Autologous cell-based therapy for male and female pattern hair loss using dermal sheath cup cells: A randomized placebo-controlled double-blinded dose-finding clinical study.

BACKGROUND: Few effective treatments are available for male pattern hair loss (MPHL) or, especially, for female pattern hair loss (FPHL). Recently, cell-based therapies using autologous or allogeneic cells have been used clinically. OBJECTIVE: We examined the safety and efficacy of autologous cell-based therapy using dermal sheath cup (DSC) cells to treat MPHL and FPHL. METHODS: DSCs dissected from occipital hair follicles were cultured to manufacture DSC cells. Participants with MPHL or FPHL received single injections of 7.5 × 106, 1.5 × 106, or 3.0 × 105 DSC cells or a placebo in 4 randomized separate regions on the scalp, and hair densities and diameters were measured for 3, 6, 9, and 12 months. RESULTS: Fifty men and 15 women aged 33 to 64 years were injected with DSC cells. Total hair density and cumulative hair diameter at the 3.0 × 105 DSC cells injection site was significantly increased compared with the placebo after 6 and 9 months. Men and women showed similar improvements, and there were no serious adverse events. LIMITATIONS: No lower cell numbers were tested, and the positive effect was temporary until 9 months. CONCLUSION: The results suggest that cell therapy with autologous DSC cells may be useful as a new therapeutic method for treating MPHL and FPHL.

Successful treatment of porocarcinoma with maxacalcitol and imiquimod.

This is the first report of a case of porocarcinoma that was successfully treated with maxacalcitol and imiquimod.

Gene Expression Profiling of the Intact Dermal Sheath Cup of Human Hair Follicles.

Cells that constitute the dermal papillae of hair follicles might be derived from the dermal sheath, the peribulbar component of which is the dermal sheath cup. The dermal sheath cup is thought to include the progenitor cells of the dermal papillae and possesses hair inductive potential; however, it has not yet been well characterized. This study investigated the gene expression profile of the intact dermal sheath cup, and identified dermal sheath cup signature genes, including extracellular matrix components and bone morphogenetic protein-binding molecules, as well as transforming frowth factor beta 1 as an upstream regulator. Among these, gremilin-2, a member of the bone morphogenetic protein antagonists, was found by in situ hybridization to be highly specific to the dermal sheath cup, implying that gremlin-2 is a key molecule contributing to maintenance of the properties of the dermal sheath cup.

High migratory activity of dermal sheath cup cells associated with the clinical efficacy of autologous cell-based therapy for pattern hair loss.

BACKGROUND: Autologous cell-based therapy using dermal sheath cup (DSC) cells was reported as a new treatment for male and female pattern hair loss. However, the mechanisms underlying its action remain unclear. OBJECTIVE: We investigated the mechanisms underlying the efficacy of DSC cells in cell-based therapy. METHODS: We conducted multivariate analysis to categorize individuals based on treatment response as responders and non-responders. The differentially expressed genes in DSC cells from the two groups were evaluated using bulk transcriptome, quantitative polymerase chain reaction, and single-cell transcriptome analyses. We performed live cell imaging combined with immunostaining to characterize the DSC subpopulation associated with responders. RESULTS: We identified nine and three genes as high efficacy (HE) and low efficacy (LE) marker genes, respectively. The HE subpopulations were enriched for cell migration-related genes in single-cell analysis. In contrast, the LE subpopulation was enriched for basement membrane and vasculature-related genes. Moreover, DSC cells in culture were immunocytochemically and morphologically heterogeneous, expressing characteristic factors. Furthermore, live cell imaging showed that DSC cells expressing integrin subunit alpha 6 (ITGA6), an HE subpopulation gene, had markedly higher mobility than those expressing the LE subpopulation genes collagen type IV or CD36. CONCLUSIONS: ITGA6-positive DSC cells, with superior migratory activity, may contribute to cell-based therapy by promoting cell migration into nearby hair follicles.

Universal acquired melanosis: carbon baby.

We report a 3-year-old boy born with light brown skin that progressively became much darker. The color change was insidious in onset at the age of 3 months, asymptomatic, and progressive involving the entire body surface. Hyperpigmentation may be congenital or acquired, hereditary or nonhereditary, localized or universal, of known or unknown origin. Universal acquired melanosis is a rare form of hyperpigmentation, which has been synonymously referred to as ''carbon baby.''

