Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation.

Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint" to maintain the stem cell quality and quantity.

Hair follicle stem cells provide a functional niche for melanocyte stem cells.

In most stem cell systems, the organization of the stem cell niche and the anchoring matrix required for stem cell maintenance are largely unknown. We report here that collagen XVII (COL17A1/BP180/BPAG2), a hemidesmosomal transmembrane collagen, is highly expressed in hair follicle stem cells (HFSCs) and is required for the maintenance not only of HFSCs but also of melanocyte stem cells (MSCs), which do not express Col17a1 but directly adhere to HFSCs. Mice lacking Col17a1 show premature hair graying and hair loss. Analysis of Col17a1-null mice revealed that COL17A1 is critical for the self-renewal of HFSCs through maintaining their quiescence and immaturity, potentially explaining the mechanism underlying hair loss in human COL17A1 deficiency. Moreover, forced expression of COL17A1 in basal keratinocytes, including HFSCs, in Col17a1-null mice rescues MSCs from premature differentiation and restores TGF-ß signaling, demonstrating that HFSCs function as a critical regulatory component of the MSC niche.

Malignant blue nevus: case report of a Japanese man with a distant cutaneous metastasis.

We report a 55-year-old Japanese patient with a malignant blue nevus (MBN) on the scalp. The patient had regional lymph nodes metastases at his first visit, and a distant cutaneous metastatic papule appeared on the back 1 year later despite therapeutic intervention. Histology of the primary tumor lacked a junctional component and showed a typically biphasic pattern in the degree of pigmentation similar to a cellular blue nevus (BN). One pattern showed nests of less-pigmented, oval-shaped cells with a fairly uniform appearance, and the other pattern showed an aggregation of spindle-shaped cells containing a large amount of melanin pigment intermingled with heavily pigmented melanophages. Histology of metastatic regional lymph nodes also showed a biphasic proliferative pattern of oval-shaped, pale cells and spindle-shaped, richly pigmented cells. A distant cutaneous metastatic papule on the back showed massive proliferation of atypically large, pale, and oval-shaped melanoma cells with heavily pigmented melanophages just beneath the uninvolved epidermis. These histologic features were different from those of metastatic tumor proliferation from conventional melanoma. It seems probable that MBN might maintain a different biological and histopathologic character from conventional melanoma when it grows in metastatic sites.