Editors’ Picks from Experimental Dermatology

Epidermal suction blister gene expression study suggests an influence of non pigmentary genes for the regulation of ethnic skin color

Differences in visible skin pigmentation are a major determinant of skin color associated with ethnic background. The initial goal of this study (Yin et al, 2014) performed on epidermal extracts from individuals of Caucasian, Asian, and African ancestry, was to identify differentially expressed genes with a special focus on known pigment-related genes. However, only a few of them were found to be significantly differently expressed, such as FRZB, CDH12, SOX5 and KITLG. The major result was that the skin of Caucasians and Asians had highly similar gene expression patterns that differed significantly from the pattern of African skin. Interestingly, ADRA2C (α-2C adrenergic receptor) had a high expression level in African skin but low expression levels in Asian and Caucasian skin. α2-adrenoceptors are G-protein-coupled receptors that mediate many of the physiological effects of norepinephrine and epinephrine and they can regulate skin color in zebrafish (Ruuskanen et al, 2005). In humans, their so far unsuspected role in the regulation of pigmentation needs further investigation. NINL was found to be expressed at a significantly different level in Caucasian and Asian skin, in which comparable melanocyte populations and very similar melanin contents have been found. NINL has been shown to be involved in microtubule organization, and high levels of NINL expression cause lysosomes to disperse towards the cell periphery (Casenghi et al, 2005). Since melanosomes are lysosome-related organelles and their distribution is regulated by various cytoskeletal components, including microtubules, the authors hypothesize that the higher expression level of NINL in Asian skin might play a critical role in the different distribution patterns of melanosomes that result in visible skin color differences

Submitted by Alain Taieb, Bordeaux, France

References:

Yin L et al  (2014) Epidermal gene expression and ethnic pigmentation variations among individuals of Asian, European and African ancestry. Exp Dermatol. Oct;23(10):731-5. doi: 10.1111/exd.12518

Ruuskanen JO, Peitsaro N, Kaslin JV et al. J Neurochem 2005; 94: 1559-1569.

Casenghi M, Barr FA, Nigg EA. J Cell Sci 2005; 118: 5101-5108.

 

Bypassing epidermal immunity: A case of soft tissue infection in psoriatic skin

Psoriatic skin is characterized by an enhanced protective epidermal shield of antimicrobial peptides and proteins (AMPs). It is commonly believed that enhanced AMP levels in the skin from psoriasis patients, in contrast to those of atopic dermatitis patients, confer resistance to skin infections (Gambichlet et al, 2008; Ong et al, 2002; Howell et al, 2006).  However, if bypassed through penetrating injuries, epidermal AMPs are not sufficient to protect from bacterial soft tissue infection, as reported by Steinz et al (2014). This clinical observation goes against the paradigm that AMPs provide antimicrobial resistance and highlights that the route of infection and not local AMP deficiency may contribute to disturbed skin immunity. In addition, it remains to be determined whether topical psoriasis treatments, such as vitamin D derivatives or steroids, may inhibit the cutaneous immune system, resulting in enhanced infection susceptibility.

Submitted by Amanda S. MacLeod, Durham, NC, USA

References:

Gambichler T, Skrygan M, Tomi NS, Othlinghaus N, Brockmeyer NH, Altmeyer P, Kreuter A. (2008) Differential mRNA expression of antimicrobial peptides and proteins in atopic dermatitis as compared to psoriasis vulgaris and healthy skin. Int Arch Allergy Immunol. 47(1):17-24.

Ong PY1, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 10:347(15):1151-60.

Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, Leung DY (2006) Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24(3):341-8.

Steinz K, Schubert S, Harder J, Gerdes S, Mrowietz U, Gläser R. (2014) Bacterial soft tissue infection in psoriasis despite induction of epidermal antimicrobial peptides. Exp Dermatol. 23(11):862-4

 

Stress and itch: Understanding the psychological aspects is important

The main complaint of patients suffering of atopic dermatitis is itch. Stress is understood to diminish the perception threshold of itch in this and many other diseases. However, it remained unclear which factors could explain this relationship.

Schut et al. wondered if certain coping strategies could be activated under stress. Coping can be defined as adaptable thoughts and behaviors intended to manage subjective demanding experiences. They investigated the role of coping as a possible mediating factor between stress and itch in patients with atopic dermatitis. Coping and itch were assessed by self-report measures, while stress was not only measured by a validated questionnaire, but also by a physiological stress marker, the post-awakening level of cortisol. Using a regression- and a mediation analysis, this study showed a relationship between perceived stress and itch, which was fully mediated by negative itch-related cognitions. More than 62% of the variance of itch intensity could be explained by negative itch-related cognitions.

These findings help to explain the positive effects of cognitive restructuring in the treatment of chronic itch. They provide a further scientific rationale for cognitive restructuring in the treatment of atopic dermatitis.

Submitted by Laurent Misery, Brest, France

Reference:

Schut C, Wiek U, Tews N, Gieler U, Deinzer R, Kupfer J. (2015) Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression- and mediation analysis. Exp Dermatol 24(2):148-50

 

Hair Follicles’ Promise in Wound Healing

Jimenez et al.’s interesting essay, “Reflections on how wound healing-promoting effects of the hair follicle can be translated into clinical practice,” reviews experimental and clinical evidence regarding the potential benefits of using hair follicles in wound healing, and possible common pathways with hair cycling, including the role of molecular and cellular mechanisms.

The authors provide examples of the use of hair-related therapies to manage chronic wounds, such as cultured epidermal autografts obtained from the outer root sheath, and hair-bearing donor skin. Although the essay focuses on the influence of hair biology in wound healing, the points discussed are also applicable to therapies for depigmenting disorders and hair neogenesis for cicatricial alopecias, among others.

While the clinical evidence is still preliminary, in our opinion further research in hair biology may provide greatly needed new and effective wound healing therapies.

Submitted by Katherine L. Baquerizo Nole and Robert S. Kirsner, University of Miami, Miami, Florida, USA

References:

Jimenez F, Poblet E, Izeta A. (2015) Reflections on how wound healing-promoting effects of the hair follicle can be translated into clinical practice. Exp Dermatol  24(2):91-4.

Editors’ Picks from Experimental Dermatology

The dark side of type XVII collagen

Gostynski et al. identified a so far unrecognized function of type XVII collagen (COL17). Based on detailed clinical observations, the authors demonstrated that in human skin, melanocytes’ supply to the epidermis depends on COL17 expression (Gostynski et al, 2014).

This striking discovery was found by the clinical observation of revertant skin in patients with epidermolysis bullosa (EB), characterized by genetic deficiency of type XVII collagen (COL17), laminin-332, or type VII collagen (COL7). In addition to correction to a healthy phenotype, hyperpigmentation (compared to non-revertant skin of the patients) was often observed in the revertant skin. A more detailed investigation showed that hyperpigmentation only occurred in patients with an underlying deficiency of COL17. In these patients, revertant skin showed not only hyperpigmentation but also an increase in melanocyte density. In contrast, neither hyperpigmentation nor an increase in melanocyte density was observed in patients with deficiency in either laminin-332 (LAMB3 gene) or COL7 (COL7A1 gene), in whom revertant skin could be identified by the healthy phenotype only.

Taken together, these data strongly point towards a new role for COL17, namely controlling melanocyte numbers and function. Albeit further work is required to unravel the precise molecular mechanism of this phenomenon, this paper nicely highlights the function of matrix proteins beyond being a mere static framework for cell-cell / cell-matrix adhesion. In my opinion there is another reason why this paper is interesting for dermatology research: The discoveries presented here were initiated by a clinical observation. This is a perfect example of translational research, and I wish I would see more papers like this!

Gostynski A, Pasmooij AMG, Del Rio M et al. Pigmentation and melanocyte supply to the epidermis depend on type XVII collagen. Exp Dermatol. 2014 Feb;23(2):130-2. doi: 10.1111/exd.12304.

 

By Ralf J. Ludwig, Dept. of Dermatology, University of Lübeck, Germany

 

 

 

Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between

Krisztian Nemeth’s excellent publication, “Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between,” highlights several timely and key considerations regarding the use of mesenchymal stem cells (MSCs) for immune based therapy. While the manuscript focuses primarily on the immune modulatory properties of MSCs, the principles discussed are important considerations in all clinical efforts using MSCs. Although many properties have been assigned to these specialized cells, little has been discussed about the variability of MSCs derived from different sources. Donor demographics, tissue origin, processing of cells in culture, and passage number are among numerous inconsistencies found within the literature, which can impact MSC function. The authors provide a rational argument that differences in immune suppressive properties between MSC preparations, as well as donor MSC response to medications given recipients, could significantly affect clinical outcome. Other functional differences in MSCs may also have significant impact on regenerative medicine applications. Further investigation is needed to develop more specific testing that can characterize differences between MSC preparations and provide a better functional match between donors and recipients.

Nemeth K. Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between Exp Dermatol. 2014 May 26. doi: 10.1111/exd.12459.

