Hair-follicle associated pluripotent (HAP)-cell-sheet implantation enhanced wound healing in diabetic db/db mice.

Diabetes often results in chronic ulcers that fail to heal. Effective treatment for diabetic wounds has not been achieved, although stem-cell-treatment has shown promise. Hair-follicle-associated-pluripotent (HAP)-stem-cells from bulge area of mouse hair follicle have been shown to differentiate into keratinocytes, vascular endothelial cells, smooth muscle cells, and some other types of cells. In the present study, we developed HAP-cell-sheets to determine their effects on wound healing in type-2 diabetes mellitus (db/db) C57BL/6 mouse model. Flow cytometry analysis showed cytokeratin 15 expression in 64% of cells and macrophage expression in 3.6% of cells in HAP-cell-sheets. A scratch cell migration assay in vitro showed the ability of fibroblasts to migrate and proliferate was enhanced when co-cultured with HAP-cell-sheets. To investigate in vivo effects of the HAP-cell-sheets, they were implanted into 10 mm circular full-thickness resection wounds made on the back of db/db mice. Wound closure was facilitated in the implanted group until day 16. The thickness of epithelium and granulation tissue volume at day 7 were significantly increased by the implantation. CD68 positive area and TGF-ß1 positive area were significantly increased; meanwhile, iNOS positive area was reduced at day 7 in the HAP-cell-sheets implanted group. After 21 days, CD68 positive areas in the implanted group were reduced to under the control group level, and TGF-ß1 positive area had no difference between the two groups. These observations strongly suggest that the HAP-cell-sheets implantation is efficient to facilitate early macrophage activity and to suppress inflammation level. Using immuno-double-staining against CD34 and α-SMA, we found more vigorous angiogenesis in the implanted wound tissue. The present results suggest autologous HAP-cell-sheets can be used to heal refractory diabetic ulcers and have clinical promise.

A case of AA amyloidosis complicated by proliferating pilomatricoma and a review of the literature.

Although AA amyloidosis is primarily caused by inflammatory conditions, associations between AA amyloidosis and solid cancers have occasionally been described. Herein, we report the case of a 48-year-old man in whom resection of a proliferating pilomatricoma with deposition of AA amyloid resulted in remission of concomitant AA gastrointestinal amyloidosis. A rapidly growing, giant, reddish, ulcerated tumor measuring 16 × 13 cm in size was identified on the upper left arm on a visit to our hospital. Gastrointestinal AA amyloidosis was diagnosed from colorectal mucosal biopsy at the same time, and weight loss and profuse diarrhea were clinically evident. As treatment, the tumor was resected with a 10-mm surgical margin. Histologically, the tumor predominantly comprised a lobular proliferation of basophilic cells peripherally, filled with eosinophilic, cornified material and shadow cells with mitoses observed in basophilic cells. Specimens revealed eosinophilic, homogeneous deposits around tumor nests, which were confirmed as amyloid deposits by positive staining with Congo red stain. These deposits were immunohistochemically positive on staining with anti-serum amyloid A antibody. Collectively, proliferating pilomatricoma with AA amyloidosis was diagnosed. After tumor resection, chronic diarrhea resolved and no amyloid deposition was apparent in colorectal biopsy. It is important to remember that if amyloid deposition is present in a tumor, aggressive tumor excision may alleviate systemic amyloidosis.

Rat hair-follicle-associated pluripotent (HAP) stem cells can differentiate into atrial or ventricular cardiomyocytes in culture controlled by specific supplementation.

There has been only limited success to differentiate adult stem cells into cardiomyocyte subtypes. In the present study, we have successfully induced beating atrial and ventricular cardiomyocytes from rat hair-follicle-associated pluripotent (HAP) stem cells, which are adult stem cells located in the bulge area. HAP stem cells differentiated into atrial cardiomyocytes in culture with the combination of isoproterenol, activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF), and cyclosporine A (CSA). HAP stem cells differentiated into ventricular cardiomyocytes in culture with the combination of activin A, BMP4, bFGF, inhibitor of Wnt production-4 (IWP4), and vascular endothelial growth factor (VEGF). Differentiated atrial cardiomyocytes were specifically stained for anti-myosin light chain 2a (MLC2a) antibody. Ventricular cardiomyocytes were specially stained for anti-myosin light chain 2v (MLC2v) antibody. Quantitative Polymerase Chain Reaction (qPCR) showed significant expression of MLC2a in atrial cardiomyocytes and MLC2v in ventricular cardiomyocytes. Both differentiated atrial and ventricular cardiomyocytes showed characteristic waveforms in Ca2+ imaging. Differentiated atrial and ventricular cardiomyocytes formed long myocardial fibers and beat as a functional syncytium, having a structure similar to adult cardiomyocytes. The present results demonstrated that it is possible to induce cardiomyocyte subtypes, atrial and ventricular cardiomyocytes, from HAP stem cells.

