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Concept: Dermis

169

The mammalian hair follicle arises during embryonic development from coordinated interactions between the epidermis and dermis. It is currently unclear how to recapitulate hair follicle induction in pluripotent stem cell cultures for use in basic research studies or in vitro drug testing. To date, generation of hair follicles in vitro has only been possible using primary cells isolated from embryonic skin, cultured alone or in a co-culture with stem cell-derived cells, combined with in vivo transplantation. Here, we describe the derivation of skin organoids, constituting epidermal and dermal layers, from a homogeneous population of mouse pluripotent stem cells in a 3D culture. We show that skin organoids spontaneously produce de novo hair follicles in a process that mimics normal embryonic hair folliculogenesis. This in vitro model of skin development will be useful for studying mechanisms of hair follicle induction, evaluating hair growth or inhibitory drugs, and modeling skin diseases.

Concepts: Developmental biology, Stem cell, Stem cells, Cell biology, Skin, Induced pluripotent stem cell, Pluripotency, Dermis

169

BACKGROUND: Estrogen has been reported to accelerate cutaneous wound healing. This research studies the effect of young coconut juice (YCJ), presumably containing estrogen-like substances, on cutaneous wound healing in ovairectomized rats. METHODS: Four groups of female rats (6 in each group) were included in this study. These included sham-operated, ovariectomized (ovx), ovx receiving estradiol benzoate (EB) injections intraperitoneally, and ovx receiving YCJ orally. Two equidistant 1-cm full-thickness skin incisional wounds were made two weeks after ovariectomy. The rats were sacrificed at the end of the third and the fourth week of the study, and their serum estradiol (E2) level was measured by chemiluminescent immunoassay. The skin was excised and examined in histological sections stained with H&E, and immunostained using anti-estrogen receptor (ER-alpha an ER-beta) antibodies. RESULTS: Wound healing was accelerated in ovx rats receiving YCJ, as compared to controls. This was associated with significantly higher density of immunostaining for ER-alpha an ER-beta in keratinocytes, fibroblasts, white blood cells, fat cells, sebaceous gland, skeletal muscles, and hair shafts and follicles. This was also associated with thicker epidermis and dermis, but with thinner hypodermis. In addition, the number and size of immunoreactive hair follicles for both ER-alpha and ER-beta were the highest in the ovx+YCJ group, as compared to the ovx+EB group. CONCLUSIONS: This study demonstrates that YCJ has estrogen-like characteristics, which in turn seem to have beneficial effects on cutaneous wound healing.

Concepts: Wound healing, Healing, Estradiol, Skin, Dermis, Epidermis, Sebaceous gland, Coconut water

167

The objective of this study was to prepare a suitable formulation for dermal delivery of diflucortolone valerate (DFV) that would maintain the localization in skin layers without any penetration and to optimize efficiency of DFV. Drug-loaded lecithin/chitosan nanoparticles with high entrapment efficiency (86.8%), were successfully prepared by ionic interaction technique. Sustained release of DFV was achieved without any initial burst release. Nanoparticles were also incorporated into chitosan gel at different ratios for preparing a more suitable formulation for topical drug delivery with adequate viscosity. In ex-vivo permeation studies, nanoparticles increased the accumulation of DFV especially in the stratum corneum + epidermis of rat skin without any significant permeation. Retention of DFV from nanoparticle in chitosan gel formulation (0.01%) was twofold higher than commercial cream, although it contained ten times less DFV. Nanoparticles in gel formulations produced significantly higher edema inhibition in rats compared with commercial cream in in-vivo studies. Skin blanching assay using a chromameter showed vasoconstriction similar to that of the commercial product. There were no barrier function changes upon application of nanoparticles. In-vitro and in-vivo results demonstrated that lecithin/chitosan nanoparticles in chitosan gel may be a promising carrier for dermal delivery of DFV in various skin disorders.

Concepts: Colloid, Skin, Topical, Dermis, Epidermis, Keratin, Stratum corneum, Topical steroid

145

Myopericytoma is a soft tissue tumor with perivascular myoid differentiation. It accounts for 1% of the vascular tumors and involves mostly cutaneous or subcutaneous tissue of the limbs in adults. Malignant myopericytoma is exceedingly rare. A 15-year old girl presented with slowly progressive mass over left shoulder region. Histopathology and immunohistochemistry after complete excision revealed it as malignant myopericytoma.

Concepts: Cancer, Oncology, Soft tissue sarcoma, Anatomical pathology, Histology, Neoplasm, Tissue, Dermis

121

Two main Dirofilaria species infect dogs: D. immitis and D. repens. While D. immitis has a worldwide distribution, D. repens is currently found only in Europe, Asia, and Africa. Adult D. repens are located in subcutaneous tissues of natural hosts where they survive for long periods of time. First-stage larvae, microfilariae, circulate in the peripheral bloodstream, where they are taken up by the mosquito intermediate hosts. Infected mosquitoes then transmit infective third-stage (L3) larvae to new hosts through the blood meal. In dogs, most infections are asymptomatic, although cutaneous disorders such as pruritus, dermal swelling, subcutaneous nodules, and ocular conjunctivitis can be observed. Currently, two factors have increased the concerns about this parasitic infection 1) its spread throughout the European countries and to other continents and its prevalence in dog populations, where in some cases it has overcome D. immitis; and 2) its zoonotic potential, which is much greater than that of D. immitis.