Efficacy of autologous dermal sheath cup cell transplantation in male and female pattern hair loss: A Single-Arm, Multi-Center, phase III equivalent clinical study.

A previous, proof-of-concept clinical study suggested that dermal sheath cup cell injections into the affected areas of male/female pattern hair loss (PHL) may have some amelioratory effects, the clinical efficacy of which needs further examination. A phase III equivalent clinical study was conducted to further probe the therapeutic potential of this novel approach and verify its safety and efficacy in improving the appearance of PHL. Thirty-six participants with PHL were injected with dermal sheath cup cell harvested from non-affected occipital hair follicles twice in quarterly intervals. Global photographic assessment and phototrichogram were performed in a blinded manner. Patient-reported outcomes were assessed for 12 months. On global photographic assessment, 30% of the participants showed improvement. The analysis of phototricogram data detected the increases in the cumulative hair diameter, hair cross-sectional area, and mean hair diameter of 107.6 ± 152.6 µm/cm2 , 13069.1 ± 10960.7 µm2 /cm2 , and 0.9 ± 0.9 µm (ratios vs. baseline: +1.4%, +3.4%, and +2.2%), respectively. The female and high terminal hair ratio groups achieved better improvement. Of the total participants, 62.9% noted some degree of improvement. No serious adverse events were detected. This novel approach exhibited visible effects while ensuring safety and patient satisfaction. Therefore, it holds promise as a possible therapeutic option for treating PHL, especially in women.

Mammary Paget's Disease Presenting as an Annular Plaque.

Dear Editor,Mammary Paget's disease (MPD) is an adenocarcinoma localized within the epidermis of the nipple and/or the areola of the breast, and it is as a rule associated with a carcinoma of the underlying lactiferous ducts, where it usually starts. MPD is relatively rare, observed in 0.7-4.3% of all breast cancers (1). We present a patient with MPD and atypical clinical finding as an annular plaque. A 74-year-old Japanese woman with a past medical history of hypothyroidism presented with a 6-month history of an itching plaque on the left areola. The patient had been treated with the application of topical steroids for a duration of approximately 5 months, and showed no clinical improvement. Physical examination showed a pink plaque encircling the nipple on the left areola (Figure 1, a). The right nipple and areola appeared normal (Figure 1, b). No palpable masses were detected within either breast. A 3.5 mm punch biopsy of the skin at the 6 o'clock position of the left areola was performed. Histological examination showed single and small aggregations of atypical cells with large hyperchromatic nuclei and pale-staining, ample cytoplasm throughout the epidermis. There was a lymphocytic infiltration in the dermis (Figure 1, c). Immunohistochemical studies were positive for CK7 and negative for S-100 and HMB45. With the diagnosis of MPD, the patient underwent a partial mastectomy of the left breast center area, consisting of surgical excision of the left nipple, the adjacent surrounding areolar skin, and subcutaneous tissues. Subsequently, radiation therapy for the residual breast was prepared. As has been described in detail by Kanitakis, the skin lesion develops insidiously as a scaly, fissured, or oozing erythema of the nipple and, more rarely, the areola. Advanced lesions present as a well-demarcated, round, ovoid, or polycyclic eczema-like plaque with a pink or red hue. It is occasionally slightly infiltrated and has an erosive, oozing, scaly, or crusted surface. The lesions are almost invariably unilateral, showing centrifugal spread. Retraction or ulceration of the nipple are often noted (1). The present case exhibited a very rare clinical finding of a plaque encircling the nipple, which has not been reported previously. It was initially difficult to establish the diagnosis of MPD, and biopsy was needed to obtain a definitive diagnosis. Differential diagnosis of MPD comprises eczema as atopic dermatitis or contact dermatitis, erosive adenomatosis, and malignant skin condition such as Bowen's disease, superficial basal cell carcinoma, or superficially spreading melanoma. As in the present case, individuals presenting with an annular plaque are often considered to have sebaceous hyperplasia. Sebaceous hyperplasia is a common, benign skin condition involving hypertrophy of the sebaceous glands, common in middle-aged or older adults (2). These lesions can be single or multiple and manifest as yellow, soft, small papules. These papules are occasionally seen around the nipple, forming an annular plaque. In general, sebaceous hyperplasia is described as yellow-colored papules among Caucasians. However, caution is needed, since it is characterized by skin-colored papules among some Asians.In the present case, some pigmentation (2 to 3 mm in diameter) was observed on the left nipple. Pigmented MPD have been reported, and the mechanism underlying the pigmentation is not yet fully understood, but it has been proposed that Paget cells may release melanocytic chemoattractants or basic fibroblast growth factors that stimulate the proliferation of melanocytes within the tumor nests (3). The possibility of physiological pigmentation cannot be ruled out in the present case; on the other hand, the possibility of pigmented MPD cannot be ruled out either, since no pigmentation was observed on the right nipple.

