Publications by authors named "Sabine A Eming"

81 Publications

Macrophage-Mediated Tissue Vascularization: Similarities and Differences Between Cornea and Skin.

Front Immunol 2021 7;12:667830. Epub 2021 Apr 7.

Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Macrophages are critical mediators of tissue vascularization both in health and disease. In multiple tissues, macrophages have been identified as important regulators of both blood and lymphatic vessel growth, specifically following tissue injury and in pathological inflammatory responses. In development, macrophages have also been implicated in limiting vascular growth. Hence, macrophages provide an important therapeutic target to modulate tissue vascularization in the clinic. However, the molecular mechanisms how macrophages mediate tissue vascularization are still not entirely resolved. Furthermore, mechanisms might also vary among different tissues. Here we review the role of macrophages in tissue vascularization with a focus on their role in blood and lymphatic vessel formation in the barrier tissues cornea and skin. Comparing mechanisms of macrophage-mediated hem- and lymphangiogenesis in the angiogenically privileged cornea and the physiologically vascularized skin provides an opportunity to highlight similarities but also tissue-specific differences, and to understand how macrophage-mediated hem- and lymphangiogenesis can be exploited for the treatment of disease, including corneal wound healing after injury, graft rejection after corneal transplantation or pathological vascularization of the skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.667830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058454PMC
April 2021

Regulation of the Wound Healing Response during Aging.

J Invest Dermatol 2021 Apr 6;141(4S):1063-1070. Epub 2021 Feb 6.

Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany; Institute of Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany. Electronic address:

An effective healing response is critical to promote and ensure healthy aging. Major discoveries in both fields-repair and aging-have led to a better understanding of the mechanisms regulating the healing response and of the complexity of the aging process. It will now be important to translate and connect those findings to improve our insights into the decline of regeneration in the elderly. Furthermore, we need to understand how this process can be stalled to maintain and promote tissue resilience. Furthermore, it remains to be explored how the findings in model organisms are conserved in human wounds and how these findings might be translated into the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.11.014DOI Listing
April 2021

Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle.

Cell Metab 2020 10 8;32(4):629-642.e8. Epub 2020 Sep 8.

Max Planck Institute for Biology of Ageing, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Cologne, Cologne, Germany; Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address:

Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to return to the SC state requires suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism that occurs during early HFSC lineage progression. HFSC fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche. Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs. These findings highlight the importance of spatiotemporal control of SC metabolic states in organ homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.08.011DOI Listing
October 2020

Role of collagen XII in skin homeostasis and repair.

Matrix Biol 2020 12 2;94:57-76. Epub 2020 Sep 2.

Translational Matrix Biology, University of Cologne, Medical Faculty, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Electronic address:

Skin integrity and function depends to a large extent on the composition of the extracellular matrix, which regulates tissue organization. Collagen XII is a homotrimer with short collagenous domains that confer binding to the surface of collagen I-containing fibrils and extended flexible arms, which bind to non-collagenous matrix components. Thereby, collagen XII helps to maintain collagen suprastructure and to absorb stress. Mutant or absent collagen XII leads to reduced muscle and bone strength and lax skin, whereas increased collagen XII amounts are observed in tumor stroma, scarring and fibrosis. This study aimed at uncovering in vivo mechanisms by which collagen XII may achieve these contrasting outcomes. We analyzed skin as a model tissue that contains abundant fibrils, composed of collagen I, III and V with collagen XII decorating their surface, and which is subject to mechanical stress. The impact of different collagen XII levels was investigated in collagen XII-deficient (Col12-KO) mice and in mice with collagen XII overexpression in the dermis (Col12-OE). Unchallenged skin of these mice was histologically inconspicuous, but at the ultrastructural level revealed distinct aberrations in collagen network suprastructure. Repair of excisional wounds deviated from controls in both models by delayed healing kinetics, which was, however, caused by completely different mechanisms in the two mouse lines. The disorganized matrix in Col12-KO wounds failed to properly sequester TGFβ, resulting in elevated numbers of myofibroblasts. These are, however, unable to contract and remodel the collagen XII-deficient matrix. Excess of collagen XII, in contrast, promotes persistence of M1-like macrophages in the wound bed, thereby stalling the wounds in an early inflammatory stage of the repair process and delaying healing. Taken together, we demonstrate that collagen XII is a key component that assists in orchestrating proper skin matrix structure, controls growth factor availability and regulates cellular composition and function. Together, these functions are pivotal for re-establishing homeostasis after injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.matbio.2020.08.002DOI Listing
December 2020