Direct implantation of hair-follicle-associated pluripotent (HAP) stem cells repairs intracerebral hemorrhage and reduces neuroinflammation in mouse model.

Intracerebral hemorrhage (ICH) is a leading cause of mortality with ineffective treatment. Hair-follicle-associated pluripotent (HAP) stem cells can differentiate into neurons, glial cells and many other types of cells. HAP stem cells have been shown to repair peripheral-nerve and spinal-cord injury in mouse models. In the present study, HAP stem cells from C57BL/6J mice were implanted into the injured brain of C57BL/6J or nude mice with induced ICH. After allo transplantation, HAP stem cells differentiated to neurons, astrocytes, oligodendrocytes, and microglia in the ICH site of nude mice. After autologous transplantation in C57BL/6J mice, HAP stem cells suppressed astrocyte and microglia infiltration in the injured brain. The mRNA expression levels of IL-10 and TGF-ß1, measured by quantitative Real-Time RT-PCR, in the brain of C57BL/6J mice with ICH was increased by HAP-stem-cell implantation compared to the non-implanted mice. Quantitative sensorimotor function analysis, with modified limb-placing test and the cylinder test, demonstrated a significant functional improvement in the HAP-stem-cell-implanted C57BL/6J mice, compared to non-implanted mice. HAP stem cells have critical advantages over induced pluripotent stem cells, embryonic stem cells as they do not develop tumors, are autologous, and do not require genetic manipulation. The present study demonstrates future clinical potential of HAP-stem-cell repair of ICH, currently a recalcitrant disease.

Hair follicle associated pluripotent (HAP) stem cells jump from transplanted whiskers to pelage follicles and stimulate hair growth.

Stimulation of hair growth in hair loss has been a difficult goal to achieve. Hair follicle-associated pluripotent (HAP) stem cells express nestin and have been shown to differentiate to multiple cell types including keratinocytes, neurons, beating cardiac muscles and numerous other cell types. HAP stem cells originate in the bulge area of the hair follicle and have been shown to migrate within and outside the hair follicle. In the present study, the upper part of vibrissa follicles from nestin-driven green-fluorescent protein (GFP) transgenic mice, containing GFP-expressing HAP stem cells, were transplanted in the dorsal area of athymic nude mice. Fluorescence microscopy and immunostaining showed the transplanted HAP stem cells jumped and targeted the bulge and hair bulb and other areas of the resident nude mouse pelage follicles where they differentiated to keratinocytes. These results indicate that transplanted nestin-GFP expressing HAP stem cells jumped from the upper part of the whisker follicles and targeted nude-mouse hair follicles, which are genetically deficient to grow normal hair shafts, and differentiated to keratinocytes to produce normal mature hair shafts. The resident nude-mouse pelage follicles targeted by jumping whisker HAP stem cells produced long hair shafts from numerous hair follicles for least 2 hair cycles during 36 days, demonstrations that HAP stem cells can stimulate hair growth. The present results for hair loss therapy are discussed.

Hair-follicle-associated pluripotent (HAP) stem cells differentiate into mature beating cardiomyocyte sheets on flexible substrates in vitro.

Cardiomyocytes have been differentiated from various stem cells such as human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), but it is difficult to produce mature cardiomyocytes. We showed rat hair-follicle-associated pluripotent (HAP) stem cells have pluripotency and produced mature beating cardiomyocyte sheets differentiated from rat HAP stem cells. The upper parts of rat vibrissa hair follicles were cultured in 10% FBS DMEM and stained with antibodies of the ectoderm, mesoderm, endoderm system to show the differentiation of multiple cell types. Moreover, HAP stem cells were cultured under three different conditions to decide the most suitable culture conditions for making beating cardiomyocyte sheets. The beating cardiomyocyte sheets were shown to be mature by staining sarcomere structures. Isoproterenol alone and the combination of isoproterenol, activin A, bone morphogenetic protein 4 (BMP4) and basic fibroblast growth factor (bFGF) effectively induced beating long-fiber cardiomyocytes, which formed beating sheets, only in the presence of all four agents. Flexible substrates were essential for the differentiation of sheets of mature beating cardiomyocytes for HAP stem cells. The features of the cardiomyocytes differentiated from HAP stem cells demonstrate they have clinical potential for heart regeneration.

