Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.

Hair differentiates from follicle stem cells through progenitor cells in the matrix. In contrast to stem cells in the bulge, the identities of the progenitors and the mechanisms by which they regulate hair shaft components are poorly understood. Hair is also pigmented by melanocytes in the follicle. However, the niche that regulates follicular melanocytes is not well characterized. Here, we report the identification of hair shaft progenitors in the matrix that are differentiated from follicular epithelial cells expressing transcription factor KROX20. Depletion of Krox20 lineage cells results in arrest of hair growth, confirming the critical role of KROX20 + cells as antecedents of structural cells found in hair. Expression of stem cell factor (SCF) by these cells is necessary for the maintenance of differentiated melanocytes and for hair pigmentation. Our findings reveal the identities of hair matrix progenitors that regulate hair growth and pigmentation, partly by creating an SCF-dependent niche for follicular melanocytes.

Deregulation of RAS signaling in Neurofibromatosis type 1 (NF1) results in the development of multiple neurofibromas, complex tumor of the peripheral nerves with no effective medical treatment. There is increasing evidences that neurofibroma initiates through loss of NF1 function in the Schwann cell lineage, followed by a cascade of interactions with other cell types in the surrounding tumor microenvironment. In NF1 patients, neurofibromas always develop along peripheral nerves and do not migrate to distant organs, including the central nervous system. In this study, we sought to identify the contributions of these peripheral nerves in neurofibroma formation. Using in vivo and in vitro three-dimensional (3D) culturing system, we show that peripheral nerves are absolutely required for neurofibroma tumorigenesis and report a novel 3D skin raft culture system for neurofibroma formation in vitro to decipher tumor pathogenesis. This interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for understanding early cellular events that dictate tumorigenesis. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in neurofibroma development and, therefore, viable therapeutic targets in neurofibroma therapy.

Dorman-Chanarin syndrome (DCS) is an autosomal recessive, neutral lipid storage disorder with ichthyosis to loss-of-function mutation in CGI-58, characterized by the presence of intracellular lipid droplets in cells of multiple organs. CGI-58 is an activator of adipose triglyceride lipase (ATGL) contributing to triglyceride (TG) lipolysis. Although dysfunction of CGI-58 is considered to be the primary cause, the pathomechanism of ichthyosis in DCS still remains undefined. Here, we report a case of 72-year-old man with DCS, harboring a novel missense mutation in the exon 3 of CGI-58 gene in one allele, presented ichthyosiform erythroderma with a distinct seasonal variation (J Dermatol Sci 2010; 57: 102). His skin lesions were aggravated in summer but resolved spontaneously during winter. Biochemical analysis of scales from his lesions, revealed increased levels of TG and decreased levels of fatty acids (FA), indicating dysfunction of ATGL. Notably, the patient showed higher levels of TG but lower FA in the scales taken in summer than those in winter, suggesting that 'seasonal' fluctuated activity of ATGL might be associated with the clinical severity (J Dermatol Sci 2010; 57: 102). Strikingly, topical application of menthol containing pasting resulted in local resolution of his ichthyosiform lesions. Furthermore, improvement of water retention capability was observed at the ameliorated lesion by menthol pasting. Since menthol is an agonist of transient receptor potential M8 (TRPM8), which is activated by low temperature below 22 o C. We now speculate that temperature-dependent mechanism may be involved in the etiology of DCS in this specific patient. Our case gives a new piece of puzzle to elucidate the association between lipid metabolism pathway and thermo-regulation in keratinocytes.