Celebrating the 50 Anniversary of ESDR.

J Invest Dermatol 2020 09;140(9S):S145-S146

Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.02.043DOI Listing
September 2020

Long-term in vivo imaging of Drosophila larvae.

Nat Protoc 2020 03 10;15(3):1158-1187. Epub 2020 Feb 10.

Institute for Genetics, University of Cologne, Cologne, Germany.

The Drosophila larva has been used to investigate many processes in cell biology, including morphogenesis, physiology and responses to drugs and new therapeutic compounds. Despite its enormous potential as a model system, longer-term live imaging has been technically challenging because of a lack of efficient methods for immobilizing larvae for extended periods. We describe here a simple procedure for anesthetization and uninterrupted long-term in vivo imaging of the epidermis and other larval organs, including gut, imaginal discs, neurons, fat body, tracheae, muscles and hemocytes, for up to 8 h. We also include a procedure for probing cell properties by laser ablation. We provide a survey of the effects of different anesthetics, demonstrating that short exposure to diethyl ether is the most effective for long-term immobilization of larvae. This protocol does not require specific expertise beyond basic Drosophila genetics and husbandry, and confocal microscopy. It enables high-resolution studies of many systemic and subcellular processes in larvae.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41596-019-0282-zDOI Listing
March 2020

Diabetes Impedes the Epigenetic Switch of Macrophages into Repair Mode.

Immunity 2019 08;51(2):199-201

Department of Dermatology, University of Cologne, Kerpenerstr 62, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. Electronic address:

In this issue of Immunity, Kimball et al. (2019) show that restoring expression of the chromatin modifying enzyme Setdb2 in macrophages rescues impaired wound healing associated with type 2 diabetes. Their findings reveal epigenetic regulation as central to the resolution of macrophage-mediated inflammation in tissue repair and have therapeutic implications for the treatment of diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2019.07.009DOI Listing
August 2019

Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation.

J Allergy Clin Immunol 2020 01 8;145(1):283-300.e8. Epub 2019 Aug 8.

Department of Dermatology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany. Electronic address:

Background: Perturbation of epidermal barrier formation will profoundly compromise overall skin function, leading to a dry and scaly, ichthyosis-like skin phenotype that is the hallmark of a broad range of skin diseases, including ichthyosis, atopic dermatitis, and a multitude of clinical eczema variants. An overarching molecular mechanism that orchestrates the multitude of factors controlling epidermal barrier formation and homeostasis remains to be elucidated.

Objective: Here we highlight a specific role of mammalian target of rapamycin complex 2 (mTORC2) signaling in epidermal barrier formation.

Methods: Epidermal mTORC2 signaling was specifically disrupted by deleting rapamycin-insensitive companion of target of rapamycin (Rictor), encoding an essential subunit of mTORC2 in mouse epidermis (epidermis-specific homozygous Rictor deletion [Ric] mice). Epidermal structure and barrier function were investigated through a combination of gene expression, biochemical, morphological and functional analysis in Ric and control mice.

Results: Ric newborns displayed an ichthyosis-like phenotype characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structure, and aberrant filaggrin (FLG) processing. Despite a compensatory transcriptional epidermal repair response, the protective epidermal function was impaired in Ric mice, as revealed by increased transepidermal water loss, enhanced corneocyte fragility, decreased dendritic epidermal T cells, and an exaggerated percutaneous immune response. Restoration of Akt-Ser473 phosphorylation in mTORC2-deficient keratinocytes through expression of constitutive Akt rescued FLG processing.

