title: Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis.
abstract: Hamartomas are composed of cells native to an organ but abnormal in number, arrangement or maturity. In the tuberous sclerosis complex (TSC), hamartomas develop in multiple organs because of mutations in TSC1 or TSC2. Here we show that TSC2-null fibroblast-like cells grown from human TSC skin hamartomas induced normal human keratinocytes to form hair follicles and stimulated hamartomatous changes. Follicles were complete with sebaceous glands, hair shafts and inner and outer root sheaths. TSC2-null cells surrounding the hair bulb expressed markers of the dermal sheath and dermal papilla. Tumour xenografts recapitulated characteristics of TSC skin hamartomas with increased mammalian target of the rapamycin complex 1 (mTORC1) activity, angiogenesis, mononuclear phagocytes and epidermal proliferation. Treatment with an mTORC1 inhibitor normalized these parameters and reduced the number of tumour cells. These studies indicate that TSC2-null cells are the inciting cells for TSC skin hamartomas, and suggest that studies on hamartomas will provide insights into tissue morphogenesis and regeneration.
authors.affiliation: Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Li
authors.forename: Rajesh L
authors.initials: RL
authors.lastname: Thangapazham
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Rajesh
authors.forename: Tzu-Cheg
authors.initials: TC
authors.lastname: Kao
authors.forename: Leonard
authors.initials: L
authors.lastname: Sperling
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Darling
mesh_terms: D000818:Animals; D001706:Biopsy; D004247:DNA / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D018859:Hair Follicle / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006222:Hamartoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D020123:Sirolimus / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004247:DNA; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus