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Portal myofibroblasts connect angiogenesis and fibrosis in liver

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Abstract

Liver fibrogenesis is a dynamic process including quantitative and qualitative changes of the extracellular matrix, of which the most prominent is the deposition of type I collagen. These changes progressively disrupt normal liver architecture and result in cirrhosis formation. In the fibrotic liver, as in all other fibrotic tissues, the extracellular matrix is produced by cells usually characterized by the de novo expression of alpha-smooth muscle actin and known as myofibroblasts. Portal myofibroblasts (PMFs) appear to be critical in pathological angiogenesis, which constantly occurs in advanced liver fibrosis. Whereas the association between angiogenesis and fibrosis during the progression of liver diseases remains to be elucidated, we suggest that collagen-type-XV-alpha1-producing PMFs could provide an important link both by stabilizing newly formed vessels and by forming a scaffold for the deposition of interstitial collagen.

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Abbreviations

α-SMA:

Alpha-smooth muscle actin

BDL:

Bile duct ligation

COL15A1:

Collagen type XV alpha1

COX-2:

Cyclooxygenase-2

HSC:

Hepatic stellate cell

HSC-MF:

Hepatic-stellate-cell-derived myofibroblast

MCD:

Methionine-choline-deficient

MMP:

Matrix metalloproteinase

NAFLD:

Non-alcoholic fatty liver disease

PDGF-BB:

Platelet-derived growth factor-BB

PDGFR-β:

Platelet-derived growth factor receptor-beta

PlGF:

Placental growth factor

PMF:

Portal myofibroblast

TAA:

Thioacetamide

TGF-β:

Transforming growth factor-beta

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  • Beaussier M, Wendum D, Schiffer E, Dumont S, Rey C, Lienhart A, Housset C (2007) Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab Invest 87:292–303

    Article  CAS  PubMed  Google Scholar 

  • Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, Housset C, Rosmorduc O (2002) Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35:1010–1021

    Article  CAS  PubMed  Google Scholar 

  • Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Mockel D, Baeck C, Hittatiya K, Eulberg D, Luedde T, Kiessling F, Trautwein C, Lammers T, Tacke F (2014) CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63:1960–1971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elpek GO (2015) Angiogenesis and liver fibrosis. World J Hepatol 7:377–391

    Article  PubMed  PubMed Central  Google Scholar 

  • Eyden B (2008) The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J Cell Mol Med 12:22–37

    Article  CAS  PubMed  Google Scholar 

  • Gao JH, Wen SL, Yang WJ, Lu YY, Tong H, Huang ZY, Liu ZX, Tang CW (2013) Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. PloS one 8:e69309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennenberg M, Trebicka J, Kohistani Z, Stark C, Nischalke HD, Kramer B, Korner C, Klein S, Granzow M, Fischer HP, Heller J, Sauerbruch T (2011) Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. Lab Invest 91:241–251

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Feng H, Kan T, Huang B, Zhang M, Li Y, Shi C, Wu M, Luo Y, Yang J, Xu F (2013) Bevacizumab attenuates hepatic fibrosis in rats by inhibiting activation of hepatic stellate cells. PloS one 8:e73492

    Article  CAS  PubMed Central  Google Scholar 

  • Iwaisako K, Jiang C, Zhang M, Cong M, Moore-Morris TJ, Park TJ, Liu X, Xu J, Wang P, Paik YH, Meng F, Asagiri M, Murray LA, Hofmann AF, Iida T, Glass CK, Brenner DA, Kisseleva T (2014) Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 111:E3297–E3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ (2001) Impaired angiogenesis in the remnant kidney model. II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 12:1448–1457

    CAS  PubMed  Google Scholar 

  • Kimura K, Nakayama M, Naito I, Komiyama T, Ichimura K, Asano H, Tsukuda K, Ohtsuka A, Oohashi T, Miyoshi S, Ninomiya Y (2016) Human collagen XV is a prominent histopathological component of sinusoidal capillarization in hepatocellular carcinogenesis. Int J Clin Oncol 21:302–309

    Article  CAS  PubMed  Google Scholar 

  • Kinnman N, Francoz C, Barbu V, Wendum D, Rey C, Hultcrantz R, Poupon R, Housset C (2003) The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest 83:163–173

    Article  CAS  PubMed  Google Scholar 

  • Lemoinne S, Cadoret A, Rautou PE, El Mourabit H, Ratziu V, Corpechot C, Rey C, Bosselut N, Barbu V, Wendum D, Feldmann G, Boulanger C, Henegar C, Housset C, Thabut D (2015) Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles. Hepatology 61:1041–1055

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Dranoff JA, Chan EP, Uemura M, Sevigny J, Wells RG (2007) Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 46:1246–1256

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Yang Z, Wang L, Lu Y, Tang B, Miao H, Xu Q, Chen X (2015) Combination of sorafenib and gadolinium chloride (GdCl3) attenuates dimethylnitrosamine(DMN)-induced liver fibrosis in rats. BMC Gastroenterol 15:159

