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The pathobiology of alopecia areata ( AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8+ T cells, CD4+ T cells and NKGD2+ NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA-related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re-evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease. [ABSTRACT FROM AUTHOR]

Discusses the case of a female patient with frictional contact dermatitis due to paper tissues. Itchy erythema in the periorbital and perioral areas; Discoid eczema; Mechanical irritation of the skin.

Discusses the case of a female patient with contact dermatitis caused by pirfenoxone, the main active component of Catalin K eye drops. Signs and symptoms; Antioxidant effects of pirfenoxone; Patch test.

Presents a case report on contact dermatitis due to alkyl diaminoethylglycine hydrochloride. Development of itchy linear infiltrative erythema on face and neck; Positive reaction to the sterilized nasal cannula; Absence of any reaction to concentrations of alkyldiaminoethylglycine hydrochloride in healthy people.

The article presents a case study of myeloid leukemia. A 70-year-old man first noticed several subcutaneous nod tiles on his chest in 1983. Physical examination showed that the patient was cachectic with markedly depressed cheeks. There was no palpable lymphadenopathy. The most remarkable characteristic of the case was that acute myeloid leukemia occurred following recurrent lobular panniculitis. The patient had fever, cytopenia, and hepatosplenomegaly, which are characteristic features of cytophagic histiocytic panniculitis.

We investigated whether the topographic regulation of melanocyte differentiation in the skin is determined by mesenchymal–epithelial interactions via fibroblast-derived factors. The melanocyte density in palmoplantar human skin (i.e. skin on the palms and the soles) is five times lower than that found in non-palmoplantar sites. Palmoplantar fibroblasts significantly suppressed the growth and pigmentation of melanocytes more than non-palmoplantar fibroblasts. Using cDNA microarray analysis, fibroblasts derived from palmoplantar skin expressed high levels of dickkopf 1 (an inhibitor of the canonical Wnt signaling pathway) while non-palmoplantar fibroblasts expressed higher levels of dickkopf 3. Transfection studies revealed that dickkopf 1 decreased melanocyte function, probably through β-catenin, glycogen synthase kinase 3 β (GSK3 β) and/or PKC α via regulation by microphthalmia-associated transcription factor (MITF) activity. Thus, our results provide a basis to explain why skin on the palms and the soles is generally hypopigmented compared with other areas of the body, and might explain why melanocytes stop migrating in the palmoplantar area during human embryogenesis. [ABSTRACT FROM AUTHOR]

Presents the case of a baseball pitcher with friction dermatitis. Speculation that the combination of pitching friction and atopic background might have resulted in the pitcher's skin lesions; Evidence that pitching friction appeared to have resulted in discoid eczema rather than this being caused by any specific contactant.

Male-pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence-based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and women's perception of MPHL has undergone change and the term "female-pattern hair loss (FPHL)" is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first-line treatments. Self-hair transplantation, irradiation by light-emitting diodes and low-level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t-flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan., (© 2018 Japanese Dermatological Association.)

Serum thymus and activation-regulated chemokine/CCL17 (sTARC) is known as a good indicator for atopic dermatitis severity. Herein, we investigate whether sTARC correlates with severity and therapeutic response for alopecia areata (AA) in our 121 patients. The sTARC mean of AA totalis and universalis was significantly higher than mild AA. Next, we compared sTARC of diffuse AA (n = 14) and severity-controlled patchy AA (n = 32) and found that sTARC in diffuse AA (564.2 ± 400.0 pg/mL) was significantly higher than that of the patchy type (344.0 ± 239.8 pg/mL), suggesting a potential role of TARC in active progression of diffuse AA. Ten patients with diffuse AA were treated with i.v. corticosteroid pulse therapy. Then, we tested whether sTARC can predict prognosis after the pulse therapy and found that baseline sTARC in the poor responders (1025.5 ± 484.8 pg/mL) was significantly higher than that in the good responders (complete remission at 24 months after the pulse therapy, 347.8 ± 135.7 pg/mL), indicating sTARC as a response biomarker in the corticosteroid pulse therapy for diffuse AA. Finally, to investigate TARC production in the affected hair follicles, we performed immunohistochemical double staining of TARC and CD68 using scalp skin specimens of diffuse AA with high titers of sTARC. The results showed their co-localization in the infiltrating cells around the AA hair follicles, suggesting that TARC is mainly produced from CD68(+) histiocytes. In conclusion, sTARC is a disease activity and response biomarker in AA, providing new insight beyond the T-helper 1/2 paradigm to solve the immunological pathogenesis of AA., (© 2013 Japanese Dermatological Association.)

