Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents

Yang, Lüjun; Hashimoto, Koji; Tohyama, Mikiko; Okazaki, Hidenori; Dai, Xiuju; Hanakawa, Yasushi; Sayama, Koji; Shirakata, Yuji

doi:10.1016/j.jdermsci.2011.10.008

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…2D). This was supported by previous studies demonstrating that TGFb1 was ex pressed in the suprabasal epithelial cells of human skin equivalents (20). The expression of latent TGFb1 was shown to increase markedly in suprabasal keratinocytes after injury, although its localization was faint in normal mouse epidermis (11).…”

Section: Discussionsupporting

confidence: 80%

“…In addition, the presence of bidirectional regulation between epithelial cells and fibroblasts needs to be considered; in human skin equivalents, myofibroblasts contribute to a hyper proliferative epidermis (20). Conversely, in the thera peutic setting, one of the potential pharmacological approaches to prevent hypertrophic scar formation should be inhibition of the TGFb1 receptor.…”

Section: Introductionmentioning

confidence: 99%

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Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

et al. 2014

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Abstract. Transforming growth factorb1 (TGFb1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGFb1 released by keratinocytes in efforts to identify promising pharma cological approaches for the prevention of hypertrophic scar formation. A threedimensional col lagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor-dependent increase in asmooth muscle actin (aSMA) immunostaining and mRNA levels in fibroblasts. Latent TGFb1 was found to be localized suprabasally and secreted. aSMA expression was inhibited by an antia v integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a twodimensional fibroblast culture, aSMA expression depended on the production of endogenous TGFb1 and required a v integrin or MMP for the response to recombinant latent TGFb1. In keratinocyteconditioned medium, MMPdependent latent TGFb1 secretion was detected. Applying this medium to the fibroblast culture enhanced aSMA production. This effect was decreased by GM6001, the antia v integrin antibody, or the preabsorption of latent TGFb1. These results indicate that keratinocytes secrete latent TGFb1, which is liberated to fibroblasts over distance and is activated to produce aSMA with the aid of a positivefeedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model. [Supplementary Figure: available only at http://dx

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

et al. 2014

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“…By air-liquid surface culture, the keratinocytes stratified and differentiated, mimicking the epidermis in vivo. The LSE model was previously investigated histologically, molecularly, and ultrastructurally and revealed the features of epidermogenesis and basement membrane development, resembling regenerating skin in wound healing [2, 3]. …”

Section: Introductionmentioning

confidence: 99%

Basic Fibroblast Growth Factor Influences Epidermal Homeostasis of Living Skin Equivalents through Affecting Fibroblast Phenotypes and Functions

Yang¹,

Zhang²,

Wu³

et al. 2018

Skin Pharmacol Physiol

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Aims: To elucidate the possible mechanisms of how basic fibroblast growth factor (bFGF) influences epidermal homeostasis in a living skin equivalent (LSE) model. Methods: Several wound healing-related growth factors were analyzed at protein and mRNA levels for dermal fibroblasts of induced alpha-smooth muscle actin (α-SMA)-positive or α-SMA-negative phenotypes. During culturing an LSE model by seeding normal human keratinocytes on a fibroblast-populated type I collagen gel, bFGF or neutralizing antibody for keratinocyte growth factor (KGF) was added to investigate its effects on fibroblast phenotypes and, subsequently, epidermal homeostasis by histology and immunohistochemistry. Results: The α-SMA-positive phenotype of fibroblasts induced by transforming growth factor beta-1 (TGF-β₁) markedly suppressed the expression of KGF and hepatocyte growth factor (HGF), and slightly upregulated vascular endothelial growth factor (VEGF) and TGF-β₁ at mRNA and protein levels, compared with α-SMA-negative fibroblasts treated with bFGF. α-SMA expression of fibroblasts at the epidermal-mesenchymal junction of the LSEs was suppressed by the addition of bFGF, and a better-differentiated epidermis was presented. The abrogation of KGF from fibroblasts by the addition of the KGF neutralizing antibody disenabled the LSE culturing system to develop an epidermis. Conclusions: bFGF, through affecting the phenotypes and functions of fibroblasts, especially KGF expression, influenced epidermal homeostasis in an LSE model.

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“…Fibroblasts are the main connective tissue type in the body and maintain the stroma for numerous other cell types including keratinocytes, myocytes, and alveolar epithelial cells [1][2][3]. When the tissue is injured, these cells are the main repair mechanism to repopulate the cells lost to injury, build new extracellular matrix (ECM) and contract it to match the new matrix with undamaged tissue [4].…”

Section: Introductionmentioning

confidence: 99%

“…However, sometimes the cells do not disengage. These cells continue to contract forcefully and deposit excessive collagen without organization such as extensive crosslinking or bundle formation [2,15]. This pathology results in a number of fibrotic diseases in the skin, heart, lungs, liver, kidneys and also the stroma reaction to epithelial tumors which aids tumor growth and metastasis [14,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Mesenchymal Cell Contraction using Carbon Nanotubes

Wailes

Levi‐Polyachenko

2013

Nanomaterials and Tissue Regeneration

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Fibrosis can develop after injury in many organ systems, including the skin, lungs, and heart, yet no treatment is currently available to target the cause of fibrosis. We hypothesize that fiber-like carbon nanotubes may be able to interact with the mesenchymal cells to inhibit the contraction that can lead to fibrosis. Collagen gels were populated with human mesenchymal cells and spherical carbon black nanoparticles, singlewall carbon nanotubes (SWNT), or multi-wall carbon nanotubes (MWNT). The contraction, viability, actin content, and antioxidant capabilities of the gels were evaluated over the course of one week. The initial mechanical properties of the gels were also investigated. Both SWNT and MWNT, but not carbon black, significantly inhibited contraction while increasing proliferation. The nanotubes were effective even though cells in every gel type expressed α-smooth muscle actin, which is indicative of a procontractile, myofibroblast phenotype. The nanoparticles were shown to not affect gel stiffness. The MWNT also act as potent antioxidants, which may be the reason they minimize contraction. Our data show that carbon nanotubes can modulate the pathological activity of mesenchymal cells while increasing cell proliferation. We demonstrate that the aspect ratio of carbon nanoparticles is an important factor in mediating nanoparticle-cell interactions. Keywords Fibrosis • Collagen Gel • MWNT • SWNT • Carbon Black

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Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents

Cited by 16 publications

References 36 publications

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Basic Fibroblast Growth Factor Influences Epidermal Homeostasis of Living Skin Equivalents through Affecting Fibroblast Phenotypes and Functions

Inhibition of Mesenchymal Cell Contraction using Carbon Nanotubes

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