[Skin aging-cellular senescence : What is the future?] / Hautalterung ­ zelluläre Seneszenz : Wohin geht die Reise?

BACKGROUND: Cellular senescence is the main cause of skin and organ aging and is associated with a wide range of aging-related diseases. OBJECTIVES: To understand which senolytics, senomorphics, and cell-based therapies have been developed to alleviate and even rejuvenate skin aging and reduce cellular senescence. METHODS: Basic literature for the mode of action of senolytics and senomorphics and their clinical perspectives in daily routine are discussed. RESULTS: Various causes lead to mitochondrial dysfunction and the activation of pro-aging signaling pathways, which eventually lead to cellular senescence with degradation of structural proteins of the dermal connective tissue and severe suppression of regenerative stem cell niches of the skin. CONCLUSIONS: Depletion of senescent cells suppress skin aging and enforce rejuvenation of skin and other organs and their function. The removal of senescent cells by cells of the native immune system is severely disturbed during aging. Selected senolytics and senomorphics are approved and are already on the market.

Free Fatty Acids Induce Lipid Accumulation, Autophagy, and Apoptosis in Human Sebocytes.

BACKGROUND: A disruption of sebocyte differentiation and lipogenesis has fatal consequences and can cause a wide spectrum of skin diseases, from acne vulgaris to sebaceous carcinoma, however, the relevant molecular mechanisms have not been fully clarified. OBJECTIVES: The induction of autophagy and apoptosis in human sebocytes in response to biologically relevant fatty acids was investigated. METHODS: Free fatty acids (arachidonic acid, linoleic acid, palmitic acid, and palmitoleic acid) and the pan-caspase inhibitor QVD-Oph were added to the supernatant of cultured human SZ95 sebocytes. Individual relevant proteins were analyzed by Western blotting. Apoptosis and cell viability were determined, and typical autophagy structures were detected through electron microscopy. To obtain cell growth curves, cell confluence was continuously monitored by real-time cell analysis. RESULTS: Fatty acids induced the development of intracellular lipid droplets with subsequent apoptosis, whereas arachidonic acid caused the most rapid effect. Cleavage products of caspase-3 were only detected in arachidonic acid-induced apoptosis. The high basal apoptotic rate of cultured SZ95 sebocytes was strongly suppressed by QVD-Oph. Fatty acid-induced apoptosis was also markedly inhibited by QVD-Oph, whereas intracellular lipid droplets further accumulated. While cell viability after incubation with linoleic acid, palmitic acid, or palmitoleic acid and QVD-Oph was comparable with that of non-treated controls, arachidonic acid significantly reduced cell viability and cell density despite the concomitant pan-caspase inhibitor treatment. Using electron microscopy, typical autophagy structures were detected, such as autophagosomes and autolysosomes, at the basal level, which became more pronounced after treatment with fatty acids. CONCLUSIONS: Our findings contribute to a better understanding of the inflammation-associated mechanisms of lipogenesis and cell death induction in human sebocytes and may help to unveil the effects of fatty acid-rich human nutrition.

Connective Tissue and Fibroblast Senescence in Skin Aging.

There is increasing evidence that skin aging is significantly enforced by the accumulation of senescent dermal fibroblasts. Various stressors damaging macromolecules inside and outside fibroblasts are responsible. In addition, NK cells fail to adequately remove senescent (SEN) fibroblasts from tissues. SEN fibroblasts by the release of the proinflammatory, tissue degrading senescent-associated secretory phenotype factors and vesicles with distinct cargo impact on their endogenous niche and spread senescence and skin aging. In this review, we will further discuss less noticed facets, including the plasticity of distinct dermal fibroblast phenotypes, the underestimated impact of the extracellular matrix itself, and the depletion of fibroblast subsets on skin homeostasis and aging.

Involvement of Pattern Recognition Receptors in the Direct Influence of Bacterial Components and Standard Antiacne Compounds on Human Sebaceous Gland Cells.