By Evangelos Badiavas, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA

 

 

 

Leucine-rich glioma inactivated protein 3: Not only a crucial molecule in neuronal development but also in the regulation of skin pigmentation

Over the last decade it has become apparent that Leucine-rich glioma inactivated proteins (LGI 1-4) are essential molecules for the development and function of the vertrebrate nervous system, as they modulate synaptic transmission and myelination (Kegel et al, 2013). LGI1-4 possess a leucine rich repeat domain and a so-called epilepsy-associated domain, and both structures are responsible for protein–protein interactions. The first LGI gene to be identified, LGI1, was detected in a glioma cell line, and it has been suggested that loss of LGI1 contributes to the malignant progression of glial tumors. Moreover, LGI1, 2 and 4 may function in synaptic remodelling and myelination of axons. Mutations in the LGI1,2 and 4 genes are associated with diverse pathological conditions such as epilepsy and psychiatric disorders. In contrast, mutations in the LGI3 gene have not been connected with a pathological phenotype. But it has been suggested that the LGI3 protein is essential for diverse functions in the nervous system, such as neuronal exocytosis and the uptake of amyloid proteins by astrocytes. Recently, it has been revealed that LGI3 plays not only a central function in the brain but also in the skin. LGI3 is highly expressed in human skin and secreted from UVB-irradiated keratinocytes (Lee et al, 2012). But the physiological role of LGI3 in the skin has not been fully understood. The present study by Jeong et al. (2014) now indicates that LGI3 stimulates melanin synthesis in melanocytes. Thus, it seems likely that LGI3 is a crucial paracrine cytokine, released from keratinocytes, that regulates skin pigmentation in response to UVB irradiation (Jeong et al, 2014).

Kegel, L., Aunin, E., Meijer, D., and Bermingham, J. R. (2013) LGI proteins in the nervous system, ASN Neuro 5, 167-181.doi: 10.1042/AN20120095.

Lee, S. H., Jeong, Y. M., Kim, S. Y., Jeong, H. S., Park, K. C., Baek, K. J., Kwon, N. S., Yun, H. Y., and Kim, D. S. (2012) Ultraviolet B-induced LGI3 secretion protects human keratinocytes, Exp Dermatol 21, 716-718.doi: 10.1111/j.1600-0625.2012.01550.x

Jeong, H. S., Jeong, Y. M., Kim, J., Lee, S. H., Choi, H. R., Park, K. C., Kim, B. J., Baek, K. J., Kwon, N. S., Yun, H. Y., and Kim, D. S. (2014) Leucine-rich glioma inactivated 3 is a melanogenic cytokine in human skin, Exp Dermatol.2014 Jun 6. doi: 10.1111/exd.12462.

 

By Burkhard Kleuser, Department of Toxicology, University of Potsdam, Germany

 

 

SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro

Epithelial to mesenchymal transition (EMT) is a crucial step in many pathologic conditions, from fibrotic disease to invasive cancer (Yan et al, 2010; Nakamura et al, 2011). The molecular background triggering this highly complex process, however, is organ-specific and only partially understood.

O’Kane and colleagues investigated how the chemokines TGF-β and TNF-α initiate EMT in cultured cutaneous keratinocytes in an attempt to model conditions encountered in scleroderma and other connective tissue diseases (2014). Chemokine stimulation led to the characteristic spindle-shaped mesenchymal cell morphology, accompanied by E-Cadherin and Zo-1 loss as well as increased Fibronectin and Vimentin on the protein level. This shift was paralleled by secretion of metalloproteases MMP-2/-9. Shortly after chemokine addition, elevated levels of phosphorylated SMAD-2, -3, and p38 were observable, suggesting a mode of action via their (TGF-β and TNF-α) canonical signaling pathways. Importantly, inhibition of the TGF-β signaling cascade and, to a minor extent, p38, prevents EMT in keratinocytes and is even capable of reversing an already established mesenchymal phenotype.

In conclusion, the authors suggest that SMAD inhibition may revert EMT by targeting TGF-β signaling and seting the stage for a novel therapeutic approach in cutaneous fibrotic diseases.

 

Nakamura M, Tokura Y. (2011) Epithelial-mesenchymal transition in the skin. J Dermatol Sci. 61:7-13. doi: 10.1016/j.jdermsci.2010.11.015.

O’Kane D et al (2014) SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro. Exp Dermatol 2014 May 21. doi: 10.1111/exd.12452

Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N, Han YP. (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 2010 May;176(5):2247-58. doi: 10.2353/ajpath.2010.090048

 

By Johannes Neu and Günther Hofbauer, Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

Editors’ Picks from Experimental Dermatology

After a brief hiatus, we welcome back Editors’ Picks from Experimental Dermatology.  Enjoy the latest discoveries!

 

Identification of HLA-E as susceptibility lucus of pemphigus vulgaris: One more step towards a genetic understanding of the disease

Pemphigus vulgaris (PV) is a devastating and potentially life-threatening autoimmune skin blistering disease (AIBD). In PV autoantibodies directed against desmoglein 3 (Dsg) and, in some cases, Dsg 1, cause intraepidermal blister formation above the basal layer of keratinocytes (1). The availability of antibody-transfer PV animal models (2) has contributed to a more detailed understanding of the events that lead to blister formation in the skin. In contrast, little is known regarding mechanisms leading to the loss of tolerance to Dsg 1 and 3 in patients with PV. Transfer of Dsg-reactive T cells has proven the crucial contribution of T cells to autoantibody production (3), and several HLA loci have been reported to be associated with PV (4). In addition, the first genome-wide association study recently identified ST18 as the first gene outside the HLA locus to be associated with PV (5). Collectively, this points towards a strong contribution of the genome to PV susceptibility. In the study by Bhanusali et al (6) a possible association of PV with HLA-E was investigated. The HLA-E genetic region is located between the classical class I genes HLA-C and HLA-A on chromosome 6p21 in humans, and there have not been any reports regarding HLA-E alleles and PV. In a cohort of 52 PV patients and 51 healthy controls Bhanusali et al document an association of HLA-E*0103X with susceptibility to PV (6). This novel observation further extends our understanding of the genetic control of PV. The identification of PV susceptibility loci may in the future help to identify individuals at risk to develop the disease. Furthermore, unraveling of the pathways encoded by these susceptibility loci may also help to identify novel therapeutic targets for this still difficult-to treat condition. In my personal opinion, this may be best approached by combined analysis of the so far existing patient cohorts collected by several groups.

REFERENCES:

(1) Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med. 2006;355(17):1800-10.

(2) Bieber K, Sun S, Ishii N, Kasperkiewicz M, Schmidt E, Hirose M, Westermann J, Yu X, Zillikens D, Ludwig RJ. Animal models for autoimmune bullous dermatoses. Exp Dermatol. 2010 Jan;19(1):2-11. doi: 10.1111/j.1600-0625.2009.00948.x

(3) Ujiie H, Shimizu H. Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models. Exp Dermatol. 2012; Dec;21(12):901-5. doi: 10.1111/exd.12011

(4) Sinha AA. The genetics of pemphigus. Dermatol Clin. 2011;Jul;29(3):381-91, vii. doi: 10.1016/j.det.2011.03.020.

(5) Sarig O, Bercovici S, Zoller L, Goldberg I, Indelman M, Nahum S, Israeli S, Sagiv N, Martinez de Morentin H, Katz O, Baum S, Barzilai A, Trau H, Murrell DF, Bergman R, Hertl M, Rosenberg S, Nöthen MM, Skorecki K, Schmidt E, Zillikens D, Darvasi A, Geiger D, Rosset S, Ibrahim SM, Sprecher E. Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris. J Invest Dermatol. 2012; Jul;132(7):1798-805. doi: 10.1038/jid.2012.46.

(6) Bhanusali DG, Sachdev A, Rahmanian A, . Gerlach JA, Tong JC, Seiffert-Sinha K and  Sinha AA, HLA-E*0103X is associated with susceptibility to Pemphigus vulgaris. Exp Derm. 2013, Feb;22(2):108-12. doi: 10.1111/exd.12077

Selected by Ralf J. Ludwig, Lübeck, Germany

 

 

Are therapeutic effects of anti-acne agents mediated by activation of FoxO1 and inhibition of TORC1?

Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. Melnik and Schmitz (2013) presented an interesting hypothesis: anti-acne agents either enhance nuclear FoxO-activity or inhibit mTORC1. Their arguments are based on the more or less well-known effects of some acne treatments. Tetracyclines inhibit NFκB activation and TNFα secretion, and their suppression of IKKβ/mTORC1 signaling may attenuate sebaceous lipogenesis. It is believed that isotretinoin increases nuclear FoxO1 levels. Azelaic acid-mediated mitochondrial ROS-release may upregulate FoxO expression and inhibit mTORC1, effects which are similar with benzoyl peroxide.  Androgen-mediated stimulation of mTORC2 and consecutive mTORC2-mediated activation of Akt inhibits FoxO1 activity and stimulates androgen receptor transcriptional activity. The hypothesis of a common mode of action of anti-acne agents as either FoxO-enhancers or mTORC1-inhibitors provides an approach of potential great clinical importance for the development of new anti-acne agents, such as FoxO-enhancers or synthetic and natural mTORC1-inhibitors, like resveratrol and epigallocatechin-3-gallate.

REFERENCES:

Melnik BC, Schmitz G Are therapeutic effects of anti-acne agents mediated by activation of FoxO1 and inhibition of TORC1? Exp Dermatol. 2013 Jul;22(7):502-4. doi: 10.1111/exd.12172.

Selected by L. Emtestam, Stockholm, Sweden

 

 

Pretreatment of epidermal growth factor promotes primary hair recovery via the dystrophic anagen pathway after chemotherapy-induced alopecia

Several treatments for chemotherapy-induced alopecia (CIA) have been reported, including scalp tourniquet, scalp cooling, and administration of ammonium trichloro(dioxoethylene-o,o’)tellurate, minoxidil, or vitamin D3. Many agents have been reported to effectively prevent CIA in animal models including interleukin-1, fibroblast growth factors, keratinocyte growth factors, cyclin-dependent kinase inhibitors, caspase-3 inhibitors, N-acetylcysteine, parathyroid hormone receptor antagonists, and laminin-511. However, many treatments and agents are not definitively effective against CIA, such as epidermal growth factor (EGF). Although its protective effect was demonstrated by Jimenez JJ et al. in 1992, the associated mechanism remains obscure.