Chronic spinal cord injury functionally repaired by direct implantation of encapsulated hair-follicle-associated pluripotent (HAP) stem cells in a mouse model: Potential for clinical regenerative medicine.

Chronic spinal cord injury (SCI) is a highly debilitating and recalcitrant disease with limited treatment options. Although various stem cell types have shown some clinical efficacy for injury repair they have not for SCI. Hair-follicle-associated pluripotent (HAP) stem cells have been shown to differentiate into neurons, Schwan cells, beating cardiomyocytes and many other type of cells, and have effectively regenerated acute spinal cord injury in mouse models. In the present report, HAP stem cells from C57BL/6J mice, encapsulated in polyvinylidene fluoride membranes (PFM), were implanted into the severed thoracic spinal cord of C57BL/6J or athymic nude mice in the early chronic phase. After implantation, HAP stem cells differentiated to neurons, astrocytes and oligodendrocytes in the regenerated thoracic spinal cord of C57BL/6J and nude mice. Quantitative motor function analysis, with the Basso Mouse Scale for Locomotion (BMS) score, demonstrated a significant functional improvement in the HAP-stem-cell-implanted mice, compared to non-implanted mice. HAP stem cells have critical advantages over other stem cells: they do not develop teratomas; do not loose differentiation ability when cryopreserved and thus are bankable; are autologous, readily obtained from anyone; and do not require genetic manipulation. HAP stem cells therefore have greater clinical potential for SCI repair than induced pluripotent stem cells (iPSCs), neuronal stem cells (NSCs)/neural progenitor cells (NPCs) or embryonic stem cells (ESCs). The present report demonstrates future clinical potential of HAP-stem-cell repair of chronic spinal cord injury, currently a recalcitrant disease.

Hair-Follicle-Associated Pluripotent (HAP) Stem Cells Can Extensively Differentiate to Tyrosine-Hydroxylase-Expressing Dopamine-Secreting Neurons.

Hair-follicle-associated pluripotent (HAP) stem cells are located in the bulge area of hair follicles from mice and humans and have been shown to differentiate to neurons, glia, keratinocytes, smooth muscle cells, melanocytes and beating cardiac muscle cells in vitro. Subsequently, we demonstrated that HAP stem cells could effect nerve and spinal-cord regeneration in mouse models, differentiating to Schwann cells and neurons in this process. HAP stem cells can be banked by cryopreservation and preserve their ability to differentiate. In the present study, we demonstrated that mouse HAP stem cells cultured in neural-induction medium can extensively differentiate to dopaminergic neurons, which express tyrosine hydroxylase and secrete dopamine. These results indicate that the dopaminergic neurons differentiated from HAP stem cells may be useful in the future to improve the symptoms of Parkinson's disease in the clinic.

Cholesterol crystal embolism-related cerebral infarction: Magnetic resonance imaging and clinical characteristics.

BACKGROUND AND AIMS: Cholesterol crystal embolism-related cerebral infarction (CCE-CI) is frequently misdiagnosed due to the lack of specific symptoms. To aid in differential diagnosis, this study comprehensively characterized the magnetic resonance imaging (MRI) and clinical manifestations of CCE-CI and compared these features to those of atherothrombotic cerebral infarction (ACI). METHODS: This single-center, retrospective, observational study was conducted at Kitasato University Hospital, Kanagawa, Japan. We identified 37 clinically or histopathologically confirmed CCE-CI cases and 110 ACI cases treated from January 2006 to May 2020. Groups were compared for mean age, sex ratio, clinical presentations, imaging manifestations, precipitating factors, comorbid conditions, medications, and smoking history. RESULTS: Of 37 eligible patients with CCE-CI, 10 (27.0%) received brain MRI, of which 8 (21.6%) exhibited high-intensity signals indicative of brain lesions on diffusion-weighted imaging (DWI). However, two patients with DWI lesions exhibited no detectable neurological abnormalities. Patients with CCE-CI frequently demonstrated bilateral DWI lesions involving the bilateral anterior and posterior circulation, a pattern absent in ACI (50% vs. 0%, p < 0.001). Compared to patients with ACI, CCE-CI patients also demonstrated significantly lower estimated glomerular filtration rate (p < 0.001) as well as more frequent eosinophilia (p = 0.006), atherosclerotic plaques ≥4-mm thick in the ascending aorta or proximal arch (p = 0.001), and aortic aneurysm (p < 0.001). CONCLUSIONS: Patients with CCE-CI develop multiple DWI lesions across several vascular territories, even in the absence of neurological symptoms. Comorbid aortic aneurysm may increase CCE-CI risk. These findings could help in the differential diagnosis of CCE-CI.