Conclusion: Our findings reveal a critical metabolic signaling relay of barrier formation in which epidermal mTORC2 activity controls FLG processing and de novo epidermal lipid synthesis during cornification. Our findings provide novel mechanistic insights into epidermal barrier formation and could open up new therapeutic opportunities to restore defective epidermal barrier conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2019.07.033DOI Listing
January 2020

[38-year-old female with a treatment-resistant ulcer : Preparation for the specialist examination: part 48].

Hautarzt 2019 Apr;70(Suppl 1):81-84

Klinik und Poliklinik für Dermatologie und Venerologie, Uniklinik Köln, Kerpenerstr. 62, 50937, Köln, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00105-019-4364-1DOI Listing
April 2019

Cellular networks in wound healing.

Science 2018 11;362(6417):891-892

Department of Dermatology, University of Cologne, Kerpenerstraße 62, 50937 Köln, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aav5542DOI Listing
November 2018

Clinical assessment of a foam dressing containing growth factor-enhancing hydrated polyurethanes.

J Wound Care 2018 09;27(9):608-618

Professor of Dermatology, Medical Director; the BOOST-CLOSURE Study Group, Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937 Cologne, Germany, Paul-Hartmann AG, Paul-Hartmann-Strasse, 89522 Heidenheim, Germany.

Objective: This study assesses a novel dressing concept in venous leg ulcer (VLU) patients. It is based on boosting endogenous growth factor activities synthesised by functional granulation tissue.

Methods: Patients received treatment for eight weeks with a hydrated polyurethane-containing foam dressing plus concomitant compression therapy. Wound area reduction (WAR), percentage of wounds achieving a relative WAR of ≥40% and ≥60%, wound pain ratings for the last 24 hours and at dressing changes, EQ-5D Quality of Life questionnaire data, dressing handling and safety parameters were recorded.

Results: There were 128 patients who received treatment and data for 123 wound treatment courses were documented. Wound area size decreased from 13.3±9.8cm to 10.5±12.2cm at week eight and median relative WAR was 48.8%. At week eight, a relative WAR ≥40% was reached by 54.5% of the wounds, 41.5% reached a relative WAR of ≥60% and complete healing was observed in 13.5% of wounds. Median wound pain ratings (last 24 hours before dressing change) declined significantly from 30 to 15.5 (100 visual analogue scale [VAS], p=0.0001) and pain at dressing changes from 30 to 12.5 (p≤0.0001). The EQ-5D VAS rating increased from 58.4±19.2mm to 63.1±19.1mm (p=0.0059).

Conclusion: This clinical assessment shows that the concept of boosting endogenous growth factors through hydrated polyurethanes has the potential to accelerate WAR in VLU patients while decreasing pain levels and improving quality of life parameters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12968/jowc.2018.27.9.608DOI Listing
September 2018

Myeloid Cell-Restricted STAT3 Signaling Controls a Cell-Autonomous Antifibrotic Repair Program.

J Immunol 2018 07 13;201(2):663-674. Epub 2018 Jun 13.

Department of Dermatology, University of Cologne, 50937 Cologne, Germany;