INTRODUCTION: Pattern recognition receptors are involved in innate and adaptive immunity by detecting microbial components. Bacteria have been accused to play a role in inflammatory acne. We investigated the potential involvement of Toll-like receptor (TLR)2, TLR4, TLR6, and CD14 in the direct influence of bacterial components and standard antiacne compounds on human sebocytes. METHODS: mRNA and protein expression of TLR2, TLR4, TLR6, and CD14 in SZ95 sebocytes was evaluated by real-time qRT-PCR and immunocytochemistry. The effects of lipopolysaccharides (LPS) and lipoteichoic acid on TLR2, TLR4, and CD14 expression and of cytokine/chemokine secretion by 13-cis-retinoic acid, all-trans-retinoic acid, retinol, and hydrocortisone at the mRNA and protein levels were assessed by real-time qRT-PCR and ELISA and verified by cocultivation with neutralizing antibodies. RESULTS: The constitutive expression of TLR2, TLR4, and CD14 in SZ95 sebocytes was augmented by exposure to LPS. Hydrocortisone induced TLR2, but markedly reduced TLR4 expression. 13-cis-retinoic acid and all-trans-retinoic acid regulated IL-6 release. LPS enhanced and hydrocortisone reduced cytokine and chemokine release. Anti-TLR4 and anti-CD14 mAb blocked LPS-induced IL-8 and IL-6 release. CONCLUSIONS: Microbial components use pattern recognition receptors to directly activate sebocytes to express a wide range of proinflammatory molecules and especially IL-8 and IL-6 in a TLR4- and CD14-specific manner. Retinoids, but mostly corticosteroids, also use this pathway to exhibit anti-inflammatory effects.

Skin Mirrors Brain: A Chance for Alzheimer's Disease Research.

The accessibility of skin and the easy isolation of its cells and matrix components provide a valuable tool for studying the molecular factors involved in human aging. Moreover, increasing evidence corroborates the use of the skin as a model for age-associated pathological conditions in the entire body. Apparently based on the fact that the nervous system and skin share a common ectodermal origin, certain genes and molecular pathways associated with the pathomechanism of neurodegenerative diseases modify their expression with progressing skin aging. Alzheimer's disease and intrinsic skin aging share a common signalling pathway with major genes been regulated in both tissues. In our studies, functional neuronal cells derived from induced pluripotent stem cells originating from normal human skin fibroblasts of patients with sporadic Alzheimer's disease expressed proteins, which are implicated in Alzheimer's disease pathophysiology. Cumulative data lead to valuable insights regarding the understanding of Alzheimer's disease and its pathogenesis, given that these innovative patient cell models display the Alzheimer's disease phenotype.

MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-ß1 levels.

Mutations in the CD18 gene encoding the common ß-chain of ß2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18-/- wounds by restoring the decreased TGF-ß1 concentrations. TGF-ß1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF-ß1 concentrations at wound sites. Low TGF-ß1 concentrations as occurring in CD18-/- wounds induce TGF-ß1 release from MSCs, whereas high TGF-ß1 concentrations suppress TGF-ß1 production. This regulation depends on TGF-ß receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-ß1 signaling. Inactivation of TGF-ß receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-ß1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.

2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs.

Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A-DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1-deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1-/- epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker γH2AX. In accordance with diminished α6-Integrinhigh+CD34⁺ epidermal stem cells, reduced colony formation of Mysm1-/- epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1-deficient epidermal compartment, resulting in increased pro-apoptotic and anti-proliferative gene expression. In Mysm1-/-p53-/- double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1-/- developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development.

Professional caregivers' knowledge in dermatology : Improving knowledge and communication to dermatologists in geriatric facilities.