Pigmentary complication by contact immunotherapy (CI) for alopecia areata (AA) has been reported but its pathophysiology remains unknown. To characterize pigmentary complication by CI and its pathophysiology, we examined the incidence of hyperpigmentation in 186 consecutive patients treated with CI using diphenylcyclopropenone. From clinical data of AA totalis (AAT) or universalis (AAU) patients (n = 78), we studied the correlations between this complication and age, sex, atopic background, duration and treatment responsiveness, duration of CI, final concentration of diphenylcyclopropenone and administration of anti-histamines by χ(2)-test or Mann-Whitney U-test. Additionally, the histopathology of pigmentation was studied. As a result, 11 (5.91%) of the 186 patients had hyperpigmentation in this series. All of them had AAT or AAU, suggesting that the pigmentation is apt to occur in severe AA. When the AAT or AAU patients with (n = 11) and without hyperpigmentation (n = 67) were compared, those with pigmentation showed poorer responsiveness to CI (P < 0.05) but no significant tendency for other factors. Histopathologically, skin specimens showed lichenoid or vacuolar interface dermatitis with necrotic keratinocytes and dermal melanophages, consistent with pigmented contact dermatitis (PCD). Together, pigmentary complication by CI corresponds to PCD from therapeutic sensitizer, representing clinical indicator of poor responsiveness., (© 2010 Japanese Dermatological Association.)

A 51-year-old man had been followed up for approximately 10 years at our clinic for persistent itchy eczematous lesions on his limbs and trunk. At the first visit, physical examination revealed itchy lichenificated and eczematous eruptions and many pruriginous papules over his entire body. Laboratory data showed remarkably high levels of immunoglobulin E (20,000 IU/mL). He was diagnosed as having severe atopic dermatitis (AD). Topical treatment with a potent corticosteroid (class I-II) did not significantly decrease the eruptions and occasional administration of a systemic corticosteroid elicited only a subtle response. The pruriginous lesions did not respond at all to topical or systemic corticosteroids. We used semiquantitative reverse transcription polymerase chain reaction to examine the expression of glucocorticoid receptor (GR)alpha and GRbeta mRNA in peripheral blood mononuclear cells (PBMC) of this patient and compared those with six other patients with AD and three normal controls. As a result, the expression of GRalpha was remarkably decreased compared to normal controls and the other AD patients. Therefore, his poor response to corticosteroid was at least partially caused by this GRalpha decrease in the PBMC.

To study the effect of fexofenadine on extensive alopecia areata (AA), we evaluated retrospectively 121 patients with AA having alopecia in more than 50% of the scalp and followed them for at least 6 months. Patients were treated by immunotherapy using diphenylcyclopropenone or squaric acid dibutylester with or without oral fexofenadine. The regrowth score was estimated as decrease of Severity of Alopecia Tool (SALT) score. In AA with atopic background (atopic AA), the mean regrowth score of the fexofenadine group was 1.333 (n = 33) and that of the control 0.471 (n = 34). The fexofenadine group showed significantly better regrowth than control by Mann-Whitney's U-test (P = 0.00213). In non-atopic AA, the mean regrowth score of the fexofenadine group was 1.303 (n = 33) and that of the control 1.048 (n = 21). There was no significant difference by Mann-Whitney's U-test (P = 0.872). Together, fexofenadine is a helpful reagent in the treatment extensive atopic AA with contact immunotherapy.

