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: Shaowei Li, Rajesh L Thangapazham, Ji-An Wang, Sangeetha Rajesh, Tzu-Cheg Kao, Leonard Sperling, Joel Moss, Thomas N Darling
• Journal: Nature communications (Nat Commun) Vol. 2 Pg. 235 ( 2011) ISSN: 2041-1723 [Electronic] England
• PMID: 21407201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Multiprotein Complexes
• Proteins
• TSC1 protein, human
• TSC2 protein, human
• Tsc1 protein, mouse
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• DNA
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Biopsy
• DNA (analysis)
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression (drug effects)
• Gene Expression Profiling
• Hair Follicle (growth & development, metabolism, pathology)
• Hamartoma (genetics, metabolism, pathology)
• Humans
• Immunohistochemistry
• Keratinocytes (drug effects, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Nude
• Multiprotein Complexes
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Proteins (genetics, metabolism)
• Sequence Analysis, DNA
• Sirolimus (administration & dosage)
• Skin Neoplasms (genetics, metabolism, pathology)
• TOR Serine-Threonine Kinases
• Transplantation, Heterologous
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (genetics, metabolism)