Seung Hwan Paik et al. (2013) reported that topical EGF application decreased the chemotherapy-induced apoptosis of keratinocytes in the hair matrix. Additionally, EGF retarded the progression of CIA and promoted primary recovery after CIA via the dystrophic anagen pathway, suggesting that treatments that promote the dystrophic anagen pathway may decrease chemotherapy-induced damage to hair follicles.

Although topical EGF application is very effective in the treatment of CIA, drug cost may need to be addressed. It is also possible that topical EGF application may promote tumor development if the blood concentration of EGF increases. Nevertheless, CIA treatment using EGF may become a new, effective alopecia-protection strategy.

REFERENCES:

Paik SH, Yoon JS, Ryu HH, Lee JY, Shin CY, Min KH, Jo SJ, Kim KH, Kwon O.  Pretreatment of epidermal growth factor promotes primary hair recovery via the dystrophic anagen pathway after chemotherapy-induced alopecia.  Exp Dermatol. 2013 Jul;22(7):496-9. doi: 10.1111/exd.12182.

Selected by H. Imanishi, D. Tsuruta, Osaka, Japan.

 

 

Ozone – and its impact on epidermal keratinocytes

Because the skin is an interface between the body and the environment it is chronically exposed to several forms of stress among which ozone (O₃) has been shown to be one of the most toxic. It is generally understood that, although O₃ is not a radical species per se, the toxic effects of O₃ are mediated through free radical reactions and they are achieved either directly by the oxidation of biomolecules to give classical radical species (hydroxyl radical) or by driving the radical-dependent production of cytotoxic, nonradical species (aldehydes) (FRBM, Pryor W, 1994).

The work by McCarthy et al provides evidence that the effect of ozone on human keratinocytes  — besides the well-established induction of lipid peroxidation cascade — can also affect mitochondria sirtuin expression, specifically, SIRT3. This study first confirms the presence of SIRT3 in keratinocytes and then shows for the first time that SIRT3 levels decreased after ozone exposure. As SIRT3 has been shown to regulate SOD activity, an enzyme that catalyzes the dismutation of superoxide (O2−) into oxygen and hydrogen peroxide, this study adds a new insight on the possible sources of oxidative stress detected after O₃ exposure, and it might explain the increased levels of H₂O₂ induced by O₃. In addition, based on the authors’ previous work (Dong et al, 2012), it could be interesting to understand whether SIRT4, which is also located in the mitochondria, can be modulated by ozone and whether its expression is inversely related to SIRT3, as demonstrated for UV exposure.

REFERENCES:

McCarthy JT, Pelle E, Dong K, Brahmbhatt K, Yarosh D, Pernodet N. Effects of ozone in normal human epidermal keratinocytes. Exp Dermatol. 2013 May;22(5):360-1. doi: 10.1111/exd.12125

Dong K, Pelle E, Yarosh DB, Pernodet N.  Sirtuin 4 identification in normal human epidermal keratinocytes and its relation to sirtuin 3 and energy metabolism under normal conditions and UVB-induced stress. Exp Dermatol. 2012 Mar;21(3):231-3. doi: 10.1111/j.1600-0625.2011.01439.x.

Selected by G. Valacchi, Ferrara, Italy

 

 

Towards a molecular understanding of comorbidity in psoriasis

Patients with psoriasis are not only burdened by their chronic cutaneous inflammation but also suffer from metabolic disorders such as obesity and cardiovascular disease. So far, it has been unclear if this comorbidity is caused by psoriasis, causative of psoriasis, or observed by chance. As susceptibility to complex diseases such as psoriasis and its associated diseases results from an interplay of genetic and environmental factors, it seems plausible that the comorbidity of psoriasis with other diseases indicates common genetic controls.

Unexpectedly, however, two studies independently showed very little genetic overlap of psoriasis with its associated comorbid entities (1, 2). This points towards the environment controlling the observed metabolic and cardiovascular comorbidity of psoriasis. This assumption has now been experimentally addressed by Xue and colleagues (3): In large patient / control cohorts Xue et al. (i) demonstrate that  obesity is a risk factor for psoriasis, (ii) detect an increased cutaneous expression of leptin in psoriatic skin, and (iii) show a functional relevance of this increased leptin expression.

Leptin is a bioactive product released by adipose tissue to regulate weight, and it is increased in obesity, as confirmed by Xue et al (3). In addition, this paper nicely demonstrates that leptin increases the proliferation of keratinocytes and enhances the secretion of pro-inflammatory cytokines independent of other stimuli (3), two hallmarks of psoriasis.

Collectively, this study identifies leptin as a molecular link between obesity and psoriasis, and it underscores how important it is to systematically explore the role of leptin in skin biology and pathology (4). Taking into account the new Xue et al. study and the missing genetic association, diet seems to be a good candidate to be causative for both psoriasis and psoriasis-associated metabolic and cardiovascular comorbidity.

REFERENCES:

(1) Lu Y, Chen H, Nikamo P et al. Association of cardiovascular and metabolic disease genes with psoriasis. J Invest Dermatol. 2013 Mar;133(3):836-9. doi: 10.1038/jid.2012.366.

(2) Gupta Y, Möller S, Zillikens D, Boehncke WH, Ibrahim SM, Ludwig RJ. Genetic control of psoriasis is relatively distinct from that of metabolic syndrome and coronary artery disease. Exp Dermatol 2013 Aug;22(8):552-3. doi: 10.1111/exd.12192

(3) Xue K, Liu H, Jian Q, Liu B, Zhu D, Zhang M, Gao L and Li C, Leptin induces secretion of pro-inflammatory cytokines by human keratinocytes in vitro – a possible reason for increased severity of psoriasis in patients with a high body mass index Exp Dermatol.2013 Jun;22(6):406-10. doi: 10.1111/exd.12162.

(4) Poeggeler B, Schulz C, Pappolla MA, Bodó E, Tiede S, Lehnert H, Paus R. Leptin and the skin: a new frontier. Exp Dermatol. 2010 Jan;19(1):12-8. doi: 10.1111/j.1600-0625.2009.00930.x.

 

Selected by Ralf J. Ludwig, Lübeck, Germany

Editors’ Picks from Experimental Dermatology (June issue)

“Frozen leukocytes“: To roll or not to roll

Phenotypic or functional analysis of peripheral blood mononuclear cells (PBMC) is a valuable tool for both basic and clinical research. However, at the time of specimen collection, analysis is not always possible. Hence, several preservation strategies (mostly freezing) have been developed to allow phenotypic characterization of PBMC. Yet, little is known regarding the effect of freezing on PBMC functions. Migration of PBMC in and out of tissues is a key function of PBMC, and it had so far been unclear if freeze/thaw affects that important functional feature.

Lockmann and Schön (2013) have addressed this issue in a new study. In a flow chamber system, they demonstrate that PBMC isolated from healthy donors show similar rolling and adhesion behavior on resting and activated HUVEC cells before and after freeze/thaw. This nicely illustrates that cryopreserved PBMC can indeed be used to investigate dynamic interactions with endothelial cells. These findings are a milestone that fully justifies detailed functional analyses of cryopreserved  PMBCs (and subsets) from patients with inflammatory diseases.

Lockmann A and Schön MP, Phenotypic and functional traits of PBMC preserved by controlled cryoconservation: Implications for reliable sequential studies of dynamic interactions with endothelial cells. Exp Dermatol. 2013 May;22(5):358-9. doi: 10.1111/exd.12123.

Selected by Ralf J. Ludwig, Lübeck, Germany

 

The sound of silence: autosomal recessive congenital ichthyosis caused by a synonymous mutation in ABCA12 

Autosomal recessive congenital ichthyosis (ARCI) is a rare congenital keratinisation disorder with multiple phenotypes of varying severity. These include harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). Mutations in a number of genes have been identified as being linked with ARCI, amongst the most rare of which are abnormalities in the ABCA12 gene. This gene encodes for an epidermal lipid transporter (ATP-binding cassette A12). Impaired activity of the ABCA12 protein reduces granular layer lipid transport, resulting in malformation or complete absence of lamellar granules.

Although “silent” synonymous sequence alterations are now recognised in a number of human pathologies, Goldsmith et al. (2013) have, for the first time, identified such a mutation in a severe case of CIE in an 18 year old female. The ABCA12 mutation identified results in aberrant splicing and may impact both on transmembrane and ATP-binding domains of the protein. Interestingly, both aberrant and wild-type splice variants were produced, resulting in a less severe phenotype than is associated with null-mutations.

In providing evidence of a novel synonymous sequence alteration resulting in ARCI, this study adds to the growing body of evidence suggesting the importance of such mutations in human disease. In addition, the authors highlight the potential development of future treatment therapies for ARCI aimed at manipulating splicing mechanisms.

Goldsmith T, Fuchs-Telem D, Israeli S, Sarig O, Padalon-Brauch G, Bergman R, Indelman M, Sprecher E, Nousbeck J. The sound of silence: autosomal recessive congenital ichthyosis caused by a synonymous mutation in ABCA12. Exp Dermatol. 2013 Apr;22(4):251-4. doi: 10.1111/exd.12110

Selected by Iain Haslam, Manchester, UK

 

Visualization of dermal innervations in an ex vivo human skin model

Re-innervation processes are key cutaneous regenerative events following skin injuries. Yet, the exact mechanisms (especially in human skin) are poorly understood, mostly due to lack of proper visualization techniques. In a new METHODS LETTER, Sevrain et al. (2013)  introduce the two-photon excitation fluorescence (TPEF) microscopy method as an appropriate technique to monitor the processes of how afferent neurons re-innervate human skin.