Myeloid cells can be beneficial as well as harmful in tissue regenerative responses. The molecular mechanisms by which myeloid cells control this critical decision of the immune system are not well understood. Using two different models of physiological acute or pathological chronic skin damage, in this study we identified myeloid cell-restricted STAT3 signaling as important and an injury context-dependent regulator of skin fibrosis. Targeted disruption of STAT3 signaling in myeloid cells significantly accelerated development of pathological skin fibrosis in a model of chronic bleomycin-induced tissue injury, whereas the impact on wound closure dynamics and quality of healing after acute excision skin injury was minor. Chronic bleomycin-mediated tissue damage in control mice provoked an antifibrotic gene signature in macrophages that was characterized by upregulated expression of IL-10, SOCS3, and decorin. In contrast, in STAT3-deficient macrophages this antifibrotic repair program was abolished whereas TGF-β1 expression was increased. Notably, TGF-β1 synthesis in cultured control bone marrow-derived macrophages (BMDMs) was suppressed after IL-10 exposure, and this suppressive effect was alleviated by STAT3 deficiency. Accordingly, coculture of IL-10-stimulated control BMDMs with fibroblasts suppressed expression of the TGF-β1 downstream target connective tissue growth factor in fibroblasts, whereas this suppressive effect was lost by STAT3 deficiency in BMDMs. Our findings highlight a previously unrecognized protective role of myeloid cell-specific STAT3 signaling in immune cell-mediated skin fibrosis, and its regulatory pathway could be a potential target for therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1701791DOI Listing
July 2018

Dataset on the activation of Müller cells through macrophages upon hypoxia in the retina.

Data Brief 2018 Feb 22;16:489-500. Epub 2017 Nov 22.

Department of Ophthalmology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

The dataset presented in this article complements the article entitled "Myeloid cells contribute indirectly to VEGF expression upon hypoxia via activation of Müller cells" (C. Nürnberg, N. Kociok, C. Brockmann, T. Lischke, S. Crespo-Garcia, N. Reichhart, S. Wolf, R. Baumgrass, S.A. Eming, S. Beer-Hammer, and A.M. Joussen). This complementary dataset provides further insight into the experimental validation of the VEGF LysMCre (here named VEGF) knockout model used in the main article through genomic and quantitative Real-Time PCR in various murine tissues as well as additional flow cytometry data and immunohistochemical stainings. By providing these data, we aim to enable researcher to reproduce and critically analyze our data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dib.2017.11.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725222PMC
February 2018

Myeloid cells contribute indirectly to VEGF expression upon hypoxia via activation of Müller cells.

Exp Eye Res 2018 01 14;166:56-69. Epub 2017 Oct 14.

Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. Electronic address:

Anti-VEGF-directed therapies have been a milestone for treating retinal vascular diseases. Depletion of monocyte lineage cells suppresses pathological neovascularization in the oxygen-induced retinopathy mouse model. However, the question whether myeloid-derived VEGF-A expression is responsible for the pathogenesis in oxygen-induced retinopathy remained unknown. We analyzed LysMCre-driven myeloid cell-specific VEGF-A knockout mice as well as mice with complete depletion of circulating macrophages through clodronate-liposome treatment in the oxygen-induced retinopathy model by immunohistochemistry, qPCR, and flow cytometry. Furthermore, we analyzed VEGF-A mRNA expression in MIO-M1 cells alone and in co-culture with BV-2 cells in vitro. The myeloid cell-specific VEGF-A knockout did not change relative retinal VEGF-A mRNA levels, the relative avascular area or macrophage/granulocyte numbers in oxygen-induced retinopathy and under normoxic conditions. We observed an insignificantly attenuated pathology in systemically clodronate-liposome treated knockouts but evident VEGF-A expression in activated Müller cells on immunohistochemically stained sections. MIO-M1 cells had significantly higher expression levels of VEGF-A in co-culture with BV-2 cells compared to cultivating MIO-M1 cells alone. Our data show that myeloid-derived cells contribute to pathological neovascularization in oxygen-induced retinopathy through activation of VEGF-A expression in Müller cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2017.10.011DOI Listing
January 2018

Baseline factors affecting closure of venous leg ulcers.

J Vasc Surg Venous Lymphat Disord 2017 11;5(6):829-835.e1

Smith & Nephew, Inc, Fort Worth, Tex; Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, Tex.

Objective: The objective of this study was to characterize factors associated with closure of venous leg ulcers (VLUs) in a pooled analysis of subjects from three randomized clinical trials.

