Transforming growth factor-β (TGF-β) is generally acknowledged to be the cytokine with the broadest range of activities in repair of injured tissue, based both on the variety of cell types that produce and/or respond to it and on the spectrum of its cellular responses (Roberts and Sporn, 1990). TGF-β is released from degranulating platelets and secreted by all of the major cell types participating in the repair process, including lymphocytes, macrophages, endothelial cells, smooth muscle cells, epithelial cells, and fibroblasts (see Fig. 1). A unique feature of this molecule is that its autoinduction results in sustained expression at the site of a wound and extends the effectiveness of both the initial burst of endogenous TGF-β released upon injury and exogenous TGF-β that might be applied to a wound. The ability of TGF-β to improve and/or accelerate tissue repair has been studied extensively in a variety of animal models of both normal and impaired healing. A limited number of clinical trials are in progress, but it is anticipated that many new applications for TGF-β will ultimately be found, once problems with appropriate timing and formulation can be solved.

Transforming Growth Factor-β

To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with plac...

https://www.nejm.org/doi/pdf/10.1056/NEJM198005013021801

Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study.

http://chaos.utexas.edu/manuscripts/1067542353.pdf

The optical stretcher: a novel laser tool to micromanipulate cells.

Dynamic interactions between growth factors and extracellular matrix (ECM) are integral to wound healing. These interactions take several forms that may be categorized as direct or indirect. The ECM can directly bind to and release certain growth factors (e.g., heparan sulfate binding to fibroblast growth factor-2), which may serve to sequester and protect growth factors from degradation, and/or enhance their activity. Indirect interactions include binding of cells to ECM via integrins, which enables cells to respond to growth factors (e.g., integrin binding is necessary for vascular endothelial growth factor-induced angiogenesis) and can induce growth factor expression (adherence of monocytes to ECM stimulates synthesis of platelet-derived growth factor). Additionally, matrikines, or subcomponents of ECM molecules, can bind to cell surface receptors in the cytokine, chemokine, or growth factor families and stimulate cellular activities (e.g., tenascin-C and laminin bind to epidermal growth factor receptors, which enhances fibroblast migration). Growth factors such as transforming growth factor-β also regulate the ECM by increasing the production of ECM components or enhancing synthesis of matrix degrading enzymes. Thus, the interactions between growth factors and ECM are bidirectional. This review explores these interactions, discusses how they are altered in difficult to heal or chronic wounds, and briefly considers treatment implications.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1524-475X.2009.00466.x

Interactions between extracellular matrix and growth factors in wound healing.

The secreted polypeptide transforming growth factor-beta (TGF-beta) exerts its multiple activities through type I and II cell surface receptors. In epithelial cells, activation of the TGF-beta signal transduction pathways leads to inhibition of cell proliferation and an increase in extracellular matrix production. TGF-beta is widely expressed during development and its biological activity has been implicated in epithelial-mesenchymal interactions, e.g., in branching morphogenesis of the lung, kidney, and mammary gland, and in inductive events between mammary epithelium and stroma. In the present study, we investigated the effects of TGF-beta on mouse mammary epithelial cells in vitro. TGF-beta reversibly induced an alteration in the differentiation of normal mammary epithelial NMuMG cells from epithelial to fibroblastic phenotype. The change in cell morphology correlated with (a) decreased expression of the epithelial markers E-cadherin, ZO-1, and desmoplakin I and II; (b) increased expression of mesenchymal markers, such as fibronectin; and (c) a fibroblast-like reorganization of actin fibers. This phenotypic differentiation displays the hallmarks of an epithelial to mesenchymal transdifferentiation event. Since NMuMG cells make high levels of the type I TGF-beta receptor Tsk7L, yet lack expression of the ALK-5/R4 type I receptor which has been reported to mediate TGF-beta responsiveness, we evaluated the role of the Tsk7L receptor in TGF-beta-mediated transdifferentiation. We generated NMuMG cells that stably overexpress a truncated Tsk7L type I receptor that lacks most of the cytoplasmic kinase domain, thus function as a dominant negative mutant. These transfected cells no longer underwent epithelial to mesenchymal morphological change upon exposure to TGF-beta, yet still displayed some TGF-beta-mediated responses. We conclude that TGF-beta has the ability to modulate E-cadherin expression and induce a reversible epithelial to mesenchymal transdifferentiation in epithelial cells. Unlike other transdifferentiating growth factors, such as bFGF and HGF, these changes are accompanied by growth inhibition. Our results also implicate the Tsk7L type I receptor as mediating the TGF-beta-induced epithelial to mesenchymal transition.

/pdf/tgf-beta-induced-transdifferentiation-of-mammary-epithelial-565e1oexwe.pdf

TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors.

The possible in vivo role of TGF-beta 1 in regulating various proteins of the extracellular matrix, including fibronectin, collagen I and III, and glycosaminoglycans, was examined by immunohistochemical methods during critical stages of lung morphogenesis in the 11- to 18-day-old mouse embryo. Sections of Bouin-fixed, paraffin-embedded whole embryos were exposed to polyclonal antibodies specific to synthetic peptides present in the precursor part of TGF-beta 1 (pro-TGF-beta 1), in the processed TGF-beta 1 (antibody CC), collagen I and III, fibronectin, followed by the PAP or ABC technique to visualize the location of the antibody. GAG were stained with Alcian Blue 8GX. Our results indicate colocalization of TGF-beta 1 expression and that of matrix proteins in the developing lung when branching morphogenesis (cleft formation) and tissue stabilization occur. The presence of TGF-beta 1 at the epithelial-mesenchymal interfaces of stalks and clefts at a time when matrix proteins can first be visualized in these areas, suggests a direct participation of the growth factor in the development of the basic architecture of the lung.

Colocalization of TGF-beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis

Transforming growth factor-beta. Major role in regulation of extracellular matrix.

The behavior of HeLa-S3 cells under the influence of supranormal temperatures.

Strain MC29 Avian Leukosis Virus. Myelocytoma, Endothelioma, and Renal Growths: Pathomorphological and Ultrastructural Aspects

Summary Tubuloreticular structures that are frequently present in the cytoplasm of lymphoid cells grown in vitro were studied with cytochemical methods at high resolution. The structures are easily digested by Pronase and pepsin; they are not sensitive to trypsin or RNase. From the results obtained, we conclude that the tubuloreticular structures are of proteinaceous nature and that they are mainly composed of proteins of the acidic type. Their significance in the cell is not yet known and, therefore, further investigation is required.

https://cancerres.aacrjournals.org/content/canres/32/12/2696.full.pdf

Ursula Heine

Papers

Colocalization of TGF-beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis

Transforming growth factor-beta. Major role in regulation of extracellular matrix.

The behavior of HeLa-S3 cells under the influence of supranormal temperatures.

Strain MC29 Avian Leukosis Virus. Myelocytoma, Endothelioma, and Renal Growths: Pathomorphological and Ultrastructural Aspects

Ultramorphological and ultracytochemical studies on tubuloreticular structures in lymphoid cells.