BACKGROUND: Research regarding effective collaboration and communication between professional caregivers and dermatologists and the need for further education and training for caregivers in the field of geriatric dermatology still remains relatively scarce. OBJECTIVE: To document the state of knowledge of professional caregivers in the field of geriatric dermatology and make recommendations for dermatological education and postgraduate training. METHODS: A questionnaire with open and closed questions was used to evaluate the level of knowledge and current need for information in geriatric dermatology. A total of 58 professional caregivers from several hospital departments, including geriatric wards and nursing homes participated in this study. Quantitative and qualitative data were generated and responses to open questions were categorized according to the most quoted contents. The study was approved by the Charité University in Berlin ethics committee. RESULTS: The study demonstrates that there is a lack of dermatological knowledge. Participants indicated a huge information need regarding skin tumors (77.2 %), prevention of skin diseases (50.0 %) and pruritus (41.4 %). According to the caregivers, communication problems with physicians arise in view of using standardized terms of skin diseases (22.9 %) and formulating unclear care records of skin diseases (20.8 %). CONCLUSION: Difficulties in communication between professional caregivers and physicians can influence patients' punctual and well-founded treatment; therefore, further education must be mediated vividly and practically. Moreover, training should focus on learning standardized terms and descriptions for optimizing the flow of information with physicians and written communication, such as care records.

Pathogenesis of wound healing disorders in the elderly.

The elderly constitute the age group most susceptible to wound healing disorders and chronic wounds, the most prevalent being venous leg ulcers, pressure ulcers, and diabetic foot ulcers. However, other age-associated diseases should also be taken into consideration in the diagnostic workup of chronic wounds, and not be underestimated. A better understanding of the pathomechanisms involved in the wound healing process is of key importance in combatting the difficulties associated with the treatment of chronic wounds. In recent decades, considerable progress has been made in the development of pioneering therapeutic strategies for chronic wounds. In this context, the use of growth factors and cytokines, tissue engineering, and cell therapy - including stem cells - have proven very promising. Nevertheless, prior to their introduction into routine clinical practice, large controlled clinical trials are required to assess the safety of these techniques.

Pathogenese von Wundheilungsstörungen bei älteren Patienten.

Ältere Menschen sind für Wundheilungsstörungen und chronische Wunden am anfälligsten, insbesondere für venöse Beinulzera, Dekubitalulzera und diabetische Fußulzera. Jedoch sollten bei der diagnostischen Abklärung chronischer Wunden weitere altersassoziierte Krankheiten in Betracht gezogen werden. Ein besseres Verständnis der an Wundheilungsstörungen beteiligten Pathomechanismen ist wichtig für die Bewältigung der Schwierigkeiten bei der Behandlung chronischer Wunden. In den letzten Jahrzehnten wurden beachtliche Fortschritte bei zukunftsweisenden Therapien chronischer Wunden erzielt. In diesem Zusammenhang haben sich Wachstumsfaktoren und Zytokine, Gewebeanzucht (Tissue Engineering) und Zelltherapie - auch mit Stammzellen - als sehr vielversprechend erwiesen. Vor Einführung in die klinische Praxis muss jedoch die Sicherheit dieser Techniken durch umfangreiche klinische Studien nachgewiesen werden.

Biomarkers of skin aging.

Aging is a complex process not only influenced by inherited but also by several environmental factors. It is characterized by a progressive loss of function in multiple tissues, which leads to an increased probability of death. On the other hand, several morphological and histological changes are registered in aged skin that is mostly dependent on the cumulative exposure in environmental aging promoters, such as ultraviolet radiation. Understanding of individual pathogenesis and introduction of preventive measurements require objective assessment, i.e., the administration of biomarkers. Because of the complexity of skin aging, the exact definition of biomarkers is a major research challenge. In this article, we summarize the basic knowledge involving skin aging and its biomarkers.