Methods: Closure of VLUs after treatment with HP802-247, an allogeneic living cell therapy consisting of growth-arrested human keratinocytes and fibroblasts, vs standard therapy with compression bandaging was evaluated in three phase 3 clinical trials of similar design. Two trials enrolled subjects with VLUs ranging from 2 cm to 12 cm in area with 12-week treatment periods; the third trial enrolled subjects with VLUs between >12 cm and ≤36 cm with a 16-week treatment period. The first trial went to completion but failed to demonstrate a benefit to therapy with HP802-247 compared with placebo, and because of this, the remaining trials were terminated before completion. On the basis of no differences in outcomes between groups, subjects from both HP802-247 and control groups were pooled across all three studies. Cox proportional hazards regression analysis was employed to evaluate factors associated with VLU closure.

Results: This analysis included data from 716 subjects with VLU. Factors evaluated for association with healing included age, gender, race, diabetes, glycated hemoglobin level, body mass index, treatment (HP802-247 vs compression alone), and ulcer characteristics including location and area and duration at baseline. In an initial model including all of these putative factors, the following were significant at the P < .10 level: diagnosis of diabetes mellitus, gender, wound location (ankle or leg), baseline wound area, and wound duration at baseline. In a final model including only these factors, all but diabetes mellitus were significant at the P < .05 level. Effect sizes were as follows (hazard ratio [95% confidence interval]): female gender (1.384 [1.134-1.690]), wound location on the leg (1.490 [1.187-1.871]), smaller wound area at baseline (0.907 [0.887-0.927]), and shorter wound duration at baseline (0.971 [0.955-0.987]).

Conclusions: Factors associated with VLU lesions including location, area, and duration were important predictors of healing. Women were more likely than men to achieve wound closure. Factors including body mass index, the presence of diabetes mellitus, and higher concentrations of glycated hemoglobin were not significant independent predictors of wound closure in this analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvsv.2017.06.017DOI Listing
November 2017

Transient Ingrowth of Lymphatic Vessels into the Physiologically Avascular Cornea Regulates Corneal Edema and Transparency.

Sci Rep 2017 08 3;7(1):7227. Epub 2017 Aug 3.

Department of Ophthalmology, University of Cologne, Köln, Germany.

Lymphangiogenesis is essential for fluid homeostasis in vascularized tissues. In the normally avascular cornea, however, pathological lymphangiogenesis mediates diseases like corneal transplant rejection, dry eye disease, and allergy. So far, a physiological role for lymphangiogenesis in a primarily avascular site such as the cornea has not been described. Using a mouse model of perforating corneal injury that causes acute and severe fluid accumulation in the cornea, we show that lymphatics transiently and selectively invade the cornea and regulate the resolution of corneal edema. Pharmacological blockade of lymphangiogenesis via VEGFR-3 inhibition results in increased corneal thickness due to delayed drainage of corneal edema and a trend towards prolonged corneal opacification. Notably, lymphatics are also detectable in the cornea of a patient with acute edema due to spontaneous Descemet´s (basement) membrane rupture in keratoconus, mimicking this animal model and highlighting the clinical relevance of lymphangiogenesis in corneal fluid homeostasis. Together, our findings provide evidence that lymphangiogenesis plays an unexpectedly beneficial role in the regulation of corneal edema and transparency. This might open new treatment options in blinding diseases associated with corneal edema and transparency loss. Furthermore, we demonstrate for the first time that physiological lymphangiogenesis also occurs in primarily avascular sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-07806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543160PMC
August 2017

Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities.

Int J Mol Sci 2017 Jun 12;18(6). Epub 2017 Jun 12.

Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.

The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms18061257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486079PMC
June 2017

Inflammation and metabolism in tissue repair and regeneration.

Science 2017 06 8;356(6342):1026-1030. Epub 2017 Jun 8.

Schools of Biochemistry and Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK.