The authors established co-cultures of murine sensory neurons (labeled with a vital, fluorescence dye [FM1-43] with high affinity to neurons) and human full-thickness skin explants, which were long-term (10 days) cultured at the air-liquid interface in defined media. Re-innervated skin explants were then fixed in paraformaldehyde and were subjected to TPEF in combination with the assessment of endogenous second-harmonic generation (SHG) signals from the collagen-rich dermis. The authors present convincing evidence of detecting the sprouting of neurites in the dermis (as identified by co-visualizing the SHG signals of collagen fibers of the dermal extracellular matrix) and, moreover, in the close vicinity of the basal layers of the epidermis. Importantly, the presented technique allows a significant (cca. 300 μm) in-depth analysis of the 3D tissue which is at least twice the depth limitations of the standard confocal microscopy method.

The technique mastered by the investigators allows the detailed in-depth investigation of cutaneous re-innervation processes in intact (i.e. unsectioned and hence undistorted) 3D ex vivo models of human skin. Moreover, when combined with time-lapse microscopy, this technology may be used to evaluate the growth and sprouting of cutaneous sensory afferents in “real-time”.

Sevrain D, Le Grand Y, Buhé V, Jeanmaire C, Pauly G, Carré JL, Misery L, Lebonvallet  N. Two-photon microscopy of dermal innervations in a human re-innervated model of skin. Exp Dermatol. 2013 Apr;22(4):290-1. doi: 10.1111/exd.12108. Epub 2013 Feb 28.

Selected by Tamas Bíró, Debrecen, Hungary

 

Mesenchymal stem cell therapy in wound healing

Over the past decade, significant progress has been made in understanding stem cell biology in the skin and its translation into new therapies for patients.  Mesenchymal stem cells (MSCs) have been used in a wide range of conditions including systemic inflammatory and autoimmune disorders that affect the skin, as well as in certain inherited skin fragility disorders. Khosrotehrani (2013) now provides a comprehensive overview of MSC properties and current clinical applications in physiologic and pathologic skin conditions, with particular emphasis on cutaneous wound healing.

Because engraftment of MSCs in skin wounds is inconsistent, Khosrotehrani suggests that MSCs are inappropriate for cell replacement therapies in a wound healing context.  The author also hypothesizes that a replete niche and competition with resident mesenchymal populations in the dermis cause the insufficient engraftment of newly delivered MSCs.  However, the author also suggests that paracrine effects of exogenous MSCs may provide a therapeutic benefit for wound healing:  MSCs and their culture supernatants (MSC ‘juice’) can modulate tissue repair and host immune responses, suggesting a broader role for MSCs in dermatological therapy.  Taken together, along with concise but comprehensive up-to-date information on MSC applications in in vitro models, pre-clinical animal models and clinical studies,  the author offers a consistent and logical analysis of the challenges one faces with MSCs therapy..

Khosrotehrani K.  Mesenchymal stem cell therapy in skin: why and what for? Exp Dermatol. 2013 May;22(5):307-10. doi: 10.1111/exd.12141.

Selected by Takashi Hashimoto, Kurume, Fukuoka, Japan

 

Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis

Since the initial proposition that skin acts as a neuroendocrine organ (Endocr Rev 21, 457-481, 2000), a flurry of data from different laboratories have substantiated the concept of neuroendocrinology of the skin (Adv Anat Embryol Cell Biol 212, 1-15, 2012). Most recently, Deing et al. (2013) have enriched the cutaneous neuroendocrinology theater with another player,  oxytocin (OXT). Specifically, they provide evidence that a functionally active oxytocin regulatory system is expressed in the human skin.

The authors have detected OXT receptors (OXTR) in epidermal keratinocytes and dermal fibroblasts. Ligand activation of these receptors led to increases in Ca+2 and inhibition of cell proliferation. Furthermore, silencing of the OXTR gene induced oxidative stress and enhanced proinflammatory activity of skin cells. Additional analyses showed decreased production of oxytocin and decreased expression of OXTR in skin affected by atopic dermatitis. The authors conclude that oxytocin signaling can play a role in the regulation of skin immune functions and that defects in this system are detectable in atopic dermatitis.

These important findings offer new insights into the role of the OXT/OXTR-mediated signaling in the regulation of epidermal barrier formation and anti-oxidative responses as well as in the attenuation of proinflammatory activities. This adds an intriguing and important new frontier to the rapidly developing field of cutaneous neuroendocrinology..

Deing V, Roggenkamp D, Kühnl J, Gruschka A, Stäb F, Wenck H, Bürkle A, Neufang G. Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis. ExpDermatol 2013: 22: 399-405. doi: 10.1111/exd.12155

Selected by Andrzej Slominski, Memphis, USA

Editors’ Picks from Experimental Dermatology (February and March issues)

Chrysanthemum extract apigenin improves barrier repair after tape stripping

Apigenin, a chrysanthemum extract, has been used for skin care in Asia for ages but knowledge on how this agent acts is scarce. It was shown before that apigenin exhibits preventive activity against UVB-induced skin tumors (Tong et al., 2007),and that an apigenin-enriched diet attenuates the development of atopic dermatitis-like lesions (Yano et al 2009).

The Man group (2013) now reports the influence of apigenin on early skin barrier repair after tape stripping in murine skin. Treatment with apigenin resulted in elevated filaggrin expression, increased density of lamellar bodies, and more intense immunostaining for antimicrobial peptides. In cultured human keratinocytes, addition of apigenin resulted in elevated mRNA levels of the lipid-synthesizing enzymes HMGCoA, SPT1, and FAS. In summary, this report demonstrates a positive effect of apigenin on skin barrier repair and highlights that various mechanisms may contribute to this effect. Treatment of diseases with barrier repair dysfunction may therefore be a future field of application for apigenin.

Selected by J. Brandner, Hamburg, Germany

Maihua Hou, Richard Sun, Melanie Hupe, Peggy L. Kim, Kyungho Park, Debra Crumrine, Tzu-kai Lin, Juan Luis Santiago, Theodora M. Mauro, Peter M. Elias and Mao-Qiang Man (2013) Topical Apigenin Improves Epidermal Permeability Barrier Homeostasis in Normal Murine Skin by Divergent Mechanisms. Exp Dermatol Accepted manuscript online: 30 JAN 2013 doi: 10.1111/exd.12102, will be published in Vol 22, Nr. 3, March 2013

Tong X, Van Dross RT, Abu-Yousif A, Morrison AR, Pelling JC (2007) Apigenin prevents UVB-induced cyclooxygenase 2 expression: coupled mRNA stabilization and translational inhibition.  Mol Cell Biol. Jan;27(1):283-96.

Yano S, Umeda D, Yamashita S, Yamada K, Tachibana H (2009) Dietary apigenin attenuates the development of atopic dermatitis-like skin lesions in NC/Nga mice.  J Nutr Biochem. Nov;20(11):876-81

 

 

Functional melanocortin 1 receptor Mc1r is not necessary for an inflammatory response to UV radiation in adult mouse skin

Melanocortin receptor type 1 (MC1R) is recognized for its role in the regulation of melanin pigmentation. In addition, a majority of investigators believes that it also plays a crucial role in anti-inflammatory responses and in induction of protective responses counteracting the damaging effects of ultraviolet radiation (UVR).

Most recently, researchers from George Washington University and Jagiellonian University (2013), using C57BL/6-c, C57BL/6, and C57BL/6-Mc1r^e/e  mouse strains, have reported the surprising finding that loss of function in the MC1R neither impacts  inflammatory responses to UV nor affects  UVR-induced immunosuppression. These findings are in striking contrast with the generally accepted opinion that constitutive or ligand-induced MC1R activity plays an important role in modulation of cutaneous immune activity in response to UVR. Interestingly, the authors also showed that UVR induced similar DNA damage in the epidermis and dermis of C57BL/6-c, C57BL/6, and C57BL/6-Mc1r^e/e strains of mice.

By challenging the existing dogmas on the precise role of MC1R in non-pigmentary responses to the UVR, these results will undoubtly stimulate further research to validate the presented data or to determine to which degree these phenomena extend beyond the C57BL/6 mouse model.

Selected by A. Slominski, Memphis, USA

Wolnicka-Glubisz A, De Fabo E,  Noonan F. (2013) Functional melanocortin 1 receptor Mc1r is not necessary for an inflammatory response to UV radiation in adult mouse skin. Exp Dermatol Accepted manuscript online: 25 JAN 2013 doi: 10.1111/exd.12100.

 

 

 

 

Human follicular dermal cells support keratinocyte growth: trichogenicity is a virtue?

Autologous transplantation of artificially assembled epidermal sheet has been used for the treatment of severe burns, intractable ulcers, and genodermatoses. Rapid in vitro expansion of patient-derived keratinocytes is a key step for successful treatment. Among currently available keratinocyte culture techniques, the one established by Rheinwald and Green (R&G) in 1975 is still considered to be very efficient. Yet, this protocol requires inactivated 3T3 murine feeder cells and “specially mixed” culture medium (I hope that everyone agrees that it is a bit of a hassle to prepare).

Hill et al. (2013) demonstrated that human dermal papilla (DP) and dermal sheath (DS) cells support human keratinocyte growth in orthodox MEM medium at a level comparable to that achieved with R&G’s condition.  The authors also showed that secreted protein acidic and rich in cysteine (SPARC) expression levels correlated with improved keratinocyte support. Yet, forced expression of SPARC in human dermal fibroblasts was not sufficient to endow these cells with such supportive properties.

DP and DS cells possess hair- inductive capacities, which distinguish those cells from other dermal cells and may enable supporting keratinocyte growth. In this sense, trichogenicity is probably a virtue.

Selected by M. Ohyama, Tokyo, Japan

R.P. Hill, A. Gardner, H.C. Crawford, R. Richer, A. Dodds, W.A. Owens, C. Lawrence, S. Rao, B. Kara, S.E. James and C.A. Jahoda (2013) Human hair follicle dermal sheath and papilla cells support keratinocyte growth in monolayer co-culture. Exp Dermatol Accepted manuscript online: 1 FEB 2013 doi: 10.1111/exd.12107, will be published in Vol 22, Nr. 3, March 2013

Rheinwald JG, Green H.  (1975) Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells.  Cell. Nov;6(3):331-43

 

 

 

Evidence for a regulatory loop between IFNγ and IL-33 in skin inflammation

Atopic dermatitis (AD) is characterized by a delicate cutaneous micromilieu of various cytokines and chemokines. Among those, interleukin-33 (IL-33), a member of the IL-1 cytokine family, has recently gained much attention due to its role in Th2 responses and damage- induced inflammation. Understanding the role of IL-33 in inflammatory diseases such as AD and allergic asthma might lead to novel treatments. Therefore, Seltmann and coworkers (2013) investigated the expression and secretion of IL-33 in resident skin cells and its impact on CD4+ T cells. The authors showed that keratinocytes and dermal fibroblasts differ in their regulation of IL-33. While in fibroblasts, TNFα, and IL-1β were the strongest inducers, IFNγ is clearly the key regulator of IL-33 in keratinocytes. Notably, keratinocytes from AD patients showed stronger responses, suggesting disturbed IL-33 regulation in these cells. Interestingly, secreted IL-33 acts on T cells and increases their production of IFNγ. The latter effect is substantially enhanced by the presence of IL-12, which is expressed in chronic AD lesions. These results suggest that IL-33 and IFNγ are closely interlinked in epidermal inflammation in AD. IFNγ induces IL-33 in keratinocytes and IL-33 acts on activated T cells to further increase the release of IFNγ, thereby driving a loop of skin inflammation towards chronic responses. In this respect, IL-33 can be linked to other IL-1 family members such as IL-1 and IL-18 and might serve as a novel target for future therapies.

Selected by J. Schauber, Munich, Germany

Seltmann J, Werfel T, Wittmann M. Evidence for a regulatory loop between IFN-γ and IL-33 in skin inflammation. Exp Dermatol. 2013 Feb; 22(2): 102-7. doi: 10.1111/exd.12076.

 

 

 

The Sox21 gene plays an important role for the binding of lipids on hair

Sox genes encode a family of transcription factors and are defined as containing the high mobility group box of a gene involved in sex determination called SRY, which resides on the Y-chromosome. Knocking out the Sox21 gene leads to a down-regulation of some proteins in the mouse hair cuticle, leading to improper cuticle formation. The outermost surface of the cuticle is naturally very hydrophobic due to a monomolecular layer of fatty acids, of which 18-methyleicosanoic acid (18-MEA) is a major and uniquely important component. The fatty acids are bound to the underlying protein layer through thioester linkages. Kawaminami et al (2013) now show that after knocking out the Sox21 gene the overall level and distribution of 18-MEA on the surface of hair remain largely unchanged, while a virtually comprehensive disruption of its covalent attachment occurs. Furthermore, they show that other lipids are in individual cases subject to significant changes in their concentration levels due to the knock-out. Since the bound lipids on the surface of hair fibres are known to impart beneficial properties to hair, such as hydrophobicity, low friction, protection against penetration of chemicals, and retardation of bacterial and fungal growth, they are of special importance in hair cosmetic science.

Selected by F.J. Wortmann, Manchester, United Kingdom

Kawaminami S, Breakspear S, Saga Y, Noecker B, Masukawa Y, Tsuchiya M, Oguri M, Inoue Y, Ishikawa K, Okamoto M. Deletion of the Sox21 gene drastically affects hair lipids. Exp Dermatol. 2012 Dec; 21(12): 968-70. doi: 10.1111/exd.12050

 

Editors’ Picks from Experimental Dermatology (January & February 2013)

Correlation between local cortisol metabolism and epidermal hyperproliferative disorders

(a) Immunohistochemical staining of healthy skin and skin tumors with anti-11b-HSD1 and anti-11b-HSD2 antibody. BCC: basal cell carcinoma, SCC: squamous cell carcinoma, SK: seborrhoeic keratosis. Rabbit IgG was used as isotype control. Bar = 100 lm. (b) Quantification of 11b-HSD1 and 11b-HSD2 staining. Bars show the staining index of healthy skin, BCC, SCC and SK. The results are expressed as mean _ SD of 20 normal epidermis samples, 14 BCCs, 18 SCCs and 15 SKs (*P < 0.05 compared with healthy skin).

Recent findings have shown constitutive and regulated production of cortisol by human skin. Cutaneous cortisol can be generated through sequential metabolism of endogenously produced cholesterol or from progesterone that is delivered via the circulation. Thus, the recognized neuroendocrine functions of human skin are extended by a major glucocorticoidogenic capability.

Two key enzymes that regulate local cortisol availability for the glucocorticoid receptor are 11ß-HSD1 and 11ß-HSD2.  11β-HSD1 expresses ketoreductase activity (at a high

NADPH/NADP⁺ ratio) with the transformation of inactive cortisone into hormonally active cortisol. 11ß-HSD2, in turn, is an NADP⁺−dependent enzyme that acts exclusively as a dehydrogenase to inactivate cortisol to cortisone. Both of these enzymes are expressed in human skin.

Terao et al. (2013) now report that 11ß-HSD1 decreases in hyperpoliferative disorders like seborrhoeic keratosis and squamous and basal cell carcinoma, while 11ß-HSD2 increases in seborrhoeic keratosis and basal cell carcinoma. Furthermore, treatment of mouse skin with TPA reduces expression of 11ß-HSD1, while forced 11ß-HSD2 overexpression stimulates keratinocyte proliferation.

These important findings offer new insights not only into the potential role of 11ß-HSD1 and 11ß-HSD2 in the development of cutaneous hyperproliferative disorders and perhaps skin carcinogenesis, but also raise the possibility that these enzymes are notable regulators of epidermal homeostasis under physiological conditions. Targeting these enzymes, for example by topically applied small molecules, may therefore represent an exciting novel strategy for the therapeutic manipulation of hyperproliferative human skin disorders.

Selected by A. Slominski, Memphis, TN, USA

Terao M, Itoi S, Murota H, Katayama I. (2013) Expression profiles of cortisol-inactivating enzyme, 11β-hydroxysteroid dehydrogenase-2 in human epidermal tumors and its role in keratinocyte proliferation. Exp Dermatol. 22:98-101. doi:10.1111/exd.12075

 

 

Are NK cells really important in the pathogenesis of psoriasis?

There is considerable evidence suggesting that NK cells play a role in the pathogenesis of psoriasis. In their recent study, Batista et al (2013) specifically looked at the expression of CD57, which is known to be associated with the senescence of NK cells. The investigators found that the frequency of CD7-CD56+CD16+ (NK cell markers) was much higher in involved psoriatic skin. This implies that IFN-g production is higher in the involved area, due to the decreased frequency of CD57+CD56+CD16+ NK senescence cells. Furthermore, their study showed increased expression of NKG2A, a key NK cell activating receptor whose expression correlates well with the level of IFN-g production by NK cells, in involved versus uninvolved psoriatic skin. Therefore, this study further strengthens the concept that NK cells play an important role in the pathogenesis of psoriasis and should, thus, be specifically targeted by future anti-psoriatic therapy.

Selected by A. Gilhar, Haifa, Israel

Batista MD, Ho EL, Kuebler PJ, et al (2013) Skewed distribution of natural killer cells in psoriasis skin lesions. Exp Dermatol 22:64-6. doi:10.1111/exd.12060

 

 

Environmental factors predominately contribute to phenotype variations in XP-C patients

Xeroderma pigmentosum (XP) patients have defects in the nucleotide excision DNA repair pathway. XP complementation group C (XP-C) constitutes one-third of all cases and is therefore the most frequent form of XP. This recessive disorder is characterized by increased sun sensitivity, freckling, pigmentary changes, skin atrophy and UV-induced skin cancer.

To date, there are only four major reports on the genetic background of XP-C. Schäfer et al (2013) now complement these studies by identifying 16 additional German XP-C patients from different ethnic backgrounds. All patients carried homozygous mutations, indicating parental consanguinity. Five mutations are novel, and all of them, except for a single amino acid deletion, lead to premature stop codons and nonsense-mediated mRNA decay. This genetic uniformity may be reflected in the homogeneous phenotypes of the patients.

The authors demonstrated diminished post-UV cell survival and nucleotide excision DNA repair capability of fibroblasts for all patients. Interestingly, they note that one-third of their patients reported sun sensitivity. This particular symptom could not be correlated to a particular mutation or functional outcome. The authors observe that skin cancer occurs mostly in the patients who do not experience sun sensitivity and consequently are less likely to avoid UV exposure. Thus, photosensitivity is a protective factor. Why it affects some patients and not others, even though they have the same mutation, is one of the many mysteries of XP that remains to be solved.

