Myofibroblasts and mechano-regulation of connective tissue remodelling

Tomasek, James J.; Gabbiani, Giulio; Hinz, Boris; Chaponnier, Christine; Brown, Robert A.

doi:10.1038/nrm809

Cited by 3,688 publications

(3,873 citation statements)

References 123 publications

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“…Periostin was found to have no discernable effect on the basal proliferation rate of DD cells while inducing a significant increase in proliferation of PF cells. The induction of fibroblast proliferation followed by differentiation into contractile fibroblasts is a normal component of the proliferative phase of cutaneous wound repair [72] and we speculate that one role of periostin may be to induce PF cells to initially proliferate and then eventually differentiate towards a proto-myofibroblast phenotype [65] with contractile bundles composed of cytoplasmic actins [73]. In contrast, primary DD cells in culture may already be in this proto-myofibroblast state, explaining why periostin treatment readily induced their differentiation to α smooth muscle actin expressing myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…We have also noted that α smooth muscle actin levels in PF cells were occasionally, but not consistently, up-regulated by periostin treatment in some cultures (data not shown). These data have led us to speculate that exposure to periostin in the ECM may induce PF cells to differentiate from a fibroblast phenotype toward a "proto-myofibroblast" phenotype, a transition phase prior to commitment to a differentiated myofibroblast phenotype, with inconsistently upregulated α smooth muscle actin levels [65]. It will be interesting to test if a longer-term treatment of PF cells with ECM-associated periostin induces PF cells to take on a DD cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

Vi¹,

Feng²,

Zhu³

et al. 2009

Experimental Cell Research

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Dupuytren's disease, (DD), is a fibroproliferative condition of the palmar fascia in the hand, typically resulting in permanent contracture of one or more fingers. This fibromatosis is similar to scarring and other fibroses in displaying excess collagen secretion and contractile myofibroblast differentiation. In this report we expand on previous data demonstrating that POSTN mRNA, which encodes the extra-cellular matrix protein periostin, is up-regulated in Dupuytren's disease cord tissue relative to phenotypically normal palmar fascia. We demonstrate that the protein product of POSTN, periostin, is abundant in Dupuytren's disease cord tissue while little or no periostin immunoreactivity is evident in patient-matched control tissues. The relevance of periostin up-regulation in DD was assessed in primary cultures of cells derived from diseased and phenotypically unaffected palmar fascia from the same patients. These cells were grown in type-1 collagen-enriched culture conditions with or without periostin addition to more closely replicate the in vivo environment. Periostinwas found to differentially regulate the apoptosis, proliferation, α smooth muscle actin expression and stressed Fibroblast Populated Collagen Lattice contraction of these cell types. We hypothesize that periostin, secreted by disease cord myofibroblasts into the extra-cellular matrix, promotes the transition of resident fibroblasts in the palmar fascia toward a myofibroblast phenotype, thereby promoting disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

Vi¹,

Feng²,

Zhu³

et al. 2009

Experimental Cell Research

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“…Another characteristic is that myofibroblasts connect to each other through gap junctions and form multicellular contractile units during contraction. In contrast, fibroblasts do not have these characteristics [Tomasek et al, 2002]. Compared to dermal fibroblasts, human myofibroblasts from implants inserted subcutaneously also responded differently to cytokines.…”

mentioning

confidence: 93%

“…human gingival fibroblasts; myofibroblasts; α smooth muscle actin; TGFβ; p38 MAP kinase Myofibroblasts are contractile cells that share characteristics of fibroblasts and smooth muscle cells [Tomasek et al, 2002]. One of the major features of myofibroblast differentiation is the expression of smooth muscle cell markers.…”

Section: Introductionmentioning

confidence: 99%

Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

Fang

Svoboda

2005

J of Cellular Biochemistry

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Cigarette smoking has been suggested as a risk factor for several periodontal diseases. It has also been found that smokers respond less favorably than non-smokers to periodontal therapy. Previous work in our lab has shown that nicotine inhibits human gingival cell migration. Since myofibroblasts play an important role in wound closure, we asked if nicotine affects gingival wound healing process by regulating myofibroblast differentiation. Human gingival fibroblasts (HGFs) from two patients were cultured in 10% fetal bovine serum cell culture medium. Cells were pretreated with different doses of nicotine (0, 0.01, 0.1, and 1 mM) for 2 h, and then incubated with transforming growth factor beta (TGF-β1) (0, 0.25, 0.5, and 1 ng/ml) with or without nicotine for 30 h. The expression level of α-smooth muscle actin (α-SMA), a specific marker for myofibroblasts, was analyzed by Western blots, immunocytochemistry, and real-time polymerase chain reaction (real-time PCR). Phosphorylated p38 mitogen-activated protein kinase (Phospho-p38 MAPK) activity was analyzed by Western blots. TGF-β1 induced an increase of α-SMA protein and mRNA expression, while nicotine (1 mM) inhibited the TGF-β1-induced expression of α-SMA but not β-actin. Nicotine treatment down-regulated TGF-β1-induced p38 MAPK phosphorylation. Our results demonstrated for the first time that nicotine inhibits myofibroblast differentiation in human gingival fibroblasts in vitro; supporting the hypothesis that delayed wound healing in smokers may be due to decreased wound contraction by myofibroblasts. Keywordshuman gingival fibroblasts; myofibroblasts; α smooth muscle actin; TGFβ; p38 MAP kinase Myofibroblasts are contractile cells that share characteristics of fibroblasts and smooth muscle cells [Tomasek et al., 2002]. One of the major features of myofibroblast differentiation is the expression of smooth muscle cell markers. These markers include α-SMA, γ-SMA, smooth muscle 22 (SM22), calponin, smoothelin, meta-vinculin, h-caldesmon [Halayko and Solway, 2001]. Among these, α-SMA has been suggested as the most reliable marker of myofibroblast differentiation [Gabbiani, 2003]. Also, Dr. Masur's lab demonstrated that myofibroblast differentiation was cell density dependent in corneal fibroblasts. They found that the lower the cell density when cells were seeded in culture, the more cells differentiated into myofibroblasts. However, the myofibroblast phenotype was not terminal. The cells lost the myofibroblast

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“…The myofibroblast is a mesenchymal cell type that performs important functions during wound healing (Tomasek, Gabbiani, Hinz, Chaponnier, & Brown, 2002). In addition to producing components of the extracellular matrix (ECM), including collagens, fibronectin, proteoglycans, and others, myofibroblasts contract and provide rigidity to the connective tissue surrounding the wound.…”

Section: Introductionmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Myofibroblasts and mechano-regulation of connective tissue remodelling

Cited by 3,688 publications

References 123 publications

Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

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