Although dermoscopy is used mainly for diagnosing pigmented skin lesions, this device has been reported to be useful in observing alopecia areata and frontal fibrosing alopecia. Herein, we investigated the dermoscopic features and their incidence of androgenetic alopecia (AGA; n = 50 men) and female AGA (FAGA; n = 10 women) in Asian people. More than 20% hair diameter diversity (HDD), which reportedly is an early sign of AGA and corresponds to hair follicle miniaturization, was observed in the affected area of all AGA and FAGA cases, suggesting that HDD is an essential feature to diagnose AGA and FAGA. Peripilar signs, corresponding to perifollicular pigmentation, were seen in 66% (33/50) of AGA and 20% (2/10) of FAGA women. This incidence in the present study was lower than previously reported in white subjects possibly because the Asian skin color conceals slight peripilar pigmentation. Yellow dots were observed in 26% (13/50) of AGA and 10% (1/10) of FAGA cases and the number of yellow dots in AGA and FAGA was limited to 10 on the overall hair loss area. Yellow dots possibly indicate the coincidence of AGA and enlargement of the sebaceous glands caused by common end-organ hypersensitivity to androgen. In conclusion, dermoscopy is useful to diagnose AGA and FAGA and provides insights into the pathogenesis of AGA.

Sex hormones are known to be associated with increases of melanocytes and melanin production in human skin. However, the expression of estrogen receptor (ERalpha) in melanocytic lesions has been controversial. In 1996, a new subset of estrogen receptor was cloned, and named estrogen receptor beta (ERbeta). We used immunohistochemical staining to characterize the expression of ERalpha and ERbeta in normal skin and in melanocytic lesions. Normal sebaceous glands and hair follicles were positive for ERalpha and ERbeta. Other adnexal structures and constituents in the skin were positive for ERbeta, but not for ERalpha. Melanocytic nevi and malignant melanomas were negative for ERalpha, but both were positive for ERbeta. The ubiquitous expression of ERbeta may play a fundamental role in various normal skin cells and melanocytic tumors.

Although dermoscopy is conventionally utilized with immersion gel for diagnosis of pigmented tumor, we utilized dry dermoscopy, which is dermoscopy without immersion gel, for clinical treatment of alopecia areata (AA). The scalp skin and hair of a 38-year-old Japanese male, and 23-, 22- and 47-year-old Japanese females with AA, whose normal hair color was black, were examined by dry dermoscopy. Exclamation mark hairs, short hairs, fractured hairs and black dots, all characteristic of AA, were detected by dry dermoscopy of the scalp of the 23-year-old female with ophiasis type AA. In the case of the 47-year-old female with round hair loss on the occipital scalp and diffuse hair loss over the fronto-vertical region, dry dermoscopy was useful for diagnosis of AA based on hair characteristic of AA. After she received corticosteroid pulse therapy with 500 mg of i.v. methylprednisolone on 3 successive days, her hair showed apparent regrowth and disappearance of the abnormal hairs characteristic of AA, evidenced by dry dermoscopy 1 month later. In a case of long-lasting AA in the 23-year-old female, we found a follicular plaque-like appearance at the opened hair follicle pores by dry dermoscopy. Histopathologically, the incompletely differentiated remnant hair shaft was packed in the follicular infundibulum. In addition, regrowing vellus hairs, which were difficult to clinically recognize, were detected by dry dermoscopy. Dry dermoscopy is therefore useful for both diagnosis and follow up of AA.