Selected by P.M. Steijlen, Maastricht, the Netherlands

Schäfer A, Hofmann L, Gratchev A, et al (2013) Molecular genetic analysis of 16 XP-C patients from Germany: environmental factors predominately contribute to phenotype variations. Exp Dermatol 22:24–29. doi:10.1111/exd.12052

 

Hair growth control via the mTOR pathway?

The hair follicle continuously undergoes cycles of regeneration coupled with a high proliferation and protein synthesis activity (anagen), followed by an apoptosis-driven organ involution (catagen) and a relative resting phase (telogen). Hair follicle cycling is governed by signaling interactions between specialized, inductive fibroblasts (dermal papilla cells) and hair matrix keratinocytes. Numerous soluble factors, transcription factors, and adhesion molecules play indispensable roles in these signaling interactions.

Kellenberger AJ and Tauchi M (2013) now show that HF cycling is regulated by yet another biologically important molecule, which increasingly attracts interest in several areas of investigative dermatology and has become an important frontier in skin research: mammalian target of rapamycin complex 1 (mTORC1).

The investigators reveal a phase-specific mTORC1 kinase activity: it is high during anagen and low during telogen. Immunohistochemical investigation shows co-expression of an important stem cell marker (keratin 15) in the majority of phophorylated mTOR-positive cells. Moreover, a specific mTORC1 inhibitor, rapamycin, delays spontaneous anagen induction, suggesting that mTORC1 may be involved in the onset of anagen.

These intriguing findings in mice may pave the way for a new treatment of human hair growth disorders, i.e. hirsutism and alopecia, by selectively up- or down-regulating mTORC1 kinase activity.

Selected by M. Nakamura, Kitakyushu, Japan

Kellenberger AJ and Tauchi M (2013) Mammalian target of rapamycin complex 1 (mTORC1) may modulate the timing of anagen entry in mouse hair follicles. Exp Dermatol 22:77-80. doi:10.1111/exd.12062

 

 

PPRE-luciferase mice: A powerful new tool for translational PPAR biology research

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors that belong to the nuclear hormone receptor family. PPARs were primarily shown to play important roles in lipid and glucose metabolism. There are three PPAR isotypes, PPARα, PPARβ/δ and PPARγ, with distinct tissue expression. All three are expressed in skin, where they regulate various aspects of skin homeostasis. PPARs control keratinocyte proliferation and differentiation, regulate wound healing, and modulate skin inflammation. PPAR activation exerts anti-inflammatory effects in various skin conditions such as irritant and allergic contact dermatitis, atopic dermatitis, and UV-induced erythema.

New experimental tools will accelerate the discovery of novel drugs targeting PPARs. El-Jamal et al. (2013) recently generated new PPAR responsive element-luciferase (PPRE-Luc) mice. These were topically treated with PPARα and PPARγ agonists to determine optimal ligand doses, bioluminescence kinetics, and isoform specific effects. Using these new PPRE-luciferase mice will be useful for screening and characterizing novel PPAR ligands.

Novel compounds optimized in this system will improve our ability to treat many inflammatory skin disorders. It is hoped that these mice will become widely available in the near future to facilitate further in vivo-research into the complex roles of PPARs in skin and to ultimately allow the development of new therapeutic strategies that target these fatty acid-activated transcription factors.

Selected by S. Dubrac, Innsbruck, Austria

El-Jamal N, Dubuquoy L, Auwerx J, et al (2013) In Vivo Imaging Reveals Selective PPAR Activity in the Skin of Peroxisome Proliferator-Activated Receptor Responsive Element-Luciferase Reporter Mice? Exp Dermatol 22:137-40. doi:10.1111/exd.12082

Editors’ Picks from Experimental Dermatology (January 2013)

Extracellular histones as new players in hair growth control

Histones are known as major components of the nucleosome structure in eukaryotic cells. They can be divided into linker histones (H1) or core histones (H2A, H2B, H3 and H4). Through methylation and phosphorylation modifications, histones actively participate in the epigenetic control of gene expression. Besides these key nuclear functions, diverse biological roles have been attributed to extracellular histones, including antimicrobial activities and death in sepsis. Recently, recombinant Histone H4 was reported to reduce alkaline phosphatase activity and inhibit proliferation of cultured dermal papilla (DP) cells (Hsia CW et al., 2011).

YK Sung’s lab now reports novel effects of the histones H4 and H2A on hair growth, having studied organ-cultured human hair follicles in vitro and hair follicle cycling in mice in vivo. Both histones inhibit hair shaft elongation and hair matrix cell proliferation and promote the anagen-to-catagen transformation of human hair follicles in vitro. This effect is at least partially mediated by decreased IGF-1 and alkaline phosphatase activity expression in the anagen hair bulb. When injected into the back skin of C57BL/6 mice, both histones induce premature entry into the catagen phase of the hair cycle.

These results provide strong evidence of an inhibitory effect of the tested extracellular histones on hair growth in man and mice. As colchicine treatment of DP cells induces histone H4 release (Hsia et al. 2011), the present results provide one reasonable hypothesis for a mechanism by which colchicine overdose may cause hair loss, besides the recognized anti-mitotic properties of this agent. Moreover, the release of histones H4 and H2A by DP cells could become a valuable marker for predicting hair loss as an adverse event of pharmacotherapy.

Selected by B. A. Bernard, Clichy, France

Extracellular histones inhibit hair shaft elongation in cultured human hair follicles and promote regression of hair follicles in mice.  Shin SH, Joo HW, Kim MK, Kim JC, Sung YK. Exp Dermatol. 2012 Dec;21(12):956-8

Proteomics demonstration that histone H4 is a colchicine-induced retro-modulator of growth and alkaline phosphatase activity in hair follicle dermal papilla culture. Hsia CW, Shui HA, Wang CY, Yu HM, Ho MY, Cheng KT, Tseng MJ. J Proteomics. 2011 May 16;74(6):805-16

 

Do inflammasome variants drive psoriasis?

Psoriasis is a multifactorial disease with complex inheritance of distinct susceptibility loci responsible for immunity or skin barrier function. Genome-wide association studies (GWAS) have identified 36 loci associated with psoriasis in European individuals. These loci include several candidate genes whose products are involved in innate and acquired immunity, including genes responsible for regulating cytokines of the Th17 axis.

Through a Swedish study Carlström et al. now provide genetic support for a role of the NLPR3 inflammasome in psoriasis susceptibility. The investigators genotyped 1988 individuals from 491 different families, including 741 affected individuals and 1002 healthy controls, for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and caspase recruitment domain-containing protein (CARD) 8 (one SNP). They found a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis (P=0.015). In addition, logistic regression analysis revealed that the CARD8 rs2043211 genotype was significantly linked to psoriasis [OR 1.3 (1.1–1.5), P = 0.004]. NLRP3 controls the inflammasome that regulates caspase-1-mediated interleukin (IL)-1b processing. Indeed, IL-1b has been identified, among others, as an important cytokine for the development of psoriasis. Moreover, generalized pustular psoriasis has been successfully treated with IL-1 receptor blockade.

These findings support the hypothesis that the inflammasome and its components NLRP3 and CARD8 play a role in the defective innate immune response and chronic inflammation in psoriasis. This may encourage one to therapeutically target IL-1 in psoriasis.

Selected by P. Wolf, Graz, Austria

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility.   Carlström M, Ekman AK, Petersson S, Soderkvist P, Enerback C. Exp Dermatol. 2012 Dec;21(12):932-7

 

Non-invasive ex vivo analysis of basal cell carcinoma by intravital multiphoton tomography

The rising incidence and high prevalence of skin cancer is well-appreciated, and early diagnosis improves overall outcome of affected patients. Therefore, diagnostic tools detecting even single cancer cells in vivo in distinct patients would be of great clinical benefit.

In this context Seidenari et al. present an interesting and novel approach to advance basal cell carcinoma (BCC) diagnostics and therapy using multiphoton laser tomography (MPT) in combination with fluorescence lifetime imaging (FLIM). MPT-FLIM allows non-invasive morphological analysis of human skin in vivo with a subcellular resolution by detection of endogenous, autofluorescent signals. In addition, FLIM enables one to identify single molecules or cell metabolism by measurement of the decay rate of autofluorescent signals.

In this well-performed ex vivo study, the authors develop MPT-FLIM diagnostic descriptors for BCC and test their statistical suitability. They identify 6 morphological descriptors (specificity of each single descriptor between 92 and 98%) and one FLIM parameter with a sensitivity of 100% (specificity 70%). Therefore, the application of more than 3 diagnostic descriptors clearly identified healthy and lesional skin.

This innovative, non-invasive technique deserves systematic exploration as a potential diagnostic in vivo tool which could be introduced into clinical practice in the near future.

Selected by S.W. Schneider, Mannheim, Germany

Multiphoton laser tomography and fluorescence lifetime imaging of basal cell carcinoma: morphologic features for non-invasive diagnostics.  Seidenari S, Arginelli F, Dunsby C, French P, König K, Magnoni C, Manfredini M, Talbot C, Ponti G. Exp Dermatol. 2012 Nov;21(11):831-6

 

Papillary fibroblasts differentiate into reticular fibroblasts after prolonged in vitro culture

The dermis is composed of two sub-layers, the papillary dermis and the reticular dermis. In these sub-compartments, skin fibroblasts exhibit functionally distinct features, such as their capacity to proliferate or to express extracellular matrix molecules such as collagens and glycosaminoglycans.