Hair follicle stem cell marker nestin expression in regenerating hair follicles of patients with alopecia areata.

Cells that are nestin positive and keratin 15 (K15) negative are located in the hair follicle pluripotent stem cell (hfPS) area (hfPSA). The hfPSA is located within the root of the sebaceous glands, in a region just above the hair follicle bulge area. In the current study, we investigated the expression pattern of the stem cell marker nestin in the hair follicle cycling of patients with alopecia areata. In the normal human scalp, the majority of hair follicles are in the anagen phase of development. While it is often difficult to identify nestin expression in late anagen phases, nestin-expressing cells are easily identified in proliferating cells located in the hfPSA of the growing early and middle anagen phase hair follicles. In patients exhibiting alopecia areata, the middle anagen hair follicles with growing cells were found to be nestin positive and K15 negative. In contrast, the hair follicles undergoing degradation in alopecia areata patients demonstrated lymphocytic infiltration within the nestin- and K15-negative dermal papilla cells. Both the nestin-positive hfPSA and K15-positive hair follicle bulge areas were not damaged in all phases. In addition, the regenerating early anagen hair follicles demonstrated nestin-positive and K15-negative cells within the dermal papilla and in the area surrounding the hair bulb. These results suggest that the nestin-positive cells play an important role not only in the hfPSA, but also in the dermal papilla in the regenerating hair follicle.

The Review of the Difference between Patients and Physicians in Terms of Severity Assessment and Therapeutic Goals in Androgenetic Alopecia in Japan.

We often come across differences in the severity of androgenetic alopecia (AGA) as assessed subjectively by the patients themselves and objectively by the attending physicians. For the purpose of examining the differences in the assessment of AGA between patients and physicians, we presented the Norwood classification to male patients and the Shiseido classification to female patients and asked them to assess the degree of hair loss by themselves. We compared the results with the severity as assessed by 2 specified dermatologists. The results show that the assessments of the severity of AGA were consistent between the patients and physicians in 42% (15/36) of cases, the physicians reported a higher grade of severity than the patients themselves in 30% (11/36) of cases, and the patients reported a higher grade of severity than the physicians in 28% (10/36) of cases; however, the Wilcoxon signed rank statistical analysis showed no significant difference between the patients and physicians assessments. AGA should be treated in accordance with individual symptoms and wishes and not a standardized treatment protocol.

Eosinophilic Vulvar Leukoderma.

We report the case of a 54-year-old woman with asthma and atopic dermatitis who presented a white spot on the genitalia. Histologic examination showed numerous eosinophils in the epithelium and the dermis. Eosinophilic esophagitis is defined as an esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation. We discuss the possible relationship between the two diseases.

Th2 immune response plays a critical role in the development of nickel-induced allergic contact dermatitis.

