Epidermal Cell Migration Research Articles

EGFL7 affects the migration of epidermal stem cells in refractory diabetic wounds by regulating Notch signaling pathway.

Aim: This study aimed to explore the role of EGFL7 in the healing process of refractory diabetic wounds. Methods: Epidermal stem cells (ESCs) were isolated from healthy mice and diabetic mice, identified by immunofluorescence, transfected with EGFL7 overexpression and silencing lentiviral vectors, and treated with Notch pathway inhibitor (DAPT). Results: SiEGFL7 significantly inhibited the proliferation, invasion and migration of ESCs of healthy mice. DAPT prominently inhibited the expressions of Notch1, Notch2, Hes1 and Jag1 in ESCs of healthy mice induced by overexpressed EGFL7. Overexpressed EGFL7 promoted wound healing in diabetic mice with refractory wounds. Conclusion: EGFL7 affects the proliferation and migration of ESCs in refractory diabetic wounds by regulating the Notch signaling pathway.

598 The polyamines spermidine and spermine are essential regulators of epidermal differentiation and cell migration during wound healing

The polyamines putrescine, spermidine and spermine are ubiquitously expressed cations that are essential for normal cellular function. AMD1 is a key, rate limiting enzyme that drives the conversion of putrescine to spermidine and spermine and thus can change the ratios of the three polyamines. The polyamines, specifically spermine, show a dramatic reduction in levels in aged skin yet their role within the skin is not well understood. The purpose of this study was to examine the role of polyamines in skin barrier formation and wound healing.

Optimisation of Calophyllum inophyllum seed oil nanoemulsion as a potential wound healing agent

BackgroundEfficient delivery systems of Calophyllum inophyllum seed oil (CSO) in the form of nanoemulsion were optimised to enhance its stability and ensure its therapeutic efficiency as a potential agent for various biomedical applications.MethodResponse Surface Methodology (RSM) was used to determine the effects of independent variables (oil, surfactant, water percentage and homogenisation time) on physicochemical characteristics, including droplet size, polydispersity index and turbidity.ResultsThe optimised CSO nanoemulsion (CSONE) has a 46.68 nm particle size, 0.15 Polydispersity index value and 1.16 turbidity. After 4 weeks of storage at 5 ± 1 °C and 25 ± 1 °C, the CSONE was physically stable. The optimised CSO nanoemulsion showed enhancement in cell viability and wound healing in baby hamster kidney a clone BHK-21 (BSR) cells as compared to the CSO. The wound healing property of CSONE was higher than CSO.ConclusionThus, our in vitro wound healing results demonstrated that CSO in the nanoemulsion form can promote wound healing by enhancing the proliferation and migration of epidermal cells.Graphical The coarse emulsion of Calophyllum inophyllum seed oil nano emulsion was prepared using high shear homogeniser techniques. The optimised CSONE with the droplet size of 46.68 nm was prepared from a mixture of CSO, Tween 80, and high pure water (HPW), then used for the biological investigation. The in vitro cell monolayer scratch assay revealed that CSONE in the lowest concentration of CSO resulted in 100% wound closure after 48 hrs. The optimised CSO nanoemulsion was found to be a promising and effective approach in the treatment of wounds by boosting the proliferation and migration of epidermal cells.

Research advances on the role and mechanism of epidermal stem cells in skin wound repair

Epidermal stem cells play an pivotal role in skin self-renewal, wound repair, and re-epithelialization process. The emergence of new technologies and concepts such as single-cell sequencing and gene knockout further revealed a new mechanism of epidermal stem cells in epidermal self-renewal and wound repair, providing new ideas for wound repair. In this review, the mechanisms of proliferation, differentiation, and migration of epidermal stem cells are discussed. Combined with the analysis of researches on stem cell heterogeneity and cell plasticity, the physiological function of epidermal stem cells can be further understood. The application advances of epidermal stem cells in wound repair is also summarized, which would provide some advice for workers engaged in clinical and basic research on wound repair.

Arbutin Inhibited Heat Stress-Induced Apoptosis and Promoted Proliferation and Migration of Heat-Injured Dermal Fibroblasts and Keratinocytes by Activating PI3K/AKT Signaling Pathway.