Janson et al (2013). have evaluated typical markers of reticular fibroblasts (TGM2 and CNN1) in reconstructed human skin equivalents according to their previously described method (Ghalbzouri et al, 2009). Low and high passage fibroblasts from the papillary or reticular dermis were used in long-term culture. This resulted in an increase in a senescent –like phenotype for the high passage papillary fibroblasts, which expressed the same pattern as reticular fibroblasts. Therefore, the investigators hypothesize that papillary fibroblasts constitute an undifferentiated state compared to reticular fibroblasts, which may represent a more differentiated fibroblast population.

These new insights into distinct human fibroblast differentiation patterns within the dermal compartment improve our understanding of skin-aging and facilitate the development of new, differential strategies against cutaneous senescence.

Selected by N. Bigot, Rennes, France

 

Papillary fibroblasts differentiate into reticular fibroblasts after prolonged in vitro culture (2013) David Janson, Gaelle Saintigny, Christian Mahé and Abdoelwaheb El Ghalbzouri.  Exp Dermatol, Exp Dermatol. 22(1): 48–53

Replacement of animal-derived collagen matrix by human fibroblast-derived dermal matrix for human skin equivalent products (2009) Ghalbzouri El A, Commandeur S, Rietveld MH, Mulder AA, Willemze R. Biomaterials 30:71–8

 

Measuring Up? A ‘Spray On’ Wound pH Monitor

Refractory wounds are extremely costly both in economic terms and in associated health outcomes.  For example, it is estimated that chronic wounds cost over $25 billion annually in the US and that presence of a chronic wound in patients with Diabetes Mellitus (DM) increases the risk of mortality by 50% compared to those without DM.  Predicting which wounds will heal and those that won’t is a subject of intense interest.  Assessment of bacteria, proteases, tissue biomarkers, and pH have all been targeted to attempt predict outcomes.  Specifically, extracellular pH may modify gene expression, regulate mRNA splicing patterns, and control cell growth and movement, among other effects.  Therefore, optimizing pH measurement levels would be a potential advance.

Recently, Schreml and co-workers used a fluorescein isothiocyanate covalently linked to aminoethylcellulose to form pH indicator particles, which could be conveniently sprayed on to a wound.  The resultant pH indictor appears to provide fast, simple, non-toxic and painless visualization of pH in vivo. This will provide opportunities to study pH changes over time in healing vs. non healing wounds of various types. Also, this will permit to observe the effects of intervention on pH as it correlates to healing, and to determine whether wound pH represents a potential therapeutic target.

Selected by R S Kirsner, Miami, USA

A sprayable luminescent pH sensor and its use for wound imaging in vivo. Schreml S, Meier RJ, Weiß KT, Cattani J, Flittner D, Gehmert S, Wolfbeis OS, Landthaler M, Babilas P. Exp Dermatol. 2012 Dec; 21(12):951-3

 

 

 

Editors’ Picks from Experimental Dermatology (December 2012)

New insights into the anti-inflammatory, anti-tumorigenic and anti-angiogenic properties of PPARβ/δ agonists: Targeting cathepsin B expression and function

 

Previous studies indicate that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a promising drug target involved in the serum increase of high-density lipoprotein, the decrease of triglycerids, the promotion of terminal differentiation, and anti-inflammatory activities. In addition, there are first studies of anti-carcinogenic and anti-angiogenic effects. The underlying mechanisms of PPARβ/δ agonist mediated action still had to be elucidated. Reichenbach and colleagues (2012) recently found that PPARβ/δ agonists suppress cathepsin B expression in human endothelial cells in a posttranslational manner. The expression of other cathepsins seemed to be unaffected. Transcriptional or posttranscriptional mechanisms as 3´-UTR- or miRNA-dependent mechanisms could be excluded. Cathepsin B is an important protease known to be involved in the process of angiogenesis, facilitating capillary tube formation, as well as in tumor metastasis. Therefore its suppression by PPARβ/δ agonists, as described by Reichenbach and colleagues, offers new support of the concept of their anti-inflammatory and anti-tumorigenic value.

Selected by R. Ludwig, Lübeck, Germany

Ligand activation of peroxisome proliferator-activated receptor delta suppresses cathepsin B expression in human endothelial cells in a posttranslational manner.  Reichenbach G, Starzinski-Powitz A, Doll M, Hrgovic I, Maria Valesky E, Kippenberger S, Bernd A, Kaufmann R, Meissner M.  Exp Dermatol. 2012 Oct;21(10):751-7. doi: 10.1111/exd.12002.

 

 

Protein kinase A activation suppresses sonic hedgehog signalling and basal cell carcinoma

Activation of the sonic hedgehog (Shh) pathway is the underlying mechanism for basal cell carcinomas. In this pathway the membrane Shh receptor patched suppresses smoothened (Smo) until the suppression is relieved by binding of Shh to patched. Smo, when relieved of this suppression, in turn activates the transcription factors gli 1 and 2, which then enter the nucleus and turn on genes leading to BCC. Drugs to block Smo are currently on the market and/or under development, but their toxicity is substantial and their use leads to resistance based on mutations in Smo.  So other treatment modalities would be welcome.   E. Makinodan and A.G. Marneros (2012) used an agonist of protein kinase A, forskolin, which has been shown to phosphorylate gli 1 and 2, leading to their proteosomal degradation, to demonstrate in vivo and in vitro that forskolin could block BCC development. In particular, for the in vitro studies they used a cell line, SmoA1-LIGHT2, which contains a gli dependent luciferase and a constitutively active Smo construct to demonstrate that forskolin blocked gli 1 activation of the luciferase construct. In the in vivo study they used a mouse, R26SmoM2, that when bred to a mouse with tamoxifen regulated (ERT2) K14-cre recombinase expressed a constitutively active Smo, to demonstrate that forskolin could prevent tumor formation on the ears of these mice. Whether forskolin or similar agents can be used clinically in a topical fashion to prevent or reverse BCC progression remains to be seen.

Selected by D. Bikle, San Francisco, CA, USA

Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin. Makinodan E, Marneros AG.  Exp Dermatol. 2012 Nov;21(11):847-52. doi: 10.1111/exd.12016.

 

 

Spotlight on tissue engineering to manage chronic wounds

Restoration of skin integrity in impaired healing conditions associated with aging, metabolic, or vascular disease remains an unresolved and challenging task in medicine. Wong and Gurtner provide a comprehensive and concise viewpoint on recent therapeutic developments in biotechnology and point out exciting perspectives for future research in this field (2012). The authors outline the synergistic efforts of biomedical engineers, material scientists, and cell biologists during the past decade that yielded promising therapies to manage difficult-to-treat wounds. Most importantly, rigorous basic science and clinical studies are now required to validate these novel approaches. Furthermore, recent advances in the biology of tissue repair stipulate that in addition to the inflammation-based paradigm of wound healing pathology, the role of stem cells, matrix components, and other – potentially yet unknown – molecular pathways must be further explored in current and evolving therapeutic concepts for chronic wounds.

Selected by S.A. Eming, Cologne, Germany

Tissue engineering for the management of chronic wounds: current concepts and future perspectives. Wong VW, Gurtner GC.  Exp Dermatol. 2012 Oct;21(10):729-34. doi: 10.1111/j.1600-0625.2012.01542.x.

 

 

Rosacea: inflammatory reaction of the skin immune system (SIS) to outside agents?

Christiane Casas and colleagues address the topic of Demodex folliculorum density and inflammatory protein expression in the facial skin of rosacea patients (2012). The authors report a multicentre, cross-sectional, prospective study including 50 patients with with well-defined types of facial rosacea, and 48 age- and sex-matched healthy volunteers. Patients with isolated rhinophyma, isolated ocular rosacea, granulomatous rosacea, fulminant rosacea, or steroid-induced rosacea were excluded, as were patients using antiparasitics, antibiotics active against Bacillus oleronius, or local antiseptics. Facial skin scrapings (micro-abrasions) and swabs were studied for D. folliculorum density as well as for a number of inflammation markers.

The results point to neutrophil activation induced by bacterial proteins associated with Demodex in rosacea patients. Moreover, they suggest that the NLRP3 inflammasome might be a new factor in the pathogenesis of rosacea by promoting excessive secretion of IL-1b. Furthermore, IL-18 underexpression, together with that of the ASC adaptor, could be responsible for a loss of microbial homoeostasis.

There is no doubt that there is inflammation in patients suffering from rosacea. Patients feel the burning accompanying that inflammatory response. A role for the hair follicle mite, Demodex folliculorum, has long been suspected in this inflammation. Recent findings indicate that not Demodex itself is the culprit, but the Bacillus oleronius that these mites can harbour (Jianjing L et al, 2010). Therefore, the authors excluded patients being treated with antibiotics that might have eradicated these micro-organisms.

While this work brings us closer to the goal of fully understanding the mechanisms of this sometimes devastating disease, several questions arise: Is it primarily dysfunction of the innate part of the skin immune system (SIS) that enables otherwise harmless inhabitants of the hair follicles to induce inflammation? Is a subtype of Bacillus oleronius responsible for that inflammation? Or is it, perhaps, a combination of both? Why is rosacea more common in women, peaking around age 40? Why is it so often a temporary ailment that can resolve spontaneously? Quite possibly, we have as yet only scratched the surface of the complex interplay between the skin microbiome and the SIS in rosacea.

