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Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing.

ABSTRACT: Thrombospondin-4 (THBS4) is a non-structural extracellular matrix molecule associated with tissue regeneration and a variety of pathological processes characterized by increased cell proliferation and migration. However, the mechanisms of how THBS4 regulates cell behavior as well as the pathways contributing to its effects have remained largely unexplored. In the present study we investigated the role of THBS4 in skin regeneration both in vitro and in vivo. We found that THBS4 expression was upregulated in the dermal compartment of healing skin wounds in humans as well as in mice. Application of recombinant THBS4 protein promoted cutaneous wound healing in mice and selectively stimulated migration of primary fibroblasts as well as proliferation of keratinocytes in vitro. By using a combined proteotranscriptomic pathway analysis approach we discovered that β-catenin acted as a hub for THBS4-dependent cell signaling and likely plays a key role in promoting its downstream effects. Our results suggest that THBS4 is an important contributor to wound healing and its incorporation into novel wound healing therapies may be a promising strategy for treatment of cutaneous wounds.

SUBMITTER: Klaas M

PROVIDER: S-EPMC8495264 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Thrombospondin-4 is a soluble dermal signal that selectively promotes fibroblast migration and keratinocyte proliferation for skin regeneration and wound healing

Project description:Thrombosponin-4 (THBS4) is a non-structural extracellular matrix molecule associated with tissue regeneration and a variety of pathological processes characterized by increased cell proliferation and migration. However, the mechanisms of how THBS4 regulates cell behaviour as well as the pathways contributing to its effects have remained largely unexplored. In the present study we investigated the role of THBS4 in skin regeneration both in vitro and in vivo. We found that THBS4 expression was upregulated in the dermal compartment of healing skin wounds in humans as well as in mice. Application of recombinand THBS4 protein promoted cutaneous wound healing in mice and selectively stimulated migration of primary fibroblasts as well as proliferation of keratinocytes in vitro. By using a combined proteotranstriptomic pathway analysis approach we discovered that beta-catenin acted as a hub for THBS4-dependent cell signaling and likely plays a key role in promoting its downstream effects. Out results suggest that THBS4 is an important contributor to wound healing and its incorporation into novel wound healing therapies may be a promising strategy for treatment of hard-to-heal wounds.

2022-02-17 | PXD027364 | Pride

Thrombospondin-4 is a soluble dermal inflammatory signal that activates the fibroblast migration for skin regeneration and wound healing

Project description:The present study aimed to investigate the role of Thbs4 in skin regeneration and elucidate its effects on cellular responses. Here we show that Thbs4 expression is upregulated in healing skin wounds and wound healing can be promoted by the application of recombinant Thbs4 protein. Thbs4 was shown to promote keratinocyte proliferation and fibroblast migration by activating β-catenin signalling cascade. This indicates that incorporating Thbs4 into novel wound healing therapies can be a promising therapeutic strategy for hard-to-heal chronic wounds.

2021-10-13 | GSE179969 | GEO

Thrombospondin-4 is a soluble dermal inflammatory signal that activates the fibroblast migration for skin regeneration and wound healing

Project description:Thrombospondin-4 is a soluble dermal inflammatory signal that activates the fibroblast migration for skin regeneration and wound healing

| PRJNA745989 | ENA

Fibroblast state switching orchestrates dermal maturation and wound healing.

Project description:Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed in vivo live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue-scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration.

| S-EPMC6113774 | biostudies-literature

Keratinocyte Induced Differentiation of Mesenchymal Stem Cells into Dermal Myofibroblasts: A Role in Effective Wound Healing.

Project description:We have previously demonstrated that human mesenchymal stem cells (hMSCs) migrate toward human keratinocytes as well as toward conditioned medium from cultured human keratinocytes (KCM) indicating that the hMSCs respond to signals from keratinocytes [1]. Using fluorescently labeled cells we now show that in vitro hMSCs appear to surround keratinocytes, and this organization is recapitulated in vivo. Incubation of hMSCs with KCM induced dermal myofibroblast like differentiation characterized by expression of cytoskeletal markers and increased expression of cytokines including SDF-1, IL-8, IL-6 and CXCL5. Interaction of keratinocytes with hMSCs appears to be important in the wound healing process. Therapeutic efficacy of hMSCs in wound healing was examined in two animal models representing normal and chronic wound healing. Accelerated wound healing was observed when hMSCs and KCM exposed hMSCs (KCMSCs) were injected near wound site in nude and NOD/SCID mice. Long term follow up of wound healing revealed that in the hMSC treated wounds there was little evidence of residual scarring. These dermal myofibroblast like hMSCs add to the wound healing process. Together, the keratinocyte and hMSCs morphed dermal myofibroblast like cells as well as the factors secreted by these cells support wound healing with minimal scarring. The ability of hMSCs to support wound healing process represents another striking example of the importance of keratinocyte and hMSCs interplay in the wound microenvironment resulting in effective wound healing with minimal scarring.

| S-EPMC4902180 | biostudies-literature

Electrical stimulation promotes wound healing by enhancing dermal fibroblast activity and promoting myofibroblast transdifferentiation.