Objective Studies have shown that arbutin has antioxidant and anti-inflammatory activities, which makes it suitable for treating skin wounds. We designed this study to investigate the effect of arbutin on heat-induced apoptosis, proliferation, and migration of dermal fibroblasts and keratinocytes and to explore the molecular mechanism. Methods In vitro, HaCAT and dermal fibroblast (DFL) cells were cultured and used to establish a heat stress-injured skin cell model. We investigated the effects of arbutin on apoptosis, proliferation, and migration of HaCAT and DFL cells after heat stress injury. We then used immunoblotting to detect the expression of p-PI3K, PI3K, p-AKT, and AKT proteins for studying the underlying mechanisms and used a PI3K/AKT inhibitor (LY294002) to verify the efficacy of arbutin in HaCAT and DFL cells with heat stress injury. Results Arbutin strongly inhibited heat stress-induced apoptosis, proliferation inhibition, and migration inhibition of HaCAT and DFL cells in vitro. Our results also showed that arbutin strongly decreased the ratio of Bax/Bcl2 protein expression and PCNA protein expression in HaCAT and DFL cells after treatment with heat stress. Furthermore, we also found that arbutin significantly increased the ratio of p-PI3K/PI3K and p-AKT/AKT protein expression, and LY294002 markedly reversed the effect of arbutin on heat stress-induced apoptosis, proliferation inhibition, and migration inhibition of HaCAT and DFL cells. Conclusion Our finding indicated that arbutin inhibited heat stress-induced apoptosis and promoted proliferation and migration of heat-injured dermal fibroblasts and epidermal cells by activating the PI3K/AKT signaling pathway, suggesting that arbutin may provide an alternative therapeutic approach for the treatment of skin injury.

Promoting Re-epithelialization in an oxidative diabetic wound microenvironment using self-assembly of a ROS-responsive polymer and P311 peptide micelles

Engineering smart nano-therapeutics for re-epithelialisation of chronic wounds facilitates the wound healing process. However, due to excessive oxidative stress damage and persistent inflammation in diabetic wound microenvironment, the migration of stimulating epidermal cells in diabetic wounds represents a significant challenge. Here we synthesised P311-loaded micelles by self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS) that have unique ability to transform an oxidative wound microenvironment into a proregenerative one while also providing cues for epidermal cell migration. The P311@PEPS showed an accelerated migration of epidermal cells via activation of the Akt signalling pathway, simultaneously suppressing the unfavourable oxidative wound microenvironment by scavenging reactive oxygen species (ROS), ultimately leading to the induction of an environment conducive to cell migration. Furthermore, the micelles were able to bypass the inhibitory effect of ROS on the Akt signalling pathway, thereby promoting epidermal cell migration. Additionally, we observed that diabetic wounds treated with P311@PEPS showed accelerated chronic wound healing, granulation tissue formation, collagen deposition and re-epithelialisation, thereby suggesting the efficacy of P311@PEPS as a promising nanoplatform for the treatment of chronic wounds. Statement of significanceBased on the unique conditions of the diabetic wound microenvironment, a smart drug delivery system with ROS-responsive nanomaterials has been widely investigated to enhance diabetic wound healing. In our previous studies, we observed that P311 promotes epidermal cell migration to induce wound re-epithelialisation. However, the application of P311 suffers from its instability. Herein, we developed a therapeutic platform with P311-loaded micelles (P311@PEPS), which were synthesized by the self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS). These micelles provide continuous migration signals for epidermal cells by ROS-trigged P311 release. Additionally, P311@PEPS scavenges excess ROS and provides a microenvironment that reduces inflammation, which could protect P311 from enzymatic degradation and improve the bioavailability of P311.

Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF-β1/SMAD pathway

BackgroundThe biological activity and regenerative medicine of bone marrow mesenchymal stem cells (BMSCs) have been focal topics in the broad fields of diabetic wound repair. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated during BMSC treatment. Our previous studies have shown that hypoxia is not only a typical pathological phenomenon of wounds but also exerts a vital regulatory effect on cellular bioactivity. In this study, the beneficial effects of hypoxic BMSCs on the cellular behaviors of epidermal cells and diabetic wound healing were investigated.MethodThe viability and secretion ability of hypoxic BMSCs were detected. The autophagy, proliferation and migration of HaCaT cells cultured with hypoxic BMSCs-derived conditioned medium were assessed by estimating the expression of autophagy-related proteins, MTS, EdU proliferation and scratch assays. And the role of the SMAD signaling pathway during hypoxic BMSC-evoked HaCaT cell autophagy was explored through a series of in vitro gain- and loss-of-function experiments. Finally, the therapeutic effects of hypoxic BMSCs were evaluated using full-thickness cutaneous diabetic wound model.ResultsFirst, we demonstrated that hypoxic conditions intensify HIF-1α-mediated TGF-β1 secretion by BMSCs. Then, the further data revealed that BMSC-derived TGF-β1 was responsible for the activation of epidermal cell autophagy, which contributed to the induction of epidermal cell proliferation and migration. Here, the SMAD signaling pathway was identified as downstream of BMSC-derived TGF-β1 to regulate HaCaT cell autophagy. Moreover, the administration of BMSCs to diabetic wounds increased epidermal autophagy and the rate of re-epithelialization, leading to accelerated healing, and these effects were significantly attenuated, accompanied by the downregulation of Smad2 phosphorylation levels due to TGF-β1 interference in BMSCs.ConclusionIn this report, we present evidence that uncovers a previously unidentified role of hypoxic BMSCs in regulating epidermal cell autophagy. The findings demonstrate that BMSC-based treatment by restoring epidermal cell autophagy could be an attractive therapeutic strategy for diabetic wounds and that the process is mediated by the HIF-1α/TGF-β1/SMAD pathway.

EP096: Novel pathogenic variants causing TBCK syndrome in three patients from Indian origin

TBCK or TBCK-related encephalopathy is a rare genetic disorder characterized by profound intellectual disability, severe infantile hypotonia, slow motor delay, facial dysmorphism. In most of the reported cases post-natal onset of progressive brain atrophy and white matter changes on MRI have been reported. TBCK protein is putative Rab GTPase activating protein with possible role in epidermal growth factor signaling, endocytosis, and cell migration.

FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1‐dependent autophagy

Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown. Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1flox/flox and Atg7flox/flox mice were constructed and injected with the epidermal-specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT-RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy-related genes were assessed using immunoprecipitation assays. FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent. FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.

Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing

An orchestrated wound healing program drives skin repair via collective epidermal cell proliferation and migration. However, the molecular determinants of the tissue microenvironment supporting wound healing remain poorly understood. Herein we discover that proteoglycan Agrin is enriched within the early wound-microenvironment and is indispensable for efficient healing. Agrin enhances the mechanoperception of keratinocytes by augmenting their stiffness, traction stress and fluidic velocity fields in retaliation to bulk substrate rigidity. Importantly, Agrin overhauls cytoskeletal architecture via enhancing actomyosin cables upon sensing geometric stress and force following an injury. Moreover, we identify Matrix Metalloproteinase-12 (MMP12) as a downstream effector of Agrin’s mechanoperception. We also reveal a promising potential of a recombinant Agrin fragment as a bio-additive material that assimilates optimal mechanobiological and pro-angiogenic parameters by engaging MMP12 in accelerated wound healing. Together, we propose that Agrin-MMP12 pathway integrates a broad range of mechanical stimuli to coordinate a competent skin wound healing niche.

Keratinocyte Growth Factor-Based Strategies for Wound Re-Epithelialization.

Wound re-epithelialization is a dynamic process that comprises the formation of new epithelium through an active signaling network between several growth factors (GFs) and various cell types. The main players are keratinocytes (KCs) that migrate from the wound edges over the wound bed to restore the epidermal barrier. One of the most important molecules involved in the re-epithelialization process is keratinocyte growth factor (KGF), a central player on promoting both migration and proliferation of KCs. Stromal cells, such as dermal fibroblasts, are the main producers of this factor, acting on KCs through paracrine signaling. Multiple therapeutic strategies to deliver KGF have been proposed to boost wound healing by targeting re-epithelialization. Different approaches have been explored to attain that purpose, such as topical application of this factor, controlled release of KGF from different biomaterials (hydrogels, nanoparticles, and membranes), and also gene delivery techniques. Among these strategies, KGF release via biomaterials- and genetic-based strategies shows great effectiveness in maintaining sustained KGF levels at the wound site, which is reflected in an efficient wound closure. Under this scope, this review aims not only to elucidate the potential of KGF in wound re-epithelialization but also to describe the underlying mechanism of action and further explore the therapeutic approaches using this GF. Impact statement Upon skin injury, wound re-epithelialization is one of the major milestones of the healing process. This is especially difficult to achieve on hard-to-heal wounds that are often open for long periods, as the dysregulation of the growth factors involved in this response contributes to an impaired proliferation and migration of keratinocytes. Keratinocyte growth factor (KGF) plays a central role in this problematic, as it is a potent factor that in the normal healing scenario promotes direct proliferation and migration of epidermal cells, consequently impacting re-epithelialization. Under this context, in the first part of this review, the process of wound healing and the mechanism of action of KGF are described. In the second part, various KGF delivery approaches aiming at skin re-epithelialization are reported and actively discussed. In this sense, it is herein highlighted the role of KGF in wound re-epithelialization and provided a critical overview of potential therapeutic strategies exploited so far.