Selected by J.D. Bos, Amsterdam, the Netherlands

Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Casas C, Paul C, Lahfa M, Livideanu B, Lejeune O, Alvarez-Georges S, Saint-Martory C, Degouy A, Mengeaud V, Ginisty H, Durbise E, Schmitt AM, Redoulès D.  Exp Dermatol. 2012 Dec;21(12):906-10. doi: 10.1111/exd.12030

Correlation between ocular Demodex infestation and serum immunoreactivity to Bacillus proteins in patients with Facial rosacea.  Li J, O’Reilly N, Sheha H, Katz R, Raju VK, Kavanagh K, Tseng SC.  Ophthalmology. 2010 May;117(5):870-877.e1.

 

 

Investigating stratum corneum lipids by electron spectroscopic analysis 

The lipids of the stratum corneum comprise the main components of the hydrophobic human skin barrier regulating water homoeostasis. Recently, the notion that mutations in the filaggrin gene result in ichthyosis vulgaris and are associated with atopic eczema have raised interest in the normal human skin lipid barrier, and in how skin lipids change in diseased skin.

Using the latest X-ray photoelectron spectroscopy technology, Marschewski et al. (2012) found that the human lipid skin barrier consists of 84.4% carbon, 10.8% oxygen and 4.8% nitrogen. In addition, they identified for the first time a fundamental and reproducible influence of cold atmospheric plasma treatment on the lipid barrier system of human skin, as can be especially derived from the clear structural changes in the oxygen detailed spectra.

Their experimental setting and results pave the way for more detailed fundamental analyses of the effects of plasma treatment on the lipid barrier of human skin, thus deciphering effects on each of the three main lipid components of that barrier, namely ceramides, cholesterol, and long-chain free fatty acids.

Selected by K. Kabashima, Kyoto, Japan

Electron spectroscopic analysis of the human lipid skin barrier: cold atmospheric plasma-induced changes in lipid composition. Marschewski M, Hirschberg J, Omairi T, Höfft O, Viöl W, Emmert S, Maus-Friedrichs W.  Exp Dermatol. 2012 Dec;21(12):921-5. doi: 10.1111/exd.12043.

Editors’ Picks from Experimental Dermatology (November 2012)

JID is pleased to publish highlights from the November 2012 issue of Experimental Dermatology in this space. We welcome your comments on the reported findings.

 

Liver X receptor-α upregulation may orchestrate reduced melanocyte survival in vitiligo

Liver X receptors (LXRα & LXRβ) represent a subfamily of thyroid hormone receptor-like nuclear receptors that regulate cholesterol, fatty acid, and glucose homeostasis via endogenous oxysterol ligands. These receptors form heterodimers with 9-cis retinoic acid receptor as an obligate partner, and LXR agonists show anti-inflammatory properties. LXR have been detected in human skin, where they play a role in epidermal proliferation, differentiation and barrier permeability. Their role in skin pathology remains unclear, however.

Previously the lab of Davinder Parsad reported that LXRα expression in human melanocytes is significantly higher in perilesional skin than in normal skin of vitiligo patients (Exp Dermatol 19:62-64, 2010). In this new study (1), they report that increased LXRα expression in vitiligo perilesional skin is associated with a markedly reduced MMP (-1, -2, -9) expression, and that LXRα gene knockdown in vitro increases MMP expression by melanocytes. Melanocyte adhesion to collagen IV was reduced by the LXRα natural ligand 22(R)-hydroxy-cholesterol, as was the incidence of melanocyte apoptosis.

These important findings offer new insights into the fate of differentiated melanocytes targeted in active vitiligo. Whether LXRα expression in vitiligo can be induced by oxidative stress will be fascinating to explore.

Selected by Desmond J. Tobin, Bradford, UK

1. Kumar R et al. Altered levels of LXR-a: crucial implications in the pathogenesis of vitiligo. Exp Dermatol 21:853-858, 2012 (DOI: 10.1111/exd.12017)

 

Photoprotection via epidermal proliferation

The skin’s best known protection mechanism against ultraviolet (UV) radiation is the production of melanin. For individuals with fair skin or albinism this intrinsic ability to shield cells from UV radiation is blunted or absent.

The D’Orazio lab now reports on the mechanisms and efficiency of a pigment-independent UV protection mechanism (1). Using mice humanized for epidermal Scf expression to maintain a pool of interfollicular melanocytes, together with mutant Mc1r or Tyrosinase alleles to make the models specific for fair or albino skin, the authors show that either forskolin treatment or UV irradiation promote epidermal proliferation. They go on to show that the resulting epidermal thickening alone, even in the absence of melanin production, provides significant protection against UV penetration into the skin and resulting cell damage. Keratinocyte growth factor (Kgf/Fgf7), a known stimulator of melanin uptake by keratinocytes, appears to be the driver of this epidermal thickening through induction of keratinocyte proliferation.

These insights implicate Kgf as a stimulator of diverse cellular mechanisms that constitute the skin’s full photoprotective response and suggest new approaches to aid skin photoprotection in individuals with weak or absent melanization.

Selected by Denis Headon, Edinburgh, UK

1. Scott TL et al.: Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation. Exp Dermatol 21:771-777, 2012 (DOI: 10.1111/exd.12012)

 

How adipose tissue talks to the hair follicle

The hair follicle is surrounded by a variety of cell types that deliver a plethora of signals to orchestrate hair follicle homoeostasis. A recent viewpoint essay by Schmidt & Horsley (1) highlights the poorly understood and insufficiently investigated, but likely important communication between intradermal adipocytes and the hair follicle.

The authors first explain the anatomical prerequisite for their concept, i. e., the morphological and metabolic difference between the subcutaneous white adipose tissue and intradermally located adipocytes, the latter oscillating in their expansion during hair follicle cycling. Secondly, mutant mice strains with defects in adipocytes and an abnormal hair phenotype – e. g., the genetic mouse model lacking Early B-cell factor 1 (Ebf1^-/-) – are discussed. This is followed by emphasizing the role of adipocyte-derived factors and classical adipokines like BMP2, leptin or adiponectin which regulate stem cell activity and cycling of the hair follicle. Finally, examples of lipid-associated human diseases are provided in which hair follicle homoeostasis is disrupted.

In summary, this viewpoint strongly encourages further research that explores the fascinating communication and interplay between intradermal adipocytes and the hair follicle.

Selected by Markus Böhm, Münster, Germany

1. Schmidt B and Horsley V: Unravelling hair follicle-adipocyte communication. Exp Dermatol 21;827-830, 2012 (DOI: 10.1111/exd.12001)

 

Skin barrier control by the endocannabinoid system (ECS)

The ECS and its receptors (cannabinoid receptors CB1 and CB2) impact on skin inflammation and sensory output and are increasingly appreciated as key regulators of mast cell, keratinocyte, and sebocyte functions. The Hachem lab (Brussels) now shows that the control of epidermal barrier function ranks among the expanding range of ECS tasks in murine skin physiology (1).

The authors show by examining knock-out mice that CB1 stimulation by endogenous agonists is required for rapid permeability recovery after tape stripping in vivo, while CB2-mediated signaling retards barrier repair and associated keratinocyte terminal differentiation events. This differential regulation of the epidermal barrier by the two ECS key receptors may serve as a finely tunable, intracutaneous fast-response system to environmental stressors.

These important findings also caution against the therapeutic use of CB2 agonists when treating skin diseases where the barrier already is defective and invite the speculation that, long before their adoption for purposes of central nervous signaling and computing, endocannabinoids and their receptors developed during evolution primarily to regulate vital epithelial functions.

Selected by Ralf Paus, Lübeck, Germany & Manchester, UK

1. Roelandt T et al.: Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation. Exp Dermatol  21:688-693, 2012 (DOI: 10.1111/j.1600-0625.2012.01561.x)

 

Effects of the local tissue micro-environment on hair growth

The complex multi-directional interplay among various skin-derived cells is essential for the normal homeostatic function of the skin. Two recent Experimental Dermatology papers explore the effect of humoral factors produced by human follicular keratinocytes and sebocytes on hair growth.

Lee MH et al. (1) have shown that treating dermal papilla cells and dermal sheath cells with conditioned medium obtained from follicular keratinocytes (FKCM) resulted in induction of a greater number of hair follicles in patch assays and chamber grafts. Lee WJ et al. (2), on the other hand, used conditioned media obtained from either normal sebocytes or cells from nevus sebaceous lesions. They concluded that conditioned medium of nevus sebaceous sebocytes (but not of normal cells) decreased survivability and the number of dermal papilla cells and outer root sheath cells.

The two groups also performed microarray experiments. This analysis revealed that whereas the increased trichogenicity by FKCM coincided with the activation of the BMP and β-catenin signaling pathways (1), the decreased survival of hair follicle-derived cells by diseased sebocyte-conditioned medium could be linked to the production of hair growth suppressing factors (FGF5, Dickkopf-1, IL-4, IL-6, TGFβ1 and β2, etc).

Both studies highlight the indispensable regulatory role of the cutaneous local tissue micro-environment, and therefore, may encourage one to systematically explore the putative cross-talk among the different skin-derived cells. This would open new avenues for the identification of novel players and mechanisms in the (patho)physiology of hair growth and, in a wider sense, skin (patho)physiology in general.

Selected by Tamas Bíró, Debrecen, Hungary

1. Lee MH et al.: Conditioned media obtained from human outer root sheath follicular keratinocyte culture activates signaling pathways that contribute to maintenance of hair-inducing capacity and increases trichogenicity of cultured dermal cells. Exp Dermatol 21:793-795, 2012 (DOI: 10.1111/j.1600-0625.2012.01570.x)

2. Lee WJ et al.: The effect of sebocytes cultured from nevus sebaceous on hair growth. Exp Dermatol 21:796-798, 2012  (DOI: 10.1111/j.1600-0625.2012.01572.x)