Myofibroblasts

Chamberlain LJ, Yannas EV, Arrizabalaga A, Hsu HP, Norregaard TV, and Specter M. Early peripheral nerve healing in collagen and silicone tube imolants Myofibroblasts and the cellular response. Biomaterials, 1998, 19, 1393-1403. 

Scotton CJ, Chambers RC (2007) Molecular targets in pulmonary fibrosis the myofibroblast in focus. Chest 132 1311-1321... 

Recently, the notion that the chronicity of inflammation may not actually drive the fibrogenic process has been widely appreciated (Tables 1, 2, and 3). Some propose that it is indeed the alteration of the mesenchymal cell phenotypes that disrupts the balance between collagen synthesis and degradation in the wound-healing process, highlighted by clinical evidence that shows unsuccessful treatment of fibrosis with anti-inflammatory or immunosuppressive drugs (18,19). One scenario is that mesenchymal cells (myofibroblasts and fibroblasts) are phenotypically altered and thus do not undergo apoptosis after resolution. 

Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003 171(1) 380—389. 

Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohisto-chemical and in situ hybridization study. Am J Pathol 1994 145(1) 114-125. 

Fig. 14.1. The Thl/Th2 balance is central to the regulation of normal wound repair. Tissue injury results in the initiation of an inflammatory response, mediated by a variety of cells and their by-products. Immune cells are recruited and cross-regulate the Thl/ Th2 balance that occurs in response to the cytokine environment. This balance is in turn cross-regulated by the chemokine/chemokine-receptor expression profile, which functions to amplify the inflammatory process. Cells residing in the injured tissue release profibrotic mediators, which promote fibroblast activation, proliferation, and differentiation to the myofibroblast phenotype. Myofibroblasts produce collagen to repair damaged tissue, which is an event that is favored by the inhibition of MMP activity. The Thl/Th2 balance is central to whether a normal or aberrant wound-repair process is established A Thl environment promotes normal tissue resolution (fibrinolysis), whereas a Th2 environment maintains the progression of fibrotic disease (excessive collagen deposition).

DavaUle, J., GaUois, C., Habib, A., Li, L., MaUat, A., Tao, J., Levade, T. and Lotersztajn, S., 2000, Antiproliferative properties of sphingosine 1-phosphate in hepatic myofibroblasts a cyclooxygenase-2-mediated pathway, J. Biol. Chem. 275 34628-34633. 

Abbreviations AFP, a-fetoprotein CK, cytokeratin ECM, extracellular matrix EMT, epithelial to mesenchymal transition HCC, hepatocellular carcinoma HNF, hepatocyte nuclear factor, HSC, hepatic stellate cell MFB, myofibroblast M2-PK, M2-pyruvate kinase PDGF, platelet-derived growth factor TGF, transforming growth factor. 

The transdifferentiation of HSCs to myofibroblasts, producing extracellular matrix constituents is characterized by an increased expression of several receptors, including the... 

Figure 4.2. Diagram outlining the pathogenesis of liver fibrosis. Injury to parenchymal cells (PC) results in the activation of Kupffer cells (KC) and sinusoidal endothelial cells (SEC) and the recruitment of inflammatory cells (IC). These cells release cytokines, growth factors and reactive oxygen species that induce activation and proliferation of hepatic stellate cells (HSC). HSCs gradually transform into myofibroblasts (MF), the major producers of extracellular matrix (ECM) proteins.

For non-suspension cultures, suitable matrices include liquid overlay on agarose (59), Matrigel , or Cultrex (48, 92). More recently, micropatterned arrays have been developed for adherent 3-D spheroid cultures (56) and have been used to show reduced chemosensitivity of colorectal carcinoma cells to irinotecan (58). In some cases, 3-D cultures can be enhanced by the addition of host cells. This increases complexity, but inevitably decreases flexibility and speed of analysis. However, important insights into the role of host cells have emerged stromal cells modify the gene expression and response of many tumor cell types to chemotherapeutic agents (93) and tumor-associated myofibroblasts can enhance tumor invasiveness (94). 

Rotating culture vessels such as simulated microgravity systems are primarily used to study 3-D tumor growth and differentiation. However, mixed cell populations combined with matrix proteins can be used to generate a complex microenvironment in which cell-cell interactions and invasion can be measured (95). A similar system has also been described for the coculture of endothelial cells, myofibroblasts, and tumor cell clusters embedded in Matrigel . Differential labeling of the cell populations enables their invasion and the effects of inhibitors to be measured (96). 

