More than a serum parameter: Functional relevance of soluble endoglin (solEng)

Aims: We have previously shown that Endoglin, an accessory receptor for TGF-β1, is highly expressed in hepatic stellate cells (HSC) and Myofibroblast-like cells (MFB) [1]. Additionally, we could show that endoglin is upregulated during transdifferentiation of HSC to MFB and that a soluble form of endoglin (solEng) is generated by shedding in a cultured HSC cellline (CFSC–2G) [2]. Since solEng is increasingly detected in the serum of patients with cirrhosis [3] we asked if solouble endoglin has an impact on signaling in isolated liver cells especially in HSC.Methods and Results: The rat extracellular domain of endoglin (solEng) was transiently or virally expressed in COS–7-, CHO- or HEK293-cells. SolEng was secreted as a dimer in all cells. In a model cell line for TGF-β1-signaling we found that solEng, differentially modulated TGF-β1-mediated Smad3- and Smad1/Smad5-activation as shown by the reporter gene construct (CAGA)₁₂-MLP-Luc [4] and Western blot. In line, a target gene of Smad3, i.e. Collagen I, was reduced, and a target gene of Smad1/Smad5, i.e. Id1, was increased, respectively. Overexpression of solEng in a mouse hepatic stellate cellline caused very similar changes. The Collagen I expression was decreased and α-smooth muscle actin (α-SMA) as well as Id2 were upregulated. Conclusions: Soluble endoglin not only affects the fibrotic response (Smad3-dependent) but may also be capable of modulating differentiation processes of hepatic stellate cells as shown by the activation marker α-SMA and the Id2 protein.

Literatur: References: [1] Meurer SK, Tihaa L, Lahme B, Gressner AM, Weiskirchen R. J Biol Chem. (2005) 280, 3078-3087 [2] Meurer SK, Tihaa L, Borkham-Kamphorst E, Weiskirchen R. Cell Signal. (2011) 23, 683-699 [3] Yagmur E, Rizk M, stanzel S, Hellerbrand C, Lammert F, Trautwein C, Wasmuth HE, Gressner AM. Eur. J. Gastroenterol Hepatol. (2007) 19, 755-761 [4] Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. EMBO (1998) 17, 3091-3100

TGF-beta co-receptor - TGF-beta1 - fibrosis - hepatic stellate cell - soluble Endoglin