Polymersome Wound Dressing Spray Capable of Bacterial Inhibition and H2S Generation for Complete Diabetic Wound Healing

Diabetic wounds are difficult to heal due to recurrent bacterial infection, decreased proliferation, and migration of epidermal and endothelial cells. This is related to impaired leukocyte function...

Proteolytic activation of Growth-blocking peptides triggers calcium responses through the GPCR Mthl10 during epithelial wound detection.

The presence of a wound triggers surrounding cells to initiate repair mechanisms, but it is not clear how cells initially detect wounds. In epithelial cells, the earliest known wound response, occurring within seconds, is a dramatic increase in cytosolic calcium. Here, we show that wounds in the Drosophila notum trigger cytoplasmic calcium increase by activating extracellular cytokines, Growth-blocking peptides (Gbps), which initiate signaling in surrounding epithelial cells through the G-protein-coupled receptor Methuselah-like 10 (Mthl10). Latent Gbps are present in unwounded tissue and are activated by proteolytic cleavage. Using wing discs, we show that multiple protease families can activate Gbps, suggesting that they act as a generalized protease-detector system. We present experimental and computational evidence that proteases released during wound-induced cell damage and lysis serve as the instructive signal: these proteases liberate Gbp ligands, which bind to Mthl10 receptors on surrounding epithelial cells, and activate downstream release of calcium.

VGLL4 inhibits YAP1/TEAD signaling to suppress the epidermal squamous cell carcinoma cancer phenotype.

Epidermal squamous cell carcinoma (SCC) develops in response to ultraviolet light exposure and is among the most common cancers. The transglutaminase 2 cancer cell survival protein stimulates the activity of the YAP1/TEAD transcription complex to drive the expression of genes that promote aggressive epidermal SCC cell invasion, migration, and tumor formation. Therefore, we are interested in mechanisms that may inhibit these events. Vestigial-like protein-4 (VGLL4) is a transcription cofactor/tumor suppressor that inhibits several pro-cancer pathways including YAP1 signaling. Our present studies show that VGLL4 inhibits YAP1/TEAD-dependent transcription to reduce the expression of YAP1 target genes (CCND1, CYR61, and CTGF) and pro-cancer collagen genes (COL1A2and COL3A1). We further show that loss of these YAP1 regulated genes is required for VGLL4 suppression of the cancer cell phenotype, as forced CCND1 or COL1A2 expression partially restores the aggressive cancer phenotype in VGLL4 expressing cells. Consistent with these findings, VGLL4 expression reduces tumor formation, and this is associated with reduced CCND1, CYR61, CTGF, COL1A2, and COL1A3 mRNA and protein levels, and reduced EMT marker expression. These findings indicate that VGLL4 suppresses the malignant epidermal SCC cancer phenotype by inhibiting YAP1/TEAD-dependent pro-cancer signaling.

Rosmarinic acid protects mice from imiquimod induced psoriasis-like skin lesions by inhibiting the IL-23/Th17 axis via regulating Jak2/Stat3 signaling pathway.

IL-23/Th17 (IL-17) axis plays a critical role in psoriasis. Rosmarinic acid (RA) was proved the inhibitory effect of T cell infiltration in the skin. However, whether and how RA has beneficial effects on psoriasis did not really know yet. So lipopolysaccharide (LPS)-induced abnormal proliferation Hacat cell line and Imiquimod (IMQ)-induced psoriasis-like mouse dermatitis were used to assess the pharmacological effects and mechanisms of RA by Psoriasis Area Severity Index (PASI) score, histopathology, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. The results showed that RA inhibited LPS-induced aberrant expression of Hacat cell line, and significantly alleviated IMQ-induced skin inflammation. Although RA had no obviously effect on the ratio of epidermal Langerhans cell (LC) and LC migration from the skin to the skin draining lymph nodes, RA inhibited the expression of IL-23 in skin lesions, as well as reduced the differentiation of Th17 cells and producing of IL-17A by down regulating the transcriptor factor RORγt and JAK2/Stat3 signal pathway, comparing to IMQ treated group. The findings suggest that RA inhibits psoriasis-like skin inflammation in vivo and in vitro by reducing the expression of IL-23, inhibiting Th17 dominated inflammation and down regulating the Jak2/Stat3 signal pathway.