Project description:Electrical stimulation (ES) has long been used as an alternative clinical treatment and an effective approach to modulate cellular behaviours. In this work we investigated the effects of ES on human skin fibroblast activity, myofibroblast transdifferentiation and the consequence on wound healing. Normal human fibroblasts were seeded on heparin-bioactivated PPy/PLLA conductive membranes, cultured for 24 h, and then exposed to ES of 50 or 200 mV/mm for 2, 4, or 6 h. Following ES, the cells were either subjected to various analyses or re-seeded to investigate their healing capacity. Our findings show that ES had no cytotoxic effect on the fibroblasts, as demonstrated by the similar LDH activity levels in the ES-exposed and non-exposed cultures, and by the comparable cell viability under both conditions. Furthermore, the number of viable fibroblasts was higher following exposure to 6 h of ES than in the non-exposed culture. This enhanced cell growth was likely due to the ES up-regulated secretion of FGF-1 and FGF-2. In an in vitro scratch-wound assay where cell monolayer was used as a healing model, the electrically stimulated dermal fibroblasts migrated faster following exposure to ES and recorded a high contractile behaviour toward the collagen gel matrix. This enhanced contraction was supported by the high level of ?-smooth muscle actin expressed by the fibroblasts following exposure to ES, indicating the characteristics of myofibroblasts. Remarkably, the modulation of fibroblast growth continued long after ES. In conclusion, this work demonstrates for the first time that exposure to ES promoted skin fibroblast growth and migration, increased growth factor secretion, and promoted fibroblast to myofibroblast transdifferentiation, thus promoting wound healing.

| S-EPMC3747189 | biostudies-literature

Global deletion of Ankrd1 results in a wound-healing phenotype associated with dermal fibroblast dysfunction.

Project description:The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These in vitro data were consistent with in vivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both in vitro and in vivo.

| S-EPMC4278243 | biostudies-literature

An on-chip wound healing assay fabricated by xurography for evaluation of dermal fibroblast cell migration and wound closure.

Project description:Dermal fibroblast cell migration is a key process in a physiological wound healing. Therefore, the analysis of cell migration is crucial for wound healing research. In this study, lab-on-a-chip technology was used to investigate the effects of basic fibroblast growth factor (bFGF), mitomycin C (MMC), MEK1/2 inhibitor (U0126) and fetal calf serum (FCS) on human dermal fibroblast cell migration. The microdevice was fabricated consisting of microchannels, pneumatic lines and pneumatically-activated actuators by xurographic rapid prototyping. In contrast to current approaches in in vitro wound healing such as scratch assays and silicone inserts in wellplate format, which show high variability and poor reproducibility, the current system aims to automate the wounding procedure at high precision and reproducibility using lab-on-a-chip. Traumatic wounding was simulated on-chip on fibroblast cell monolayers by applying air pressure on the flexible circular membrane actuator. Wound closure was monitored using light microscopy and cell migration was evaluated using image analysis. The pneumatically controlled system generates highly reproducible wound sizes compared to the conventional wound healing assay. As proof-of-principle study wound healing was investigated in the presence of several stimulatory and inhibitory substances and culture including bFGF, MMC, U0126 MEK1/2 inhibitor as well as serum starvation to demonstrate the broad applicability of the proposed miniaturized culture microsystem.

| S-EPMC7529912 | biostudies-literature

Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing.

Project description:New hair follicles (HFs) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50, fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.

| S-EPMC4958333 | biostudies-literature

Effect of collagen nanotopography on keloid fibroblast proliferation and matrix synthesis: implications for dermal wound healing.

Project description:Keloids are locally exuberant dermal scars characterized by excessive fibroblast proliferation and matrix accumulation. Although treatment strategies include surgical removal and intralesional steroid injections, an effective regimen is yet to be established due to a high rate of recurrence. The regressing center and growing margin of the keloid have different collagen architecture and also differ in the rate of proliferation. To investigate whether proliferation is responsive to collagen topography, keloid, scar, and dermal fibroblasts were cultured on nanopatterned scaffolds varying in collagen fibril diameter and alignment-small and large diameter, aligned and random fibrils, and compared to cells grown on flat collagen-coated substrates, respectively. Cell morphology, proliferation, and expression of six genes related to proliferation (cyclin D1), phenotype (?-smooth muscle actin), and matrix synthesis (collagens I and III, and matrix metalloproteinase-1 and -2) were measured to evaluate cell response. Fibril alignment was shown to reduce proliferation and matrix synthesis in all three types of fibroblasts. Further, keloid cells were found to be most responsive to nanotopography.

| S-EPMC4195479 | biostudies-other

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