Walter-Yohrling J, Pratt BM, Ledbetter S et al (2003) Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters a novel in vitro tumor model. Cancer Chemother Pharmacol 52 263-269... 

Fig. 1. Combined miR-21 ISFI and sm-a-actin IFIC for delineation of the cellular origin of mlR-21 in breast cancer. MiR-21 was detected with TSA-FITC substrate greerf) and sm-a-actin with Cy3 redj. Section was counter stained with DAPi (Woe). The MiR-21 ISFI signal is seen in sm-a-actin-positive myofibroblast located in the breast cancer stroma (St) surrounding clusters of miR-21 negative cancer cells (Ca). The individual fluorophores are shown in blackand white.

The obvious differential expression of miR-205 and sm-a-actin is noteworthy. MiR-205 is likely not associated with smooth muscle differentiation in general since no expression is seen in the VSMC and myofibroblasts. MiR-205 is more likely related to the basal cell characteristics also seen in skin (20). The specific targets and role of miR-205 in differentiation of basal cells are not known (45). The differential expression of miR-21 and sm-a-actin is also interesting but is not as drastic as for miR-205. In addition to myofibroblasts, both smooth muscle cells in colon (46) and myoepithelial cells in breast (44) have been found to express miR-21. 

De Vriese AS, Tilton RG, Mortier S, Lameire NH. 2006. Myofibroblast transdifferentiation of mesothelial cells is mediated by rage and contributes to peritoneal fibrosis in uraemia. Nephrol Dial Transplant. 

By using antibodies to alpha smooth muscle actin, we were able to identify activated fibroblasts (myofibroblasts). These contractile fibroblasts actively make collagen in contrast to quiescent fibroblasts. The increase in number of myofibroblasts after implantation was very similar to the increase in response to TGF-p,16 and this finding is consistent with the concept that one of the major roles of TGF-p is to activate fibroblasts in part to stimulate the formation of collagen. 

Figure 3.4 Factors affecting foreign body reaction and potential points of intervention at the level of the myofibroblast (1) inhibit synthesis or release of TGF-P (2) block stimulation by TGF-P of its membrane receptors on the activated fibroblast (3) inhibit the Smad proteins, which transfer the TGF-P effect to the nucleus (4) inhibit transcription of procollagen mRNA (5) inhibit translation of the message to form procollagen (6) inhibit prolyl-4-hydroxylase, which creates hydroxyproline and facilitates helix formation (7) inhibit lysyl oxidase, which cross-links the collagen (8) enhance the function of MMPs, which degrade collagen, or inhibit TIMPs, which degrade MMPs.

G. A. Ramm, R. S. Britton, R. O Neill, W. S. Blaner, and B. R. Bacon, Vitamin A-poor lipocytes a novel desmin-negative lipocyte subpopulation, which can be activated to myofibroblasts, Am. J. Physiol. 269 G532-541 (1995). 

G. Buniatian, B. Hamprecht, and R. Gebhardt, Glial fibrillary acidic protein as a marker of perisinusoidal stellate cells that can distinguish between the normal and myofibroblast-like phenotypes, Biol. Cell 87 65-13 (1996). 

A. M. Tiggelman, C. Linthorst, W. Boers, H. S. Brand, and R. A. Chamuleau, Transforming growth factor-beta-induced collagen synthesis by human liver myofibroblasts is inhibited by alpha 2-macroglobulin. J. Hepatol. 26 1220-1228 (1997). 

M. G. Bachem, D. Meyer, W. Schafer, U. Riess, R. Melchior, K. M. Sell, and A. M. Gressner, The response of rat liver perisinusoidal lipocytes to polypeptide growth regulator changes with their transdifferentiation into myofibroblast-like cells in culture, J. Hepatol. 78 40-52 (1993). 

T. Niki, K. Rombouts, P. J. De Bleser, K. de Smet, V. Rogiers, D. Schuppan, M. Yoshida, G. Gabbiani, and A. Geerts, A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentation of rat hepatic stellate cells in primary culture. Hepatology 29 858-867 (1999). 

---