Skin delivery of hapten and neurokinin-1 receptor antagonists by microneedle arrays targets neurogenic inflammation and prevents contact dermatitis

Abstract Contact dermatitis (CD) is a chronic inflammatory disease caused by type-1 immunity. Skin exposure to haptens stimulates the secretion of Substance-P (SP) and initiates the neurogenic inflammation that intensifies CD. Neurokinin-1 receptor (NK1R)-signaling by SP or hemokinin-1 (HK1) amplifies immune responses. Nonetheless, the role and therapeutic implications of the NK1R-SP-HK1 axis in CD remain unclear. We show that SP, HK-1 and the NK1R are required for CD. Specific deletion of the NK1R in keratinocytes decreased the rapid release of IL-1β and IL-6 at the site of contact sensitization which impaired the innate and adaptive immunity of CD whereas deletion of the receptor in dendritic cells (DC) prevented only the adaptive immune response of the disease. Therefore, we hypothesized that blockade of NK1R during sensitization would be a feasible immunosuppressive intervention to treat CD. We developed a system of microneedle arrays (MNA) that co-deliver hapten and NK1R antagonists into mouse skin. This immunosuppressive approach resulted in decreased skin migration and lymph node homing of stimulatory dermal DC transporting the hapten from the sensitization site. Conversely, the immunosuppressive MNA did not affect the migration and lymph node homing of epidermal Langerhans cells (LC), and depletion of LC resulted in loss of the NK1R antagonist beneficial effects. In addition, immunosuppressive MNA caused deletion of hapten-specific T cells and increased T-regulatory cells, which prevented CD-onset and -relapses in a hapten-specific manner. Our findings indicate that immune-regulation by engineering localized skin neuroimmune-networks can be used to treat cutaneous diseases that, like CD are caused by type-1 immunity.

Autocrine and Paracrine Effects of Vascular Endothelial Cells Promote Cutaneous Wound Healing.

Background When vascular endothelial cells are subjected to external stimuli, paracrine hormones and cytokines act on adjacent cells. The regulation of the biological behaviour of cells is closely related to the maintenance of organ function and the occurrence and development of disease. However, it is unclear whether vascular endothelial cells affect the biological behaviour of cells involved in wound repair through autocrine and paracrine mechanisms and ultimately play a role in wound healing. We aimed to verify the effect of the autocrine and paracrine functions of vascular endothelial cells on wound healing. Materials and Methods ELISA was used to detect platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor in human umbilical vascular endothelial cell-conditioned medium (HUVEC-CM). Different concentrations of HUVEC-CM were used to treat different stem cells. CCK-8 and scratch assays were used to detect the proliferation and migration ability of each cell. A full-thickness dorsal skin defect model was established in mice, and skin wound healing was observed after the local injection of HUVEC-CM, endothelial cell medium (ECM), or normal saline. H&E staining and immunofluorescence were used to observe the gross morphology of the wound tissue, the epithelial cell migration distance, and the expression of CD3 and CD31. Results HUVEC-CM promotes the proliferation and migration of epidermal stem cells, skin fibroblasts, bone marrow mesenchymal stem cells, and HUVECs themselves. Furthermore, HUVEC-CM can promote angiogenesis in mouse skin wounds and granulation tissue formation and can accelerate wound surface epithelialization and collagen synthesis, thereby promoting wound healing. Conclusion Our results clearly suggest that it is practicable and effective to promote wound healing with cytokines secreted by vascular endothelial cells in a mouse model.

Human foreskin-derived dermal stem/progenitor cell-conditioned medium combined with hyaluronic acid promotes extracellular matrix regeneration in diabetic wounds