Marked Reduction of the Number and Individual Volume of Sebaceous Glands in Psoriatic Lesions.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by plaques with inflammation, infiltration, hyper-/parakeratosis and desquamation. Microscopic findings in previous studies have revealed some degree of atrophy of the sebaceous glands in patients with psoriasis vulgaris and psoriatic alopecia. OBJECTIVE: The aim of this study was to investigate possible changes of the sebaceous glands in patients with psoriatic plaques and especially psoriatic alopecia. METHODS: Histological and stereological analyses were performed in skin specimens from involved and healthy-looking skin of 14 patients with psoriasis. Stereology detects and quantifies 3-dimensional structures ex vivo. Furthermore, the differentiation process of sebocytes of another 14 psoriatic patients was examined by immunohistochemistry of involved and uninvolved skin specimens. RESULTS: A significant reduction of the number of sebaceous glands as well as of the volume of individual sebaceous glands was assessed in the lesional compared to the nonlesional psoriatic skin. Moreover, it was likely that sebocytes in psoriatic lesions may not differentiate properly. CONCLUSION: These findings indicate that the sebaceous gland may be a player and not an innocent bystander in the development of psoriatic lesions and especially of psoriatic alopecia.

PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells.

Apoptosis is a highly conserved biochemical mechanism which is tightly controlled in cells. It contributes to maintenance of tissue homeostasis and normally eliminates highly proliferative cells with malignant properties. Induced pluripotent stem cells (iPSCs) have recently been described with significant functional and morphological similarities to embryonic stem cells. Human iPSCs are of great hope for regenerative medicine due to their broad potential to differentiate into specialized cell types in culture. They may be useful for exploring disease mechanisms and may provide the basis for future cell-based replacement therapies. However, there is only poor insight into iPSCs cell signaling as the regulation of apoptosis. In this study, we focused our attention on the apoptotic response of Alzheimer fibroblast-derived iPSCs and two other Alzheimer free iPSCs to five biologically relevant kinase inhibitors as well as to the death ligand TRAIL. To our knowledge, we are the first to report that the relatively high basal apoptotic rate of iPSCs is strongly suppressed by the pancaspase inhibitor QVD-Oph, thus underlining the dependency on proapoptotic caspase cascades. Furthermore, wortmannin, an inhibitor of phosphoinositid-3 kinase / Akt signaling (PI3K-AKT), dramatically and rapidly induced apoptosis in iPSCs. In contrast, parental fibroblasts as well as iPSC-derived neuronal cells were not responsive. The resulting condensation and fragmentation of DNA and decrease of the membrane potential are typical features of apoptosis. Comparable effects were observed with an AKT inhibitor (MK-2206). Wortmannin resulted in disappearance of phosphorylated AKT and activation of the main effector caspase-3 in iPSCs. These results clearly demonstrate for the first time that PI3K-AKT represents a highly essential survival signaling pathway in iPSCs. The findings provide improved understanding on the underlying mechanisms of apoptosis regulation in iPSCs.

Disseminated refractory pyoderma gangraenosum during an ulcerative colitis flare. Treatment with infliximab.

BACKGROUND: Pyoderma gangraenosum is an immune-mediated, inflammatory, neutrophilic dermatosis of unknown etiology, which represents one of the extraintestinal manifestations of inflammatory bowel disease. It is a rare disease that occurs in less than 1% of patients with inflammatory bowel disease and with the same ratio in patients with Crohn's disease and ulcerative colitis. MAIN OBSERVATIONS: A 36-year-old woman was diagnosed with ulcerative colitis 6 years before admission to our dermatology department with an acute disseminated pyoderma gangraenosum with mucosal involvement, during a flare of ulcerative colitis. Disease progression was interrupted by intravenous administration of the tumor necrosis factor-α inhibitor infliximab at 5 mg/kg at weeks 0, 2, and 6 (1st cycle) and every 8 weeks thereafter. Improvement of intestinal, skin and oral manifestations was evident already after the 1st cycle of treatment and has been maintained since (at least 16 months). CONCLUSIONS: This case report is one of very few on disseminated pyoderma gangraenosum with oral involvement complicating ulcerative colitis, where infliximab was shown to have a rapid efficacy on skin, mucosal and bowel symptoms.

Ex vivo human skin and SZ95 sebocytes exhibit a homoeostatic interaction in a novel coculture contact model.

