting

confidence: 52%

Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

et al. 2015

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“…INK4A (CDKN2A), which belongs to the family of cyclin-dependent kinase inhibitors, leads to cell cycle arrest in the G1 phase by causing the inhibition of cyclin D-dependent kinases [74]. Fibulin-1(FBLN1) belongs to an enormous family of plasma glycoprotein and will be significantly increased in acute liver injury [75].…”

Section: Gene Methylation Alterationsmentioning

confidence: 99%

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma

Gassa

et al. 2020

Int. J. Biol. Sci.

111

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As one of the most common malignant tumors worldwide, hepatocellular carcinoma (HCC) is known for its poor prognosis due to diagnosis only in advanced stages. Nearly 50% of the patients with the first diagnosis of HCC die within a year. Currently, the advancements in the integration of omics information have begun to transform the clinical management of cancer patients. Molecular profiling for HCC patients is in general obtained from resected tumor materials or biopsies. However, the resected tumor tissue is limited and can only be obtained through surgery, so that dynamic monitoring of patients cannot be performed. Compared to invasive procedures, circulating tumor DNA (ctDNA) has been proposed as an alternative source to perform molecular profiling of tumor DNA in cancer patients. The detection of abnormal forms of circulating cell-free DNA (cfDNA) that originate from cancer cells (ctDNA) provides a novel tool for cancer detection and disease monitoring. This may also be an opportunity to optimize the early diagnosis of HCC. In this review, we summarized the updated methods, materials, storage of sampling, detection techniques for ctDNA and the comparison of the applications among different biomarkers in HCC patients. In particular, we analyzed ctDNA studies dealing with copy number variations, gene integrity, mutations (RAS, TERT, CTNNB1, TP53 and so on), DNA methylation alterations (DBX2, THY1, TGR5 and so on) for the potential utility of ctDNA in the diagnosis and management of HCC. The biological functions and correlated signaling pathways of ctDNA associated genes (including MAPK/RAS pathway, p53 signaling pathway and Wnt-β catenin pathway) are also discussed and highlighted. Thus, exploration of ctDNA/cfDNA as potential biomarkers may provide a great opportunity in future liquid biopsy applications for HCC.

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“…Perhaps epidermal dendritic cells are critical producers of TGF-β1 in Tsk2/+ skin (Gruschwitz and Hornstein, 1992). The proposed causal relationship of TGF-β1 to skin fibrosis and the physical phenotype of tight skin in Tsk2/+ mice needs verification, but we note that at two weeks, skin from male Tsk2/+ mice expresses 170%-300% more mRNA for five TGF-β1 signature proteins (collagen type V, alpha 2; elastin; fibulin-2; α-smooth muscle actin; and cartilage oligomeric protein) (Piscaglia et al, 2009;Kurpinski et al, 2010;Sargent et al, 2010) as assessed by quantitative real-time PCR (data not shown).…”

Section: Discussionmentioning

confidence: 80%

Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and subset Distinctions

Blankenhorn¹,

Whitfield²,

Artlett³

2014

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Rationale: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of human disease, including tight skin, excessive collagen deposition, alterations in the extracellular matrix (ECM), increased elastic fibers, and occurrence of antinuclear antibodies with age. A tight skin phenotype is observed by 2 weeks of age, but measurable skin fibrosis is only apparent at 10 weeks. We completed a series of wound healing experiments to determine how fibrosis affects wound healing in Tsk2/ + mice compared with their wild-type (WT) littermates. Method: We performed these experiments by introducing four 4 mm biopsy punched wounds on the back of each mouse, ventral of the midline, and observed wound healing over 10 days. Tsk2/ + mice showed significantly delayed wound healing and increased wound size compared with the WT littermates at both 5 and 10 weeks of age. We explored the potential sources of this response by wounding Tsk2/ + mice that were genetically deficient either for the NLRP3 inflammasome (a known fibrosis mediator), or for elastic fibers in the skin, using a fibulin-5 knockout. Conclusion: We found that the loss of elastic fibers restores normal wound healing in the Tsk2/ + mouse and that the loss of the NLRP3 inflammasome had no effect. We conclude that elastic fiber dysregulation is the primary cause of delayed wound healing in the Tsk2/ + mouse and therapies that promote collagen deposition in the tissue matrix in the absence of elastin deposition might be beneficial in promoting wound healing in SSc and other diseases.

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Expression of the ECM proteins fibulin-1 and -2 in acute and chronic liver disease and in cultured rat liver cells

Cited by 8 publications

References 46 publications

Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma

Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and subset Distinctions

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