We report two cases of pressure ulcers in liver cirrhosis patients. In case 1, a 64-year-old Japanese woman had suffered from liver cirrhosis caused by hepatitis C virus and developed a pressure ulcer on her sacral and coccygeal area due to long-term bedrest. After she received a living donor liver transplantation from her child, the ulcer healed synchronizing with improvement of serum cholinesterase and bilirubin. Likewise, her systemic condition also got much better after the transplantation. In case 2, a 53-year-old Japanese man with hepatitis B virus cirrhosis and hepatocellular carcinoma developed a pressure ulcer on his sacral area. Although he received a living donor liver transplantation from his brother, his general status and pressure ulcer were fluctuating in conformity with the variance of serum bilirubin. However, at 5 weeks after the transplantation, the ulcer gradually started improving, entrained to serum bilirubin decrease. From these findings, the condition of the pressure ulcer in liver cirrhosis patients synchronized with serum bilirubin as well as systemic condition, suggesting a possible influence of bilirubin for wound healing.

Fixed eruption is a characteristic condition with recurrent an erythematous macule in the same location. Because fixed eruption is caused by medical drugs in the majority of cases, it is not so difficult to identify suspicious material by interview. However, it may be difficult in cases in which food additives are responsible. We report two rare cases of fixed eruption due to quinine contained in tonic water. In case 1, a 37-year-old man had repeated erythema on the same sites after drinking a variety of cocktails. We suspected tonic water as the causative material. Oral challenge test of tonic water was positive and patch test with quinine sulfate was positive also. In case 2, a 24-year-old woman in had noticed that her eruption appeared after drinking liquor, especially cocktails as in case 1. She was also positive upon an oral challenge test of tonic water and in a patch test of quinine sulfate.

Langerhans cell histiocytosis (LCH) is a disorder characterized by neoplastic proliferation of Langerhans cells that rarely involves the skin in adults. A 74-year-old woman presented with a fourteen year history of eosinophilic granuloma and bone involvement caused by LCH. She had received three combination therapy courses of curettage and radiation since 1987 and had remained free of LCH signs for seven years, after which she started to notice brown nodules on her left leg. Biopsy specimens taken from the lesions showed massive proliferations of large histiocytic cells. Immunoperoxidase stainings for CD1a and S-100 protein were positive. Electron microscopy identified Birbeck granules in the cytoplasm of the atypical Langerhans cells. Treatment with oral prednisolone alone has resulted in the patient remaining in complete remission for 12 months.

A 24-year-old female patient with Melkersson-Rosenthal syndrome (MRS) in association with saprodontia is reported. She presented with lower labial swelling and left facial edema. Histological examination of the involved oral mucosa showed a noncaseating epithelioid granuloma. Results from the laboratory and imaging examinations were normal or negative. Her orofacial swelling disappeared after treatment of the saprodontia of the left first molar.

A 39-year-old woman visited us because of a subcutaneous induration on her forehead of 7 months' duration. The tumor was tender, firm, and colored blue-black. Microscopically, the tumor was composed of fibroblastic and histiocytic cells showing no atypicality. In some part intra- or extracellular haemosiderin was diffusely seen. There were some blood-filled spaces of varying size without endothelial lining. From these findings, this case was diagnosed as aneurysmal fibrous histiocytoma (AFH), a variant form of dermatofibroma. Immunohistochemical analysis showed that factor XIIIa-positive histiocytic cells were distributed in the area without haemosiderin, but such cells were absent in the area with its deposition. Furthermore, the cells near the blood-filled space showed transition from factor XIIIa-positive to -negative, suggesting that the stromal instability induced by the attenuation of factor XIII may lead the formation of the blood-filled spaces in AFH.

A 69-year-old Japanese man suffered from bronchial asthma, atrial fibrillation, general fatigue, high fever, and weight loss of about 5 kg within a month. He also had intermittent claudication, a tingling feeling in his fingers and toes, and an ulcer on his toe. His laboratory data revealed leukocytosis with absolute eosinophilia. The patient was treated with predonisolone 30 mg daily. Although the ulcers healed once, the lesions recurred with tapering predonisolone. The patient visited us because of the ulcer on his toe. Physical examination showed a 2 cm ulcer surrounded by slight erythema on his right fourth toe. Magnetic resonance angiography detected tapering stenosis of the medium-sized arteries in both legs. A biopsy from his myocardium showed the infiltration of eosinophils into the myocardium. The neuron conduction rate of his lower leg was slower than that of the normal control, demonstrating mononeuritis. From these findings, we diagnosed this patient as Churg-Strauss syndrome.