    Article  PubMed  Google Scholar 

  • Lua I, Li Y, Zagory JA, Wang KS, French SW, Sevigny J, Asahina K (2016) Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers. J Hepatol 64:1137–1146

    Article  CAS  PubMed  Google Scholar 

  • May D, Djonov V, Zamir G, Bala M, Safadi R, Sklair-Levy M, Keshet E (2011) A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations. PloS one 6:e21478

    Article  CAS  PubMed  Google Scholar 

  • Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823

    Article  PubMed  Google Scholar 

  • Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M (2009) Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 49:1245–1256

    Article  CAS  PubMed  Google Scholar 

  • Novo E, Cannito S, Zamara E, Valfre di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M (2007) Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170:1942–1953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patsenker E, Popov Y, Stickel F, Schneider V, Ledermann M, Sagesser H, Niedobitek G, Goodman SL, Schuppan D (2009) Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 50:1501–1511

    Article  CAS  PubMed Central  Google Scholar 

  • Rappaport AM, MacPhee PJ, Fisher MM, Phillips MJ (1983) The scarring of the liver acini (cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol 402:107–137

    Article  CAS  PubMed  Google Scholar 

  • Sahin H, Borkham-Kamphorst E, Kuppe C, Zaldivar MM, Grouls C, Al-samman M, Nellen A, Schmitz P, Heinrichs D, Berres ML, Doleschel D, Scholten D, Weiskirchen R, Moeller MJ, Kiessling F, Trautwein C, Wasmuth HE (2012) Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 55:1610–1619

    Article  CAS  PubMed  Google Scholar 

  • Semela D, Das A, Langer D, Kang N, Leof E, Shah V (2008) Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 135:671–679

    Article  CAS  PubMed  Google Scholar 

  • Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE (2012) Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A 109:5874–5879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, Kodama Y, Miura K, Ikai I, Uemoto S, Brenner DA (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135:1729–1738

    Article  CAS  PubMed  Google Scholar 

  • Thabut D, Routray C, Lomberk G, Shergill U, Glaser K, Huebert R, Patel L, Masyuk T, Blechacz B, Vercnocke A, Ritman E, Ehman R, Urrutia R, Shah V (2011) Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 54:573–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J, Friedman SL, Carmeliet P, Jimenez W, Morales-Ruiz M (2007) Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 46:1919–1926

    Article  CAS  PubMed  Google Scholar 

  • Van Steenkiste C, Ribera J, Geerts A, Pauta M, Tugues S, Casteleyn C, Libbrecht L, Olievier K, Schroyen B, Reynaert H, Grunsven LA van, Blomme B, Coulon S, Heindryckx F, De Vos M, Stassen JM, Vinckier S, Altamirano J, Bataller R, Carmeliet P, Van Vlierberghe H, Colle I, Morales-Ruiz M (2011) Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice. Hepatology 53:1629–1640

  • Wang B, Dolinski BM, Kikuchi N, Leone DR, Peters MG, Weinreb PH, Violette SM, Bissell DM (2007) Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology 46:1404–1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan Z, Qu K, Zhang J, Huang Q, Qu P, Xu X, Yuan P, Huang X, Shao Y, Liu C, Zhang H, Xing J (2015) CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond) 129:699–710

    Article  CAS  Google Scholar 

  • Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, Mukhopadhyay D, Schuppan D, Bi Y, Simonetto D, Shah VH (2014) Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 146:1339-1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang YY, Liu RS, Lee PC, Yeh YC, Huang YT, Lee WP, Lee KC, Hsieh YC, Lee FY, Tan TW, Lin HC (2014) Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int 34:521–534

    Article  PubMed  Google Scholar 

  • Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Yamazaki M, Tsujinoue H, Imazu H, Masaki T, Fukui H (2003) Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52:1347–1354

    Article  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA) & Institute of Cardiometabolism and Nutrition (ICAN), F-75012, Paris, France

    Sara Lemoinne, Dominique Thabut & Chantal Housset

  2. Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires, Service d’Hépatologie, F-75012, Paris, France

    Sara Lemoinne & Chantal Housset

  3. Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Pitié-Salpétrière, Service d’Hépato-Gastroentérologie, F-75013, Paris, France

    Dominique Thabut

  4. Faculté de Médecine, Université Pierre et Marie Curie, Site Saint-Antoine, 27 Rue Chaligny, 75571, Paris cedex 12, France

    Chantal Housset

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  1. Sara Lemoinne
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  2. Dominique Thabut
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Correspondence to Chantal Housset.

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Lemoinne, S., Thabut, D. & Housset, C. Portal myofibroblasts connect angiogenesis and fibrosis in liver. Cell Tissue Res 365, 583–589 (2016). https://doi.org/10.1007/s00441-016-2443-5

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  • DOI: https://doi.org/10.1007/s00441-016-2443-5

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