P311 induces a TGF-β1–independent, nonfibrogenic myofibroblast phenotype

Pan, Desi; Zhe, Xiaoning; Jakkaraju, Sandhya; Taylor, Gregory A.; Schuger, Lucia

doi:10.1172/jci15614

Cited by 47 publications

(47 citation statements)

References 54 publications

(111 reference statements)

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“…Furthermore, we found that all three TGFbs are fibrogenic and placed P311 as a stimulator of fibrosis acting immediately upstream of TGF-b1 to -b3. Because P311 expression is up-regulated or down-regulated by hormones, 52 retinoic acid, 53 growth factors, 54 and mechanical tension, 4 and because P311 has proven to be decreased in muscular atrophy 55,56 and pulmonary emphysema, 6 it is likely that in pathologic conditions with decreased P311 expression scar formation will be affected in ways similar to those presented in this study, leading thereby to a higher risk of dehiscence.…”

Section: Discussionsupporting

confidence: 50%

“…Our previous data indicated that P311 stimulates TGF-b translation in vascular smooth muscle cells as well as in NIH 3T3 cells. 2,4 Therefore, as part of the present study we determined whether P311 also has a similar effect in keratinocytes and dermal fibroblasts. To this end, we transfected P311 into MFs, HFs, and HKs, which under normal conditions lack the protein.…”

Section: Discussionmentioning

confidence: 99%

“…8 P311 has been shown to induce myofibroblast differentiation and migration 4,9 and to promote nerve and lung regeneration. 5,6 Deletion of p311 in mice was reported originally to result in no overt phenotype, 10 although these animals displayed learning and memory defects.…”

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confidence: 99%

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Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

Cheng

Yue

Aslam

et al. 2017

The American Journal of Pathology

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Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF)-b1 to -b3 translation in vitro and in vivo. Because TGF-bs play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311 À/À mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-b1 to -b3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-b levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-b1 to -b3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF-bs in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery. (Am J Pathol 2017, 187: 292e303; http://dx

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

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Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

Cheng

Yue

Aslam

et al. 2017

The American Journal of Pathology

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“…In addition, myofibroblast differentiation could also be generated independent of TGF-βs. For example, the plasmid containing the cDNA of a 8 kDa protein, P311, induced myofibroblast differentiation when transfected into fibroblasts [Pan et al, 2002].…”

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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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“…It can bind to TGF-β latency associated protein and stimulate the translation of TGF-β. In addition, P311 has proved to be of importance in the process of myofibroblast differentiation and fibrosis with functions of promoting embryonic development, wound healing, as well as nerve and lung regeneration, and so on (18)(19)(20)(21)(22). In our previous studies, we found that P311 might be involved in the pathogenesis of renal fibrosis by inhibiting the EMT process via the TGF-β1-Smad-ILK pathway in vitro (23).…”

Section: Introductionmentioning

confidence: 92%