Decrease of laminin-511 in the basement membrane due to photoaging reduces epidermal stem/progenitor cells

Iriyama, Shunsuke; Yasuda, Masahito; Nishikawa, So; Takai, Eisuke; Hosoi, Junichi; Amano, Sadao

doi:10.1038/s41598-020-69558-y

Cited by 26 publications

(34 citation statements)

References 56 publications

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“…Laminin staining was also predominantly basal but was more convoluted in appearance with some inter-digitation with the epidermis as compared to collagen IV (Additional file 2: Fig S2D). We also note with interest that such inter-digitation has been observed in other human skin sections [33] and cornea [34]. It is also notable that other ECM ligands may play a role in this context, including collagen XXIII that has been shown to be a ligand for α2β1 and localises to cell-cell adhesions in the human skin [35].…”

Section: Results and Discussion α2β1 Integrins Contribute To Cell-cell Adhesion Assemblysupporting

confidence: 55%

α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

et al. 2021

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Background Keratinocytes form the main protective barrier in the skin to separate the underlying tissue from the external environment. In order to maintain this barrier, keratinocytes form robust junctions between neighbouring cells as well as with the underlying extracellular matrix. Cell–cell adhesions are mediated primarily through cadherin receptors, whereas the integrin family of transmembrane receptors is predominantly associated with assembly of matrix adhesions. Integrins have been shown to also localise to cell–cell adhesions, but their role at these sites remains unclear. Results Here we show that α2β1 integrins are enriched at mature keratinocyte cell–cell adhesions, where they play a crucial role in organising cytoskeletal networks to stabilize adherens junctions. Loss of α2β1 integrin has significant functional phenotypes associated with cell–cell adhesion destabilisation, including increased proliferation, reduced migration and impaired barrier function. Mechanistically, we show that α2β1 integrins suppress activity of Src and Shp2 at cell–cell adhesions leading to enhanced Cdc42–GDI interactions and stabilisation of junctions between neighbouring epithelial cells. Conclusion Our data reveals a new role for α2β1 integrins in controlling integrity of epithelial cell–cell adhesions.

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Section: Results and Discussion α2β1 Integrins Contribute To Cell-cell Adhesion Assemblysupporting

confidence: 55%

α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

et al. 2021

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“…We previously developed HEI as a bi-functional inhibitor of both MMP-9 and heparinase. Topical application of HEI promoted reconstruction of the basememt membrane and deposition of laminin-511 by inhibiting the activities of MMP-9 and heparinase in an organotypic human skin model 11 , thereby maintaining MCSP-positive epidermal stem cells and promoting epidermal homeostasis and barrier recovery 10,11 . Dermal regeneration of facial skin was also promoted by treatment with HEI, improving the elasticity of the papillary dermis (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…6B). We previously reported that epidermal stem cell levels were maintained by blocking the degradation of laminin-511 mediated by MMP-9 and heparinase 10 . Thus, we next investigated the effect of laminin-511 on cytokine secretion.…”

Section: Pdgfb Expression In Keratinocytes Was Reduced In An Age-dependent Manner and Was Affected By The Basement Membrane Conditionmentioning

confidence: 99%

“…1). We previously reported that treatment of organotypic human skin and skin equivalent models with both MMP and heparinase inhibitors promoted the formation of basement membrane at the dermal-epidermal junction 10,11 and also resulted in the appearance of thicker collagen bers in the papillary dermis. Therefore, we next exposed an organotypic human skin culture to these inhibitors and performed immunostaining for type I procollagen and type V collagen.…”

Section: Mmp and Heparinase Inhibitorsmentioning

confidence: 99%

“…After 4-day culture (skin equivalent model) or 5-day culture (organotypic abdominal skin model), samples were immersed in glutaraldehyde xative at 4°C overnight and then rinsed in 0.1 M phosphate buffer for 30 min at room temperature as described 10 . Samples were xed in 1% OsO 4 for 30 min at room temperature and then rinsed in triple-distilled water, embedded and subjected to routine processing.…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

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Regeneration of Collagen Fibrils at the Papillary Dermis by Reconstructing Basement Membrane at the Dermal-Epidermal Junction

Iriyama

Ogura

Nishikawa

et al. 2021

Preprint

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The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibers in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.

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Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions

et al. 2022

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Aging is a major risk factor in microvascular dysfunction and disease development, but the underlying mechanism remains largely unknown. As a result, age‐mediated changes in the mechanical properties of tissue collagen have gained interest as drivers of endothelial cell (EC) dysfunction. 3D culture models that mimic age‐mediated changes in the microvasculature can facilitate mechanistic understanding. A fibrillar hydrogel capable of changing its stiffness after forming microvascular networks is established. This hydrogel model is used to form vascular networks from induced pluripotent stem cells under soft conditions that mimic young tissue mechanics. Then matrix stiffness is gradually increased, thus exposing the vascular networks to the aging‐mimicry process in vitro. It is found that upon dynamic matrix stiffening, EC contractility is increased, resulting in the activation of focal adhesion kinase and subsequent dissociation of β ‐catenin from VE‐Cadherin mediated adherens junctions, leading to the abruption of the vascular networks. Inhibiting cell contractility impedes the dissociation of β ‐catenin, thereby preventing the deconstruction of adherens junctions, thus partially rescuing the age‐mediated vascular phenotype. The findings provide the first direct evidence of matrix's dynamic mechano‐changes in compromising microvasculature with aging and highlight the importance of hydrogel systems to study tissue‐level changes with aging in basic and translational studies.

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Decrease of laminin-511 in the basement membrane due to photoaging reduces epidermal stem/progenitor cells

Cited by 26 publications

References 56 publications

α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

Regeneration of Collagen Fibrils at the Papillary Dermis by Reconstructing Basement Membrane at the Dermal-Epidermal Junction

Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions

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