Tissue repair after injury is a complex, metabolically demanding process. Depending on the tissue's regenerative capacity and the quality of the inflammatory response, the outcome is generally imperfect, with some degree of fibrosis, which is defined by aberrant accumulation of collagenous connective tissue. Inflammatory cells multitask at the wound site by facilitating wound debridement and producing chemokines, metabolites, and growth factors. If this well-orchestrated response becomes dysregulated, the wound can become chronic or progressively fibrotic, with both outcomes impairing tissue function, which can ultimately lead to organ failure and death. Here we review the current understanding of the role of inflammation and cell metabolism in tissue-regenerative responses, highlight emerging concepts that may expand therapeutic perspectives, and briefly discuss where important knowledge gaps remain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aam7928DOI Listing
June 2017

Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice.

Nat Commun 2017 05 2;8:15162. Epub 2017 May 2.

Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.

MicroRNAs (miRs) are small non-coding RNAs that post-transcriptionally control gene expression. Inhibition of miRs by antisense RNAs (antimiRs) might be a therapeutic option for many diseases, but systemic inhibition can have adverse effects. Here we show that light-activatable antimiRs efficiently and locally restricted target miR activity in vivo. We use an antimiR-92a and establish a therapeutic benefit in diabetic wound healing. AntimiR-92a is modified with photolabile protecting groups, so called 'cages'. Irradiation activates intradermally injected caged antimiR-92a without substantially affecting miR-92a expression in other organs. Light activation of caged antimiR-92a improves healing in diabetic mice to a similar extent as conventional antimiRs and derepresses the miR-92a targets Itga5 and Sirt1, thereby regulating wound cell proliferation and angiogenesis. These data show that light can be used to locally activate therapeutically active antimiRs in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms15162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418571PMC
May 2017

Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous Wound Healing.

Am J Pathol 2017 Jun 12;187(6):1301-1312. Epub 2017 Apr 12.

Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Tight junction (TJ) proteins are known to be involved in proliferation and differentiation. These processes are essential for normal skin wound healing. Here, we investigated the TJ proteins claudin-1 and occludin in ex vivo skin wound healing models and tissue samples of acute and chronic human wounds and observed major differences in localization/expression of these proteins, with chronic wounds often showing a loss of the proteins at the wound margins and/or in the regenerating epidermis. Knockdown experiments in primary human keratinocytes showed that decreased claudin-1 expression resulted in significantly impaired scratch wound healing, with delayed migration and reduced proliferation. Activation of AKT pathway was significantly attenuated after claudin-1 knockdown, and protein levels of extracellular signal-related kinase 1/2 were reduced. For occludin, down-regulation had no impact on wound healing in normal scratch assays, but after subjecting the cells to mechanical stress, which is normally present in wounds, wound healing was impaired. For both proteins we show that most of these actions are independent from the formation of barrier-forming TJ structures, thus demonstrating nonbarrier-related functions of TJ proteins in the skin. However, for claudin-1 effects on scratch wound healing were more pronounced when TJs could form. Together, our findings provide evidence for a role of claudin-1 and occludin in epidermal regeneration with potential clinical importance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2017.02.006DOI Listing
June 2017

Updates in wound healing: Mechanisms and translation.

Exp Dermatol 2017 02;26(2):97-98

Department of Dermatology and Cutaneous Surgery, Wound Healing and Regenerative Medicine Research Program, University of Miami Miller School of Medicine, Miami, Florida, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13281DOI Listing
February 2017

Keim oder kein Keim: Herausforderungen bei der Diagnose mykobakterieller Infektionen der Haut.

J Dtsch Dermatol Ges 2016 Dec;14(12):1227-1236

Klinik und Poliklinik für Dermatologie und Venerologie, Universität Köln, Deutschland.