A 65-year-old Japanese man presented with itchy purpuric lichenoid papules of six months' duration on his legs and buttock. A topical glucocorticoid ointment was not effective. The biopsy specimen histologically showed a dense lichenoid infiltration of lymphocytes and histiocytes into the dermoepidermal junction; red blood cells were seen in the infiltration. Based on the clinical and pathological findings, we diagnosed this case as lichenoid purpura of Gougerot-Blum. The lesions disappeared when the diltiazem hydrochloride that he had been taking was discontinued.

An 81-year-old woman presented with a round erythematous macule with keratotic scales on her left hand. The skin specimen histologically showed hypergranulosis and apoptotic keratinocytes in the epidermis with lichenoid infiltration of lymphocytes. Parakeratosis seen in the hyperkeratotic cornified layer indicated lichen planus-like keratosis, as distinguished from lichen planus. Direct immunofluorescence study revealed the linear deposition of IgM in the basement membrane zone; IgG, IgA and C3 were not detected.

We here reported a case of an 82-year-old man with double involvement of extramammary Paget's disease in the genitalia and axilla. Physical examination revealed erythema and reddish tumors on the pubic area and scrotum and irregular-shaped erythema on the left axilla. The skin biopsy sample from the genital area showed Paget's cells in the epidermis and upper dermis. The specimen from the left axilla showed Paget's cells scattered in the epidermis but not in the dermis.

A polymerase chain reaction (PCR)-based strategy has been developed for analysis of clonal rearrangement of the T-cell receptor gamma gene (TCR gamma) and was shown to be useful for detection of clonal T-cell populations. In this study, we performed PCR combined with denaturing gradient gel electrophoresis (DGGE) on fresh frozen biopsy samples from 16 patients with cutaneous T-lymphoproliferative diseases in whom a definite diagnosis was difficult to make on morphological and immunohistochemical grounds alone. Ages of the patients at biopsy ranged from 28 to 81 (median 62) years, and the subjects consisted of 8 men and 8 women. They presented with erythema on the extremities in 5 cases, trunk in 7, buttock in 2, and papules on the trunk and face in one case each. Clonal rearrangement of TCR gamma was observed in 3 of 16 cases. Clinical diagnoses of these three cases were mycosis fungoides, cutaneous invasion of adult T-cell leukemia (ATL), and large granular lymphocytic leukemia (LGL) of T-cell type, respectively, but they were histologically difficult to differentiate from reactive cutaneous T-cell proliferation. The skin lesions of the LGL case worsened, and this patient died two years after biopsy. Another patient with suspected mycosis fungoides in the plaque stage died due to dissemination of tumors 22 months after biopsy. The remaining one patient with ATL survived with cutaneous lesions for over four years. Clonality was not demonstrated in the remaining 13 cases, and their clinical courses were favorable. These findings showed that demonstration of clonal TCR gamma gene rearrangement using the PCR-DGGE method is very helpful for diagnosis of cutaneous T-cell neoplasms.

Twelve patients with warts recalcitrant to various treatment, including cryotherapy, were treated with OK-432 injection therapy. Six patients received only subcutaneous injection, three received only intralesional injection, and the other three received both subcutaneous and intralesional injections. Complete clearing of the warts occurred in nine (75%) of 12 patients, while the other three patients were not cured. Grouping the patients by the method of injection, the success rate of subcutaneous injection was 5/9 (55.6%), and that of intralesional injection was 4/6 (66.7%). Although five patients complained of mild fever and malaise, these side effects gradually disappeared during the repeated injections. OK-432 injection is considered as a hopeful therapy for recalcitrant warts.