Gray-edged line sign of scabies burrow.

A scabies burrow is created by a mature female mite laying eggs through the stratum corneum, representing a kind of scabies eruption. We have noticed that the edges of the scabies burrow sometime appear as blackish-gray lines. We named these lines the "gray-edged line" sign, as a new feature of scabies burrows. The gray-edged line sign has the following two tendencies: (i) it is rarely seen on the palm or sole; and (ii) when the burrow follows a curved course, the gray-edged line often forms on the outer wall. Explaining the formation of this sign from clinical findings was difficult, so the aim of the present study was to elucidate the mechanisms underlying the gray-edged line sign. This retrospective study involved collection of data from electronic medical records of patients treated for scabies in our department between April 2015 and February 2020. We treated 32 scabies patients, including 4 patients with the gray-edged line sign. We analyzed clinical features, dermoscopy, histopathology and special stains. Fontana-Masson staining showed melanin staining in three parts: feces; some keratinocytes around the scabies burrows; and the mouth and legs of the scabies mite. The gray-edged line sign appears to represent mite feces containing melanin.

Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-ß Signaling in Angiosarcoma.

Angiosarcoma is a rare malignant tumor derived from endothelial cells, and its prognosis is poor because advanced angiosarcoma is often resistant to taxane therapy. Endoglin (CD105) acts as a coreceptor for TGF-ß signaling and is overexpressed in tumor-associated endothelial cells and enhances tumor angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibodies in various types of malignancies. Here, we investigated the role of endoglin in the pathogenesis of angiosarcoma and whether endoglin inhibition results in antitumor activity. Endoglin was overexpressed in angiosarcoma, and its inhibition was effective in promoting apoptosis and the suppression of migration, invasion, tube formation, and Warburg effect in angiosarcoma cells. Knockdown of endoglin activated caspase 3/7 that is essential for apoptosis, reduced survivin levels, and decreased paxillin and vascular endothelial cadherin phosphorylation and matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-ß signaling, the antitumor effect of endoglin in angiosarcoma was not based on Smad signaling regulation but on non-Smad TGF-ß signaling. Taken together, these results indicated that endoglin could be a novel therapeutic target for angiosarcoma.

Case of Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, Presenting With Intravascular Localization of Tumor Cells in Skin Biopsies From Both Plaque and Normal-Appearing Skin: A Case Report and Literature Review.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT), is a rare subtype of non-Hodgkin lymphoma associated with Epstein-Barr virus. This type of lymphoma is rare in Western countries but is more frequent in East Asia and Latin America. ENKTL-NT mostly occurs in the nose and paranasal area, including the upper aerodigestive tract. The skin is the second-most commonly involved organ. ENKTL-ET is characterized by an angiocentric, angiodestructive pattern of growth with ulceration and necrosis evident on histopathological examination. We provide the first description of ENKTL-NT presenting with intravascular localization of tumor cells in skin biopsies from both plaque and normal-appearing skin. Random skin biopsy might thus be useful for early diagnosis, staging, and estimation of prognosis in ENKTL-NT. Moreover, the current case indicates that ENKTL-NT and intravascular natural killer/T-cell lymphoma may represent related diseases.

Expression of anti-aging type-XVII collagen (COL17A1/BP180) in hair follicle-associated pluripotent (HAP) stem cells during differentiation.

