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Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts.
Hepatology. 2000 May; 31(5):1094-106.Hep

Abstract

Activation of hepatic stellate cells (HSCs) is the key step in liver fibrogenesis. Increased transforming growth factor beta (TGF-beta) expression and extracellular matrix production in patients with hepatic fibrosis and experimental models of liver fibrogenesis support implication of TGF-beta in the pathogenesis of this disease. However, a causative role for TGF-beta during transdifferentiation of HSCs has not been delineated in molecular detail. Using a rat cell culture model of HSC transdifferentiation, we analyzed TGF-beta signal transduction and identified changes between stellate cells and their transdifferentiated phenotype. Fully transdifferentiated myofibroblasts, opposed to HSCs, were not inhibited in proliferation activity on treatment with TGF-beta1. Furthermore, stimulation of alpha2 (I) collagen and Smad7 messenger RNA (mRNA) expression by TGF-beta1 was achieved in stellate cells but not in myofibroblasts. Northern and Western blot analyses indicated significant expression of TGF-beta receptors I and II in both cell types. In contrast, [(125)I]-TGF-beta1 receptor affinity labeling displayed strongly reduced types I, II, and III receptor presentation at the cell surface of myofibroblasts. Moreover, myofibroblasts did not display DNA-binding SMAD proteins in electrophoretic mobility shift assays with a CAGA box. These data indicate that stellate cells are responsive to TGF-beta1 treatment and transduce a signal that may play an important role in liver fibrogenesis. Myofibroblasts display decreased availability of surface receptors for TGF-beta, which could be based on autocrine stimulation. However, lack of activated SMAD complexes with DNA-binding activity and absence of alpha2 (I) collagen transcription inhibition by latency-associated peptide (LAP)/anti-TGF-beta antibody raise the possibility of TGF-beta signaling independent receptor down-regulation in myofibroblasts.

Authors+Show Affiliations

Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10796885

Citation

Dooley, S, et al. "Modulation of Transforming Growth Factor Beta Response and Signaling During Transdifferentiation of Rat Hepatic Stellate Cells to Myofibroblasts." Hepatology (Baltimore, Md.), vol. 31, no. 5, 2000, pp. 1094-106.
Dooley S, Delvoux B, Lahme B, et al. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology. 2000;31(5):1094-106.
Dooley, S., Delvoux, B., Lahme, B., Mangasser-Stephan, K., & Gressner, A. M. (2000). Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology (Baltimore, Md.), 31(5), 1094-106.
Dooley S, et al. Modulation of Transforming Growth Factor Beta Response and Signaling During Transdifferentiation of Rat Hepatic Stellate Cells to Myofibroblasts. Hepatology. 2000;31(5):1094-106. PubMed PMID: 10796885.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. AU - Dooley,S, AU - Delvoux,B, AU - Lahme,B, AU - Mangasser-Stephan,K, AU - Gressner,A M, PY - 2000/5/5/pubmed PY - 2000/5/20/medline PY - 2000/5/5/entrez SP - 1094 EP - 106 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 31 IS - 5 N2 - Activation of hepatic stellate cells (HSCs) is the key step in liver fibrogenesis. Increased transforming growth factor beta (TGF-beta) expression and extracellular matrix production in patients with hepatic fibrosis and experimental models of liver fibrogenesis support implication of TGF-beta in the pathogenesis of this disease. However, a causative role for TGF-beta during transdifferentiation of HSCs has not been delineated in molecular detail. Using a rat cell culture model of HSC transdifferentiation, we analyzed TGF-beta signal transduction and identified changes between stellate cells and their transdifferentiated phenotype. Fully transdifferentiated myofibroblasts, opposed to HSCs, were not inhibited in proliferation activity on treatment with TGF-beta1. Furthermore, stimulation of alpha2 (I) collagen and Smad7 messenger RNA (mRNA) expression by TGF-beta1 was achieved in stellate cells but not in myofibroblasts. Northern and Western blot analyses indicated significant expression of TGF-beta receptors I and II in both cell types. In contrast, [(125)I]-TGF-beta1 receptor affinity labeling displayed strongly reduced types I, II, and III receptor presentation at the cell surface of myofibroblasts. Moreover, myofibroblasts did not display DNA-binding SMAD proteins in electrophoretic mobility shift assays with a CAGA box. These data indicate that stellate cells are responsive to TGF-beta1 treatment and transduce a signal that may play an important role in liver fibrogenesis. Myofibroblasts display decreased availability of surface receptors for TGF-beta, which could be based on autocrine stimulation. However, lack of activated SMAD complexes with DNA-binding activity and absence of alpha2 (I) collagen transcription inhibition by latency-associated peptide (LAP)/anti-TGF-beta antibody raise the possibility of TGF-beta signaling independent receptor down-regulation in myofibroblasts. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10796885/Modulation_of_transforming_growth_factor_beta_response_and_signaling_during_transdifferentiation_of_rat_hepatic_stellate_cells_to_myofibroblasts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S027091390050860X DB - PRIME DP - Unbound Medicine ER -