The ratio of transforming growth factor-β1/bone morphogenetic protein-7 in the progression of the epithelial-mesenchymal transition contributes to rat liver fibrosis

Abstract

ABSTRACT. This study was designed to show whether rat liver epithelial cells could undergo epithelial-mesenchymal transition (EMT), thereby directly contributing to liver fibrosis. The role of the ratio of transforming growth factor-β1 (TGF-β1)/bone morphogenetic protein-7 (BMP-7) was evaluated in the progression of EMT or mesenchymal-epithelial transition. Primary rat liver epithelial cells were stimulated with different ratios of TGF-β1/BMP-7 and examined for evidence of transition to a mesenchymal or epithelial phenotype. Liver sections were labeled to detect antigens associated with liver epithelial cells [E-cadherin (E-cad)], EMT [fibroblast-specific protein-1 (FSP-1), vimentin], myofibroblasts [α-smooth muscle actin (α-SMA)], and intracellular signal-transduction mediated by forming liver fibrosis undergo EMT, resulting in the formation of invasive fibroblasts; this process may be driven or impeded by a response to local TGF-β1 or BMP-7. BMP-7 downregulated α-SMA and phosphorylated Smad2/3. Stimulation of cultured cells with TGF-β1 induced the expression of pSmad2/3, FSP-1, and α-SMA. Stimulation of cultured cells with BMP-7 induced the expression of E-cad. We demonstrated that the cells upregulated E-cad release compared with untreated cells, but TGF-β1 was different. We found that the equilibrium of the ratio of TGF-β1/BMP-7 was 1/10. In summary, the mechanism for this process was not determined. Demonstration of the contribution of what the ratio of TGF-β1/BMP-7 induced to EMT to the chronic liver diseases would provide a new basis for understanding pathogenesis and potential treatment.

Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats

“…hepatocytes (Zeisberg et al, 2007). BMP7 has antiapoptotic and anti-inflammatory properties, stimulates proliferation (Grgurevic et al, 2016;Sugimoto et al, 2007;Vukicevic and Grgurevic, 2016), and accelerates liver regeneration after partial hepatectomy in mice (Bataller and Brenner, 2005;Bi et al, 2014;Chen et al, 2013;Wang et al, 2013;Zhong et al, 2013). As a previously proven molecule with antifibrotic activity, BMP7 also reduced Tgfb1, Itgb1, Itgb6, and Acta2 gene expression, Following BMP1-3 inhibition, endogenous expression of Dcn mRNA and protein was increased.…”

Angiotensin-(1–7) and angiotensin II induce the transdifferentiation of human endometrial epithelial cells in vitro

“…As EECs and stromal cells originate from the same embryonic stem cell, under certain pathological conditions, the transdifferentiation of EECs to mesenchymal cells can occur, with EECs transdifferentiating into myofibroblasts with increased α-SMA expression and migrating through the basement membrane into the lamina propria (16). Myofibroblasts have a role in tissue fibrosis and have a higher capacity for proliferation and the secretion of ECM components compared with ordinary fibroblasts.…”

Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study

“…9 MSC have been reported to suppress some of the underlying inflammatory responses and oxidative stress associated with fibrosis, improve regulation of matrix deposition and remodeling, and inhibit the TGF-b pathway. [9][10][11][12][13][14] Encouraging findings have shown reduced albuminuria, collagen IV deposition, and loss of peritubular capillaries, but MSC alone could not completely reverse or restore function, despite their abilities to facilitate endothelial and epithelial proliferation. 15,16 One possible explanation for the diminished responses to MSC in chronic kidney disease may be the limited amount of energy available to the cell during ongoing cell injury, a state that leads to a rapid depletion of cytoplasmic ATP.…”