Hair-follicle-associated pluripotent (HAP) stem cells reside in the upper part of the bulge area of the the hair follicle. HAP stem cells are nestin-positive and keratin 15-negative and have the capacity to differentiate into various types of cells in vitro. HAP stem cells are also involved in nerve and spinal cord regeneration in mouse models. Recently, it was shown that the DNA-damage response in non-HAP hair follicle stem cells induces proteolysis of type-XVII collagen (COL17A1/BP180), which is involved in hair-follicle stem-cell maintenance. COL17A1 proteolysis stimulated hair-follicle stem-cell aging, characterized by the loss of stemness signatures and hair-follicle miniaturization associated with androgenic alopecia. In the present study, we demonstrate that HAP stem cells co-express nestin and COL17A1 in vitro and in vivo. The expression of HAP stem cell markers (nestin and SSEA1) increased after HAP stem-cell colonies were formed, then decreased after differentiation to epidermal keratinocytes. In contrast COL17A1 increased after differentiation to epidermal keratinocytes. These results suggest that COL17A1 is important in differentiation of HAP stem cells.

A potential significance of circ_0024169 down regulation in angiosarcoma tissue.

Circular RNAs (circRNAs) are recently characterized non-coding RNAs that have a closed continuous loop. CircRNAs might play important roles in the oncogenesis of several cancers. However, little is known about association between circRNAs and skin tumors. In this study, we tried to demonstrate the expression change of circ_0024169 in angiosarcoma, and to elucidate correlations between circ_0024169 expression in angiosarcoma tissues and clinical manifestation. RNA expression was evaluated by quantitative real-time PCR with TaqMan systems for circ_0024169 and linear isoform CUL5. Both relative circRNA levels (corrected for EEF1A1 levels) and circRNA levels/linear RNA expression ratio were evaluated. We found that both relative circ_0024169 levels and circ_0024169/CUL5 ratio was decreased in normal human dermal microvascular endothelial cells (HDMEC) and angiosarcoma cell line in vitro, compared to squamous cell carcinoma line. circ_0024169/ CUL5 ratio was significantly reduced in angiosarcoma and pyogenic granuloma than other tumors in vivo, which were more evident than decreased relative circ_0024169 levels. On the other hand, relative circ_0024169 levels showed mild inverse correlation with the follow-up periods (duration between the first hospital visit and the last hospital visit/the date of death) of angiosarcoma patients. Taken together, circ_0024169/CUL5 ratio are likely to be useful as a diagnostic biomarker for vascular tumors, whereas circ_0024169 levels may have more potential as a prognostic marker of angiosarcoma. The future studies of the function of circRNAs may lead to the clarification of detailed mechanism of oncogenesis of angiosarcoma.

Hair-follicle-associated pluripotent stem cells derived from cryopreserved intact human hair follicles sustain multilineage differentiation potential.

The bulge area of the hair follicle contains hair-follicle-associated pluripotent (HAP) stem cells. Here, we present effective cryopreservation procedures of the human hair follicle that preserve the differentiation potential of HAP stem cells. Whole hair follicles isolated from human scalp were cryopreserved by a slow-rate cooling medium and stored in liquid nitrogen. A careful thawing method was used to collect the upper parts of the human hair follicles which were cultured for four weeks in a Dulbecco's Modified Eagle's Medium with fetal bovine serum (FBS). Proliferating hair follicle cells were then shifted to DMEM/Ham's Nutrient Mixture F-12 medium without FBS and allowed to grow for one week. These proliferating cells were able to produce HAP stem cell colonies with multilineage differentiation capacity. They produced keratinocytes, smooth muscle cells, cardiac muscle cells, neurons and glial cells. Interestingly, these cryopreserved hair follicles produced pluripotent HAP stem cell colonies similar to fresh follicles. These findings suggest that the cryopreserved whole human hair follicle preserves the ability to produce HAP stem cells, which will enable any individual to preserve a bank of these stem cells for personalized regenerative medicine.

Hypoxia accelerates the progression of angiosarcoma through the regulation of angiosarcoma cells and tumor microenvironment.

