Endoglin modulates Smad-dependent and Smad-independent pathways to regulate proliferation, migration and profibrogenic responses in myofibroblasts

Aims: TGF-β1-mediated transdifferentiation of hepatic stellate cells (HSC) to myofibroblast-like cells (MFB) is the key event to initiate the fibrogenic program in the liver. This comprises upregulation of contractile elements, e.g. α-SMA, increased expression of collagen type I and connective tissue growth factor (CTGF) as well as a higher proliferation and migration rate [1]. To determine the factors that govern myoblast conversion upon TGF-β1-treatment in more detail, we analyzed a model system for TGF-β1-signaling, i.e. myoblasts, which display a myofibroblast-like phenotype when cultured in the presence of TGF-β1 [2].

Methods and Results: Endoglin, a co-receptor for TGF-β1, is highly expressed in HSC and MFB [3] and antagonizes TGF-β1 signals [4]. We compared responses of parental myoblasts with that of myoblasts stably overexpressing endoglin [5] and found that endoglin blocks basal and TGF-β1-induced synthesis of collagen type I, fibronectin and CTGF. Myoblasts expressing endoglin show no myogenic differentiation, an effect also observed when parental cells are cultured in the presence of TGF-β1 [2]. In contrast, the TGF-β1-mediated myofibroblastic differentiation is also blocked as shown by the abrogation of α-SMA expression. In addition, we found that endoglin induces the expression of Id2, which was previously shown to reduce fibrosis in an animal model of experimental liver injury [6]. The negative impact of TGF-β1 on proliferation and migration is counteracted by endoglin. Moreover, type I receptor blockers, i.e. SB431542 and Dorsomorphin, have only a minor impact on the observed endoglin effects.

Conclusions: The impact of endoglin on myofibroblast differentiation and profibrogenic responses characterizes endoglin as a negative regulator of TGF-β1-signaling. Therefore, the expression of endoglin in transdifferentiating HSC is potentially a mechanism by which the cell tries to counteract the fibrogenic processes that are mostly driven by TGF-β1.

Literatur: [1] Gressner OA, Rizk MS, Kovalenko E, Weiskirchen R, Gressner AM. J Gastroenterol Hepatol. (2008) 23, 1024-1035 [2] Scherner O, Meurer SK, Tihaa L, Gressner AM, and Weiskirchen R. J Biol Chem. (2007) 282, 13934-13943 [3] Meurer SK, Tihaa L, Lahme B, Gressner AM, Weiskirchen R. J Biol Chem. (2005) 280, 3078-3087 [4] Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P. EMBO J. (2004) 23, 4018-4028 [5] Letamendía A, Lastres P, Botella LM, Raab U, Langa C, Velasco B, Attisano L, Bernabeu C. J Biol Chem. (1998) 273, 33011-33019 [6] Kinoshita K, Iimuro Y, Otogawa K, Saika S, Inagaki Y, Nakajima Y, Kawada N, Fujimoto J, Friedman SL, Ikeda K. GUT (2007) 56, 706-714

TGF-beta - antagonism - endoglin - hepatic stellate cells - myoblasts - signaling