BackgroundDiabetic wounds remain a challenging clinical problem, which requires further treatment development. Published data showed that dermis-derived stem/progenitor cells (DSPCs) display superior wound healing in vitro. The beneficial effects of DSPCs are mediated through paracrine secretion, which can be obtained from conditioned medium (CM). Hyaluronic acid (HA) is especially suitable for skin regeneration and delivering bioactive molecules in CM. This study investigated the effect of human foreskin-derived dermal stem/progenitor cell (hFDSPC)-CM combined with HA on a diabetic mouse model and relevant mechanism in vitro.MethodshFDSPCs and human adipose-derived stem cells (hADSCs) were identified, and the respective CM was prepared. PBS, HA, hFDSPC-CM combined with HA, or hADSC-CM combined with HA was topically applied to mice. HE, CD31, CD68, CD86, and CD206 staining was performed to evaluate gross wound condition, angiogenesis, and inflammation, respectively. Masson and Picrosirius red staining was performed to evaluate collagen deposition and maturation. The effects of hFDSPC-CM and hADSC-CM on human keratinocyte cells (HaCaT) and fibroblasts were evaluated in vitro using CCK-8 and EdU assays to determine cell viability and proliferation, respectively. The scratch assay was performed to evaluate cell migration. Tube formation assay was performed on human umbilical vein endothelial cells (HUVECs) to confirm angiogenesis. Extracellular matrix (ECM) metabolic balance-related genes and proteins, such as collagen I (COL 1), collagen III (COL 3), fibronectin (FN), α-SMA, matrix metalloproteinases 1 (MMP-1), matrix metalloproteinases 3 (MMP-3), and transforming growth factor-beta 1 (TGF-β1), were analysed.ResultshFDSPC-CM combined with HA showed superior wound closure rate over hADSC-CM. Histologically, the hFDSPC-CM combined with HA group showed significantly improved re-epithelialisation, angiogenesis, anti-inflammation, collagen regeneration, and maturation compared to hADSC-CM combined with HA group. In vitro assays revealed that hFDSPC-CM displayed significant advantages on cell proliferation, migration, and ECM regeneration through a TGF-β/Smad signalling pathway compared with hADSC-CM.ConclusionshFDSPC-CM combined with HA was superior for treating diabetic wounds. The underlying mechanism may promote proliferation and migration of epidermal cells with fibroblasts, thus leading to ECM deposition and remodelling. Reduced inflammation may be due to the above-mentioned mechanism.

GDF-5 induces epidermal stem cell migration via RhoA-MMP9 signalling.

The migration of epidermal stem cells (EpSCs) is critical for wound re‐epithelization and wound healing. Recently, growth/differentiation factor‐5 (GDF‐5) was discovered to have multiple biological effects on wound healing; however, its role in EpSCs remains unclear. In this work, recombinant mouse GDF‐5 (rmGDF‐5) was found via live imaging in vitro to facilitate the migration of mouse EpSCs in a wound‐scratch model. Western blot and real‐time PCR assays demonstrated that the expression levels of RhoA and matrix metalloproteinase‐9 (MMP9) were correlated with rmGDF‐5 concentration. Furthermore, we found that rmGDF‐5 stimulated mouse EpSC migration in vitro by regulating MMP9 expression at the mRNA and protein levels through the RhoA signalling pathway. Moreover, in a deep partial‐thickness scald mouse model in vivo, GDF‐5 was confirmed to promote EpSC migration and MMP9 expression via RhoA, as evidenced by the tracking of cells labelled with 5‐bromo‐2‐deoxyuridine (BrdU). The current study showed that rmGDF‐5 can promote mouse EpSC migration in vitro and in vivo and that GDF‐5 can trigger the migration of EpSCs via RhoA‐MMP9 signalling.

Multi-tissue patterning drives anterior morphogenesis of the C. elegans embryo

Complex structures derived from multiple tissue types are challenging to study in vivo, and our knowledge of how cells from different tissues are coordinated is limited. Model organisms have proven invaluable for improving our understanding of how chemical and mechanical cues between cells from two different tissues can govern specific morphogenetic events. Here we used Caenorhabditis elegans as a model system to show how cells from three different tissues are coordinated to give rise to the anterior lumen. While some aspects of pharyngeal morphogenesis have been well-described, it is less clear how cells from the pharynx, epidermis and neuroblasts coordinate to define the location of the anterior lumen and supporting structures. Using various microscopy and software approaches, we define the movements and patterns of these cells during anterior morphogenesis. Projections from the anterior-most pharyngeal cells (arcade cells) provide the first visible markers for the location of the future lumen, and facilitate patterning of the surrounding neuroblasts. These neuroblast patterns control the rate of migration of the anterior epidermal cells, whereas the epidermal cells ultimately reinforce and control the position of the future lumen, as they must join with the pharyngeal cells for their epithelialization. Our studies are the first to characterize anterior morphogenesis in C. elegans in detail and should lay the framework for identifying how these different patterns are controlled at the molecular level.