The myofibroblast matrix: implications for tissue repair and fibrosis

Myofibroblasts, and the extracellular matrix ( ECM ) in which they reside, are critical components of wound healing and fibrosis. The ECM , traditionally viewed as the structural elements within which cells reside, is actually a functional tissue whose components possess not only scaffolding characteristics, but also growth factor, mitogenic, and other bioactive properties. Although it has been suggested that tissue fibrosis simply reflects an ‘exuberant’ wound‐healing response, examination of the ECM and the roles of myofibroblasts during fibrogenesis instead suggest that the organism may be attempting to recapitulate developmental programmes designed to regenerate functional tissue. Evidence of this is provided by the temporospatial re‐emergence of embryonic ECM proteins by fibroblasts and myofibroblasts that induce cellular programmatic responses intended to produce a functional tissue. In the setting of wound healing (or physiological fibrosis), this occurs in a highly regulated and exquisitely choreographed fashion which results in cessation of haemorrhage, restoration of barrier integrity, and re‐establishment of tissue function. However, pathological tissue fibrosis, which oftentimes causes organ dysfunction and significant morbidity or mortality, likely results from dysregulation of normal wound‐healing processes or abnormalities of the process itself. This review will focus on the myofibroblast ECM and its role in both physiological and pathological fibrosis, and will discuss the potential for therapeutically targeting ECM proteins for treatment of fibrotic disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94657/1/path4104.pd

Interleukin-1 has opposing effects on connective tissue growth factor and tenascin-C expression in human cardiac fibroblasts.

Cardiac fibroblasts (CF) play a central role in the repair and remodeling of the heart following injury and are important regulators of inflammation and extracellular matrix (ECM) turnover. ECM-regulatory matricellular proteins are synthesized by several myocardial cell types including CF. We investigated the effects of pro-inflammatory cytokines on matricellular protein expression in cultured human CF. cDNA array analysis of matricellular proteins revealed that interleukin-1α (IL-1α, 10ng/ml, 6h) down-regulated connective tissue growth factor (CTGF/CCN2) mRNA by 80% and up-regulated tenascin-C (TNC) mRNA levels by 10-fold in human CF, without affecting expression of thrombospondins 1-3, osteonectin or osteopontin. Western blotting confirmed these changes at the protein level. In contrast, tumor necrosis factor α (TNFα) did not modulate CCN2 expression and had only a modest stimulatory effect on TNC levels. Signaling pathway inhibitor studies suggested an important role for the p38 MAPK pathway in suppressing CCN2 expression in response to IL-1α. In contrast, multiple signaling pathways (p38, JNK, PI3K/Akt and NFκB) contributed to IL-1α-induced TNC expression. In conclusion, IL-1α reduced CCN2 expression and increased TNC expression in human CF. These observations are of potential value for understanding how inflammation and ECM regulation are linked at the level of the CF

Advances in tenascin-C biology

Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology

The role of tenascin-C in tissue injury and tumorigenesis

The extracellular matrix molecule tenascin-C is highly expressed during embryonic development, tissue repair and in pathological situations such as chronic inflammation and cancer. Tenascin-C interacts with several other extracellular matrix molecules and cell-surface receptors, thus affecting tissue architecture, tissue resilience and cell responses. Tenascin-C modulates cell migration, proliferation and cellular signaling through induction of pro-inflammatory cytokines and oncogenic signaling molecules amongst other mechanisms. Given the causal role of inflammation in cancer progression, common mechanisms might be controlled by tenascin-C during both events. Drugs targeting the expression or function of tenascin-C or the tenascin-C protein itself are currently being developed and some drugs have already reached advanced clinical trials. This generates hope that increased knowledge about tenascin-C will further improve management of diseases with high tenascin-C expression such as chronic inflammation, heart failure, artheriosclerosis and cancer

Vitamin D potentiates anti-tumor activity of 5-fluorouracil via modulating caspase-3 and TGF-β1 expression in hepatocellular carcinoma-induced in rats

We investigated the role of vitamin D (Vit D) alone and in combination with 5-fluorouracil (5-FU) in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. Fifty male Sprague–Dawley rats were randomized into a control group and 4 groups that received TAA (200 mg/kg, i.p.) twice per week for 16 weeks. These 4 groups were further divided as follows: HCC group; 5-FU group (75 mg/kg, i.p., once weekly for 3 weeks starting from the 12th week); Vit D group (200 IU/kg daily by oral tube for 16 weeks); and 5-FU + Vit D group (received the previously mentioned dosage regimens of 5-FU and Vit D). HCC was detected by histopathological changes in liver sections and the elevation of serum α-fetoprotein (AFP). Treatment with 5-FU + Vit D significantly decreased gene expression of nuclear factor erythroid 2-related factor 2 (NrF2) and transforming growth factor β1 (TGF-β1) at both the gene and protein level and serum AFP concentrations in comparison with their corresponding monotherapy. Moreover, 5-FU + Vit D treatment enhanced apoptosis by increasing caspase-3 gene and protein expression. Conclusively, Vit D enhances antitumor activity of 5-FU in an HCC-induced model and improves liver function of treated animals. Combination therapy in a TAA-induced HCC rat model was more effective than 5-FU or Vit D through the modulation of TGF-β1, caspase-3, and NrF2 expressions.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Hepatoprotective Effect of Curcumin on Hepatocellular Carcinoma Through Autophagic and Apoptic Pathways

Background and rationale: Microtubule-associated protein light chain 3-II (LC3-II), and Sequestosome-1 (SQSTM1) are proteins that can be used as markers for autophagic pathway. Bcl-2 protein is reported to be inversely correlated with apoptosis. We aimed to investigate the effects of curcumin on liver inflammation and fibrosis up to the first dysplastic stage of Hepatocellular carcinoma (HCC) induced by Thioacetamide (TAA) in rats and to clarify the effects of curcumin on LC3-II, SQSTM1, and Bcl-2. Male Sprague-Dawley rats were randomized into four groups: Control group, TAA group, Curcumin low-dose group, and Curcumin highdose group. The last three groups received TAA 200 mg/kg i.p. twice weekly for 18 weeks. Oxidative stress markers as hepatic malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity were measured by colorimetric methods. Hepatic SQSTM1 concentration was measured by ELISA, and gene expression levels of Bcl-2, and LC3-II were measured by RT-PCR.We also investigated the in vitro effect of curcumin on HepG2 cells viability through MTT assay, and the involvement of autophagy in this effect. Results: Curcumin increased the survival percent in rats, decreased -fetoprotein (AFP) concentration, and serum aspartate aminotransferase (AST) activity, and increased serum albumin concentration. Curcumin also significantly reduced oxidative stress in liver, inhibited apoptosis, and induced autophagy. In vitro, curcumin (50 μM) decreased HepG2 cells viabilityand the concentration of SQSTM1. Conclusions: Curcumin leads to protection against TAA induced HCC up to the first dysplastic stage through activating autophagic pathway and inhibiting apoptosis. Also, the antioxidant activity of curcumin almost prevents liver fibrosis