Kutane Mykobakteriosen sind in Deutschland selten. Dennoch ist es für eine frühzeitige Diagnose und anschließende wirksame Behandlung erforderlich, dass diese Krankheitsbilder im ärztlichen Bewusstsein verankert sind. Darüber hinaus stehen Infektionen mit Mykobakterien auf der Liste der Differentialdiagnosen vieler Hautkrankheiten. Diagnosen kutaner Mykobakteriosen beruhen auf klinischen Merkmalen und auf Laboruntersuchungen, einschließlich bakterieller Kulturen, histopathologischer Untersuchungen und PCR-basierten Verfahren. Das Wissen um Möglichkeiten und Grenzen dieser Laboruntersuchungen ist von zentraler Bedeutung, um eine angemessene klinische Entscheidung zu treffen. In diesem Beitrag diskutieren wir die aktuellen diagnostischen Möglichkeiten, die in Verdachtsfällen kutaner Mykobakteriosen zur Verfügung stehen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ddg.13001_gDOI Listing
December 2016

mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation.

Nat Commun 2016 10 27;7:13226. Epub 2016 Oct 27.

Department of Dermatology, University of Cologne, Kerpenerstr. 62, Cologne 50937, Germany.

Mammalian target of rapamycin (mTOR), a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2. The role of mTOR signalling in skin morphogenesis and epidermal development is unknown. Here we identify mTOR as an essential regulator in skin morphogenesis by epidermis-specific deletion of Mtor in mice (mTOR). mTOR mutants are viable, but die shortly after birth due to deficits primarily during the early epidermal differentiation programme and lack of a protective barrier development. Epidermis-specific loss of Raptor, which encodes an essential component of mTORC1, confers the same skin phenotype as seen in mTOR mutants. In contrast, newborns with an epidermal deficiency of Rictor, an essential component of mTORC2, survive despite a hypoplastic epidermis and disruption in late stage terminal differentiation. These findings highlight a fundamental role for mTOR in epidermal morphogenesis that is regulated by distinct functions for mTORC1 and mTORC2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms13226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095294PMC
October 2016

Insulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing.

Nat Commun 2016 10 7;7:12972. Epub 2016 Oct 7.

Institute for Genetics, University of Cologne, Zülpicherstr. 47a, Cologne 50674, Germany.

The TOR and Insulin/IGF signalling (IIS) network controls growth, metabolism and ageing. Although reducing TOR or insulin signalling can be beneficial for ageing, it can be detrimental for wound healing, but the reasons for this difference are unknown. Here we show that IIS is activated in the cells surrounding an epidermal wound in Drosophila melanogaster larvae, resulting in PI3K activation and redistribution of the transcription factor FOXO. Insulin and TOR signalling are independently necessary for normal wound healing, with FOXO and S6K as their respective effectors. IIS is specifically required in cells surrounding the wound, and the effect is independent of glycogen metabolism. Insulin signalling is needed for the efficient assembly of an actomyosin cable around the wound, and constitutively active myosin II regulatory light chain suppresses the effects of reduced IIS. These findings may have implications for the role of insulin signalling and FOXO activation in diabetic wound healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms12972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059774PMC
October 2016

Tissue fibrosis: a pathomechanistically unresolved challenge and scary clinical problem.

Exp Dermatol 2017 02;26(2):135-136

Department of Dermatology, University of Cologne, Cologne, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13165DOI Listing
February 2017

Bug or no bug: challenges in diagnosing cutaneous mycobacterial infections.

J Dtsch Dermatol Ges 2016 Dec 22;14(12):1227-1235. Epub 2016 Jul 22.

Department of Dermatology, University of Cologne, Cologne, Germany.

Cutaneous mycobacterioses are rare in Germany. Nevertheless, early diagnosis and subsequent effective treatment requires awareness of these conditions. Moreover, mycobacterial infections are on the differential diagnosis list of many skin diseases. Diagnoses of cutaneous mycobacterioses are based on clinical features, but also on laboratory investigations, including bacterial culture, histopathology and PCR-based methods. Knowledge about the opportunities and limitations of theses laboratory tests is pivotal to reasonable clinical decision-making. In this paper, we review the current diagnostic options when suspecting a case of cutaneous mycobacterial infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ddg.13001DOI Listing
December 2016