BACKGROUND: The precise roles of T helper (Th)1-type and Th2-type cytokine responses in nickel (Ni)-induced allergic contact dermatitis have not yet been clearly defined. We investigated the involvement of Th2 cytokines in Ni-induced contact hypersensitivity reaction using GATA-3 transgenic (Tg) mice. METHODS: A Ni-titanium (Ti) alloy was implanted under the skin of GATA-3 Tg mice. A Ni solution was then injected 1 month after sensitization. The ear swelling response was measured at several time points after the injection; the cytokine levels in the skin were measured at 48 h after injection, and the serum levels of IgE were measured 1 month after injection. In addition, purified CD4+ splenic cells obtained from the GATA-3 Tg mice sensitized with the Ni-Ti alloy were infused into Rag-2(-/-) mice, and the ear swelling response of these mice after a further challenge with Ni solution was also measured. RESULTS: Marked ear swelling and elevated serum IgE levels and skin tissue levels of IL-4 were observed in Ni-Ti-sensitized GATA-3 Tg mice. The Rag-2(-/-) mice transfused with the CD4+ splenic cells from the Ni-Ti alloy sensitized GATA-3 Tg mice showed a significantly more pronounced ear swelling response than the control mice. CONCLUSION: We confirmed the participation of Th2-type immune reactions in Ni-induced allergy using GATA-3 Tg mice.

Eosinophilic gastroenteritis associated with giant folds.

We describe a 54-year-old man who presented with right subcostal pain. Minocycline had been prescribed to treat pruritus, and the symptoms resolved. Subsequently, the patient consulted a local physician because of right subcostal pain. Giant folds were found in the greater curvature of the gastric body, and he was referred to the Department of Gastroenterology, Kitasato University East Hospital. Upper gastrointestinal endoscopy revealed markedly enlarged folds in the greater curvature of the stomach, with redness and edematous mucosa in the lesser curvature. Biopsy showed marked inflammatory cell infiltration (mainly eosinophils), but no atypical cells. Blood tests showed marked eosinophilia and elevated immunoglobulin E levels in the serum. The results of various allergic examinations were negative, but the clinical course suggested drug-induced eosinophilic gastroenteritis, and treatment was started. Minocycline was withdrawn without adequate resolution of symptoms. Because the leukocyte and eosinophil counts continued to increase, the patient was given suplatast, an anti-allergic agent. The symptoms and hematological values improved promptly. The patient recovered uneventfully, with no recurrence.

Linear scleroderma after contusion and injection of mepivacaine hydrochloride.

A 36-year-old woman initially was treated for a contusion by local injection of mepivacaine hydrochloride into the left dorsum of the foot. Approximately 3 months after the injury and injection, linear sclerotic plaques originating from the site of contusion and injection were recognized. These progressed in extent and severity over a period of 3 years, when she presented to our clinic. By biopsy, swelling of collagen fibers in the lower dermis was revealed and the condition was diagnosed as linear scleroderma. Our present case had multiple linear sclerotic plaques of the left lower extremity, the distribution of which was consistent with Blaschko lines. It was also revealed that the initial sclerotic plaque was at the site of the contusion and local mepivacaine hydrochloride injection. Our present case is interesting in that the findings suggest a correlation between linear scleroderma plaque occurrence and the contusion or injection of mepivacaine.

Human hair follicle pluripotent stem (hfPS) cells promote regeneration of peripheral-nerve injury: an advantageous alternative to ES and iPS cells.

The optimal source of stem cells for regenerative medicine is a major question. Embryonic stem (ES) cells have shown promise for pluripotency but have ethical issues and potential to form teratomas. Pluripotent stem cells have been produced from skin cells by either viral-, plasmid- or transposon-mediated gene transfer. These stem cells have been termed induced pluripotent stem cells or iPS cells. iPS cells may also have malignant potential and are inefficiently produced. Embryonic stem cells may not be suited for individualized therapy, since they can undergo immunologic rejection. To address these fundamental problems, our group is developing hair follicle pluripotent stem (hfPS) cells. Our previous studies have shown that mouse hfPS cells can differentiate to neurons, glial cells in vitro, and other cell types, and can promote nerve and spinal cord regeneration in vivo. hfPS cells are located above the hair follicle bulge in what we have termed the hfPS cell area (hfPSA) and are nestin positive and keratin 15 (K-15) negative. Human hfPS cells can also differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In the present study, human hfPS cells were transplanted in the severed sciatic nerve of the mouse where they differentiated into glial fibrillary-acidic-protein (GFAP)-positive Schwann cells and promoted the recovery of pre-existing axons, leading to nerve generation. The regenerated nerve recovered function and, upon electrical stimulation, contracted the gastrocnemius muscle. The hfPS cells can be readily isolated from the human scalp, thereby providing an accessible, autologous and safe source of stem cells for regenerative medicine that have important advantages over ES or iPS cells.