The sebaceous gland displays key functions of the human skin, such as hormone synthesis in situ, antimicrobial activity and participation to inflammatory responses. Consequently, there is an emerging need of advanced in vitro models to study complex interactions between the sebaceous gland and the other skin compartments. Despite the evolution of both full-skin organ culture and reconstructed three-dimensional skin models, no satisfactory solutions have been provided for the integration of sebaceous glands and/or sebaceous gland cells in those models, probably due to their problematic maintenance both in vitro and ex vivo. We have developed a coculture model of explant skin in direct contact with immortalized SZ95 sebocytes, which resulted in overall improved structural integrity of the epidermis, higher percentage of proliferating basal epidermal cells and reduced apoptosis of differentiating keratinocytes after 6 days, as detected by Ki67 and TUNEL staining, respectively. Furthermore SZ95 sebocytes exhibited morphological and biochemical signs of normal differentiation and lipid accumulation, while interleukin-6 expression in the supernatant of the cocultures was decreased in comparison with the control. The data provide evidence of a beneficial interaction between sebocytes and skin explants and provide the rationale for their integration in future three-dimensional skin models.

Acne vulgaris.

Acne vulgaris is a chronic inflammatory disease - rather than a natural part of the life cycle as colloquially viewed - of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous gland) and is among the most common dermatological conditions worldwide. Some of the key mechanisms involved in the development of acne include disturbed sebaceous gland activity associated with hyperseborrhoea (that is, increased sebum production) and alterations in sebum fatty acid composition, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratinization, induction of inflammation and dysfunction of the innate and adaptive immunity. Grading of acne involves lesion counting and photographic methods. However, there is a lack of consensus on the exact grading criteria, which hampers the conduction and comparison of randomized controlled clinical trials evaluating treatments. Prevention of acne relies on the successful management of modifiable risk factors, such as underlying systemic diseases and lifestyle factors. Several treatments are available, but guidelines suffer from a lack of data to make evidence-based recommendations. In addition, the complex combination treatment regimens required to target different aspects of acne pathophysiology lead to poor adherence, which undermines treatment success. Acne commonly causes scarring and reduces the quality of life of patients. New treatment options with a shift towards targeting the early processes involved in acne development instead of suppressing the effects of end products will enhance our ability to improve the outcomes for patients with acne.

Malignant atrophic papulosis (Köhlmeier-Degos disease) - a review.

UNLABELLED: DEFINITION OF THE DISEASE: Malignant atrophic papulosis (MAP), described independently by Köhlmeier and Degos et al., is a rare, chronic, thrombo-obliterative vasculopathy characterized by papular skin lesions with central porcelain-white atrophy and surrounding teleangiectatic rim. EPIDEMIOLOGY: Less than 200 cases have been described in the literature. The first manifestation of MAP usually occurs between the 20th and 50th year of life. CLINICAL DESCRIPTION: The cutaneous clinical picture is almost pathognomonic. The histology is not consistent but in most cases it shows a wedge-shaped connective tissue necrosis in the deep corium due to a thrombotic occlusion of the small arteries. In the systemic variant, manifestations mostly occur at the intestine and central nervous system. ETIOLOGY: The etiopathogenesis of the disease remains unknown, a genetic predisposition may occur. Vasculitis, coagulopathy or primary dysfunction of the endothelial cells have been implicated. DIAGNOSTIC METHODS: Diagnosis is only based on the characteristic skin lesions. DIFFERRENTIAL DIAGNOSIS: It depends on the clinical presentation of MAP, but systemic lupus erythematosus and other connective tissue diseases need to be considered. MANAGEMENT: No effective treatment exists for the systemic manifestations, while compounds that facilitate blood perfusion have achieved a partial regression of the skin lesions in single cases. PROGNOSIS: An apparently idiopathic, monosymptomatic, cutaneous, benign variant and a progressive, visceral one with approx. 50% lethality within 2-3 years have been reported. Systemic manifestations can develop years after the occurrence of skin lesions leading to bowel perforation and peritonitis, thrombosis of the cerebral arteries or massive intracerebral hemorrhage, meningitis, encephalitis, radiculopathy, myelitis.