Concepts: Immune system, Inflammation, Infection, Mosquito, Transmission and infection of H5N1, Europe, Asia, Dermis

46

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8(+) Trm cells on a compartmental and functional basis. In human skin epithelia, CD8(+)CD49a(+) Trm cells produced interferon-γ, whereas CD8(+)CD49a(-) Trm cells produced interleukin-17 (IL-17). In addition, CD8(+)CD49a(+) Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8(+)CD49a(+) Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8(+)CD49a(-) Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8(+) Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.

Concepts: DNA, Gene expression, Cell, Epithelium, Natural killer cell, Skin, Dermis, Epidermis

43

Here we describe a new mouse model that exploits the pattern of expression of the high-affinity IgG receptor (CD64) and allows diphtheria toxin (DT)-mediated ablation of tissue-resident macrophages and monocyte-derived cells. We found that the myeloid cells of the ear skin dermis are dominated by DT-sensitive, melanin-laden cells that have been missed in previous studies and correspond to macrophages that have ingested melanosomes from neighboring melanocytes. Those cells have been referred to as melanophages in humans. We also identified melanophages in melanocytic melanoma. Benefiting of our knowledge on melanophage dynamics, we determined the identity, origin, and dynamics of the skin myeloid cells that capture and retain tattoo pigment particles. We showed that they are exclusively made of dermal macrophages. Using the possibility to delete them, we further demonstrated that tattoo pigment particles can undergo successive cycles of capture-release-recapture without any tattoo vanishing. Therefore, congruent with dermal macrophage dynamics, long-term tattoo persistence likely relies on macrophage renewal rather than on macrophage longevity.

Concepts: Immune system, Protein, Skin, Melanin, Ear, Dermis, Epidermis, Melanocyte

39

Caloric restriction (CR) is the most effective intervention known to enhance lifespan, but its effect on the skin is poorly understood. Here, we show that CR mice display fur coat remodeling associated with an expansion of the hair follicle stem cell (HFSC) pool. We also find that the dermal adipocyte depot (dWAT) is underdeveloped in CR animals. The dermal/vennule annulus vasculature is enlarged, and a vascular endothelial growth factor (VEGF) switch and metabolic reprogramming in both the dermis and the epidermis are observed. When the fur coat is removed, CR mice display increased energy expenditure associated with lean weight loss and locomotion impairment. Our findings indicate that CR promotes extensive skin and fur remodeling. These changes are necessary for thermal homeostasis and metabolic fitness under conditions of limited energy intake, suggesting a potential adaptive mechanism.

Concepts: Angiogenesis, Vascular endothelial growth factor, Skin, Knowledge, Dermis, Epidermis, Skin anatomy, Fur

28

Objectives: Allergic reactions to Prolene are rare. This paper reports a nasal tip abscess which developed in a patient with an adverse skin reaction to Prolene after rhinoplasty. Methods and results: A 26-year-old woman presented with painful, progressive nasal tip swelling and redness. She had undergone septo-rhinoplasty two years previously. She was initially treated with endonasal drainage of the abscess and antibiotics, but a revision rhinoplasty three months later became necessary because of recurrent abscess formation. Intra-operative findings included granulation tissue with pockets of pus and knotted Prolene sutures at the tip-defining points of the lower lateral cartilages. She was patch-tested with Prolene and a cutaneous Prolene suture was placed on her back; an adverse skin reaction was seen for the latter. Conclusion: Use of non-absorbable sutures, such as Prolene, in the subcutaneous layer may be a potential, rare risk factor for adverse skin reactions.

Concepts: Collagen, Allergy, Skin, Tissue, Term, Nose, Surgical suture, Dermis

28

OBJECTIVE: To describe a tenosynoviotomy technique for treatment of sepsis of the digital flexor tendon sheath (DFTS) in horses and report long-term outcome. STUDY DESIGN: Case series. ANIMALS: Horses (n = 9). METHODS: Horses were positioned in lateral recumbency with the affected limb uppermost. A linear incision was made just lateral to the mesotenon beginning 5 cm proximal to the apices of the proximal sesamoid bones, extending 2 cm distal to the bifurcation of the superficial digital flexor tendon (SDFT). The incision was continued through the skin, subcutaneous tissue, palmar/plantar annular ligament, and DFTS. Tenotomy of the distal lateral branch of the SDFT was also performed. The site was thoroughly debrided, lavaged, and packed with gauze and allowed to heal by second intention. Follow-up was obtained via owner telephone interview. RESULTS: Mean surgery time was 32 minutes (range, 10-64 minutes). Systemic antibiotics were administered postoperatively (range, 11-46 days; mean, 23 days). Mean hospitalization was 11 days (range, 0-49 days). Follow-up was available for 7 (70%) horses. One year postoperatively, 5 (71%) horses were serviceable for their intended use, and 2 (29%) had been euthanatized. Of 5 survivors, 3 returned to ridden exercise, 1 was retired as a broodmare, and 1 was a broodmare. All owners were satisfied with the cosmetic appearance of the surgery site. CONCLUSION: Open drainage via tenosynoviotomy, performed as a salvage procedure, represents a feasible treatment for DFTS sepsis.

Concepts: Bacteria, Skin, Dermis, Ligament, Tendon, Subcutaneous tissue, Common flexor tendon, Sesamoid bone