scholarly journals A decisive function of transforming growth factor-β/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes

2011 ◽  
Vol 22 (6) ◽  
pp. 782-794 ◽  
Author(s):  
Susanne Buschke ◽  
Hans-Jürgen Stark ◽  
Ana Cerezo ◽  
Silke Prätzel-Wunder ◽  
Karsten Boehnke ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Epithelial Differentiation ◽  
Tissue Homeostasis ◽  
Epidermal Differentiation ◽  
Epidermal Keratinocytes ◽  
Hacat Keratinocytes ◽  
Mesenchymal Transition ◽  
Smad Signaling

 The mechanism by which transforming growth factor-β (TGFβ) regulates differentiation in human epidermal keratinocytes is still poorly understood. To assess the role of Smad signaling, we engineered human HaCaT keratinocytes either expressing small interfering RNA against Smads2, 3, and 4 or overexpressing Smad7 and verified impaired Smad signaling as decreased Smad phosphorylation, aberrant nuclear translocation, and altered target gene expression. Besides abrogation of TGFβ-dependent growth inhibition in conventional cultures, epidermal morphogenesis and differentiation in organotypic cultures were disturbed, resulting in altered tissue homeostasis with suprabasal proliferation and hyperplasia upon TGFβ treatment. Neutralizing antibodies against TGFβ, similar to blocking the actions of EGF-receptor or keratinocyte growth factor, caused significant growth reduction of Smad7-overexpressing cells, thereby demonstrating that epithelial hyperplasia was attributed to TGFβ-induced “dermis”-derived growth promoting factors. Furthermore impaired Smad signaling not only blocked the epidermal differentiation process or caused epidermal-to-mesenchymal transition but induced a switch to a complex alternative differentiation program, best characterized as mucous/intestinal-type epithelial differentiation. As the same alternative phenotype evolved from both modes of Smad-pathway interference, and reduction of Smad7-overexpression caused reversion to epidermal differentiation, our data suggest that functional TGFβ/Smad signaling, besides regulating epidermal tissue homeostasis, is not only essential for terminal epidermal differentiation but crucial in programming different epithelial differentiation routes.

scholarly journals Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

2018 ◽  
Vol 19 (11) ◽  
pp. 3672 ◽  
Author(s):  
Yutaro Tsubakihara ◽  
Aristidis Moustakas
Keyword(s):  
Growth Factor ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Basement Membranes ◽  
The Body ◽  
Common Denominator ◽  
Adhesion Forces ◽  
Mesenchymal Transition

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

scholarly journals Changes in cardiac resident fibroblast physiology and phenotype in aging

2018 ◽  
Vol 315 (4) ◽  
pp. H745-H755 ◽  
Author(s):  
JoAnn Trial ◽  
Katarzyna A. Cieslik
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Apparent Paradox ◽  
Smad Pathway ◽  
Activated Fibroblasts ◽  
Resident Fibroblast

The cardiac fibroblast plays a central role in tissue homeostasis and in repair after injury. With aging, dysregulated cardiac fibroblasts have a reduced capacity to activate a canonical transforming growth factor-β-Smad pathway and differentiate poorly into contractile myofibroblasts. That results in the formation of an insufficient scar after myocardial infarction. In contrast, in the uninjured aged heart, fibroblasts are activated and acquire a profibrotic phenotype that leads to interstitial fibrosis, ventricular stiffness, and diastolic dysfunction, all conditions that may lead to heart failure. There is an apparent paradox in aging, wherein reparative fibrosis is impaired but interstitial, adverse fibrosis is augmented. This could be explained by analyzing the effectiveness of signaling pathways in resident fibroblasts from young versus aged hearts. Whereas defective signaling by transforming growth factor-β leads to insufficient scar formation by myofibroblasts, enhanced activation of the ERK1/2 pathway may be responsible for interstitial fibrosis mediated by activated fibroblasts. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/fibroblast-phenotypic-changes-in-the-aging-heart/ .

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