A markedly obese, 41-year-old Japanese man who had suffered from psoriasis vulgaris for several years visited us with elephantiasis-like swelling of his lower legs of three months' duration. His right lower leg showed marked papillomatosis with thick scales, and the left lower leg was eroded and papillomatous. Although direct lymphography of his lower extremities showed no abnormality, indirect lymphography revealed local lymphatic damage in the involved skin. Histological examination showed hyperkeratosis, marked papillomatosis, proliferation of capillaries in the upper dermis, and lymphectasia in the lower dermis. The lesions were much improved by washing and topical use of corticosteroids for two months. It was suspected that obesity and the preceding psoriatic lesions caused local lymphatic disturbances, followed by the development of stasis papillomatosis.

Two cases of solitary type infantile myofibromatosis (IM) were presented. Case 1 was a 6-month-old male infant with a firm, dark red, fixed tumor on his right knee. A computerized tomographic scan revealed that the tumor was attached to the underlying muscle. Case 2 was a 1-month-old male infant with a tumor on his right knee, similar to that in case 1. In neither case was there any clinical evidence of visceral involvement. Histological and immunohistochemical findings were similar. The lesions appeared histologically as non-encapsulated nodules composed of whorled fascicles of spindle-shaped cells and a vascular element with a hemangiopericytoma-like appearance. The tumor cells were positively stained with PTAH. They were positive for alpha-smooth muscle actin and vimentin, but negative for desmin. These findings support the myofibroblastic nature of IM. In case 2, the tumor regressed spontaneously at the age of 12 months. Unlike the multicentric form, spontaneous regression of the solitary form of IM has not previously been reported.

We used fasting diet therapy with a 28-year-old woman with chronic urticaria who responded only to systemic administration of glucocorticosteroids. The rashes began to decrease on the third therapeutic day and completely disappeared on the 11th day. Although the eruptions relapsed three days after the termination of the therapy, they were milder than previous ones. We also discussed the possible efficacy of fasting diet therapy for chronic urticaria as reported in the literature.

A case of locally recurrent malignant fibrous histiocytoma was documented in a 70-year-old man. He first noticed a subcutaneous nodule forty years previously. The tumor was surgically removed four times during the last four years with local recurrence on every occasion. In the recurrent tumors, the tumor cells almost completely replaced the whole dermis and invaded skeletal muscles. They were composed of pleomorphic spindle cells arranged in a storiform pattern and bizarre histiocytic cells, which were present principally in the deeper portions of the tumor. Both types of tumor cells showed marked nuclear atypicality. In the primary tumor, surrounding a large necrotic area, spindle-shaped cells were arranged in a storiform pattern. These tumor cells exhibited only mild nuclear atypia. The recurrent tumor was strongly positive for vimentin and alpha-1-antichymotrypsin. Most tumor cells were also weakly positive for KL1, a monoclonal antibody for keratin. A Western-blot analysis revealed the presence of two bands (62 and 69 Kd) reacting with KL1 in the fractions which were obtained from the tumor according to the method for keratin extraction.

Three cases of spindle cell hemangioendothelioma were studied. Two had multiple nodules and the third had a single, recurrent lesion in the dermis or subcutis of the distal extremities. The tumor initiated at the age of 3 months in one patient and at the ages of 11 or 12 years in the remaining two. Local recurrence after surgical excision was observed in all cases. Microscopically the tumors were composed of two components; cavernous blood spaces and a proliferation of spindle cells. Among these spindle cells, there were occasional epithelioid endothelial cells with intracytoplasmic lumina. Phleboliths were observed in two cases. Most of the endothelial cells lining the cavernous spaces were positive for factor VIII-associated antigen in all cases; the intracytoplasmic lumina were also positive in two cases. The spindle cells were negative for that antigen in all cases. However, they were positive for desmin in one case. Electronmicroscopically, the spindle cells resembled primitive mesenchymal cells.