BACKGROUND: Angiosarcoma is a rare malignant tumor with a poor prognosis. It is known that hypoxic condition activates tumor progression in several cancers. Additionally, hypoxic tumor microenvironment accelerates immune escape. However, the presence and significance of hypoxia in angiosarcoma has not been adequately investigated. OBJECTIVE: To study the role of hypoxia in the progression of angiosarcoma. METHODS: The protein level of hypoxia inducible factor-1α (HIF-1α) in angiosarcoma was examined using immunohistochemistry and immunoblotting. To study the effect of hypoxia on tumor progression, cell proliferation, migration, invasion, and tube formation assays were performed in angiosarcoma cells. The influence of tumor cell supernatant in hypoxia from angiosarcoma cells on immune escape and angiogenesis was analysed to investigate the modulatory effect of hypoxia on tumor microenvironment of angiosarcoma. The molecular mechanism related to these results was investigated using immunoblotting and real time RT-PCR. RESULTS: HIF-1α protein was over-expressed in angiosarcoma tissues and cell lines under hypoxic conditions, and there was heterogeneity of oxygen supply in angiosarcoma. Hypoxia enhanced the proliferation, migration, and invasion abilities and inhibited tube formation in angiosarcoma cells. Tumor cell supernatant in hypoxia from angiosarcoma cells activated the monocyte invasion ability, facilitated its differentiation into M2-like macrophages, and suppressed cell-adhesion. These in vitro results were compatible to the pathological findings of angiosarcoma patients. CONCLUSION: Hypoxia plays a major role in progression of angiosarcoma cells by enhancing cell proliferation, migration, and invasion and by modulating the tumor microenvironment.

Hair-Follicle-Associated Pluripotent (HAP) Stem Cells Encapsulated on Polyvinylidene Fluoride Membranes (PFM) Promote Functional Recovery from Spinal Cord Injury.

Our previous studies showed that nestin-expressing hair follicle-associated-pluripotent (HAP) stem cells, which reside in the bulge area of the hair follicle, could restore injured nerve and spinal cord and differentiate into cardiac muscle cells. Here we transplanted mouse green fluorescent protein (GFP)-expressing HAP stem-cell colonies enclosed on polyvinylidene fluoride membranes (PFM) into the severed thoracic spinal cord of nude mice. After seven weeks of implantation, we found the differentiation of HAP stem cells into neurons and glial cells. Our results also showed that PFM-captured GFP-expressing HAP stem-cell colonies assisted complete reattachment of the thoracic spinal cord. Furthermore, our quantitative motor function analysis with the Basso Mouse Scale for Locomotion (BMS) score demonstrated a significant improvement in the implanted mice compared to non-implanted mice with a severed spinal cord. Our study also showed that it is easy to obtain HAP stem cells, they do not develop teratomas, and do not loose differentiation ability when cryopreserved. Collectively our results suggest that HAP stem cells could be a better source compared to induced pluripotent stem cells (iPS) or embryonic stem (ES) cells for regenerative medicine, specifically for spinal cord repair.

A case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with cytotoxic phenotype showing multiple ulcers on the entire body.

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), is a rare, aggressive, fatal type of cutaneous T-cell lymphoma. The clinical presentation of pcPTCL-NOS is characterized by generalized plaques, nodules or tumors but ulcers are uncommon. We report an atypical case of pcPTCL-NOS with cytotoxic protein expression, presenting as multiple ulcers on the entire body. A 48-year-old man first presented with pruritic papules on the trunk. The papules gradually increased in number and became ulcerated. We finally diagnosed pcPTCL-NOS because of diffuse dermal infiltration of medium- to large-sized pleomorphic CD4 positive lymphoid cells. Ulceration suggests infiltration of lymphoid cells expressing cytotoxic proteins, which can induce apoptosis in the epidermis and dermis. Our patient died of bacterial sepsis that invaded from the uncontrollable ulcers. A suspicion of pcPTCL-NOS is needed when encountering clinical pictures of refractory multiple ulcers and a biopsy should always be performed, because treatment delay may lead to a very poor prognosis.

Hair Follicle-Associated Pluripotent(HAP) Stem Cells.

The hair follicle has been known, since 1990, to contain stem cells located in the bulge area. In 2003, we reported a new type of stem cell in the hair follicle that expresses the brain stem-cell marker nestin. We have termed these cells as hair-follicle-associated pluripotent (HAP) stem cells. HAP stem cells can differentiate into neuronal and glial cells, beating cardiac-muscle cells, and other cell types in culture. HAP stem cells can be used for nerve and spinal-cord repair such that locomotor activity is recovered. A major function in situ of the HAP stem cells is for growth of the hair follicle sensory nerve. HAP stem cells have critical advantages over embryonic stem cells and induced pluripotent stem (IPS) cells for regenerative medicine in that they are highly accessible, require no genetic manipulation, are nontumorigenic, and do not present ethical issues.