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




Psoriasis Auld Lang Syne

Nature has recently published an industry-sponsored supplement that is a timely précis of psoriasis investigation and thought. It contains short, two-page reviews and interviews, on topics including epidemiology, the immune system, the skin microbiome, cardiovascular complications, stress, and the newer biologic and pharmacologically- based therapies arising from basic science results that implicate a major role for the immune system in psoriasis. In addition, a small collection of recent major papers from Nature Publishing Group (NPG) journals is presented.  Also convenient is a 6124 item bibliography from NPG journals, with free links to many papers, including many JID articles, concerning psoriasis. The breadth of the supplement will be a handy starting point for those considering the many conundrums related to psoriasis.

From 4 January Science Magazine: “Crocs’ chaotic cracked cranial covering”

Understanding the patterns of normal skin and its appendages is a persistent concern in cutaneous biology. In mammalians, many patterns are attributed to reaction-diffusion mechanisms that determine interactions between the epidermis and dermis during embryogenesis.

By contrast, the scales of the Nile Crocodile’s head result from a different physical interaction between dermis and epidermis. The January 4, 2013 cover of Science features the eye and surrounding skin of a crocodile. Many polygonal scales with sharp borders reminiscent of stratum corneum scales are shown in the article’s supplementary material. The cracks are often incomplete, exhibit a relatively random pattern, and are nonoverlapping — and thus different from stratum corneum scales.

The cracks form and their patterns are fixed during embryonic life; they are confined to the head region, which grows more rapidly than the crocodile’s body. Its beta-keratin epidermis resists pressure from the growing dermis — until cracks form successively and then propagate.  The modal number of polygon scale edges reported was five, but the number of edges was distributed significantly.

The reddish-brown dots that often appear near the edges of scales are dome pressure receptors (DPR); connected to cutaneous nerves, they are not crossed by the epidermal cracks, and crocodiles use them to hunt in dark and murky waters. DPMs seem to constrain the cracking, and edges travel where DPR are least dense.

All scales are not created equal:  on the crocodile, at least, body scales  are similar to what is seen in the skin of mammals.  Those interested in skin patterns should read the article and determine whether if physical factors affect the genesis of the shapes they study.

Milinkovitch, MM el al Crocodile head scales are not developmental units but emerge from physical cracking Science: 339:78-81, 2013


Image used with permission (Trevor kelly/shutterstock.com)


For details, we refer you to the article “Research Techniques Made Simple:  COMPARATIVE EFFECTIVENESS RESEARCH” by Vinod E Nambudiri and Abrar Qureshi at http://www.jidonline.org.



1.  Study designs used for comparative effectiveness research include:

a) Systematic review

b) Randomized controlled trial

c) Cross sectional study

d) All of the above


2. Differences in survival between two treatment groups are best compared using which of the following statistical methods?

a) Paired t-test

b) Log-rank test


d) Fisher’s exact test


3. The intraclass correlation coefficent representing the best degree of agreement between two diagnostic tools among the following is:

a) ICC < 0.01

b) ICC = 0.05

c) ICC = 0.50

d) ICC = 0.95






1.  Study designs used for comparative effectiveness research include:

d) All of the above


2. Differences in survival between two treatment groups are best compared using which of the following statistical methods?

               b) Log-rank test


3. The intraclass correlation coefficent representing the best degree of agreement between two diagnostic tools among the following is:

               d) ICC = 0.95