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 tuberous sclerosis complex (TSC), hamartomas develop in multiple organs due to mutations of 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 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 of hamartomas will provide insights into tissue morphogenesis and regeneration.

Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus

“…These results are consistent with the known cytostatic rather than cytotoxic effects of sirolimus and are in concordance with the persistence of tumor cells observed during sirolimus treatment in our xenograft model. 20 While our results support the hypothesis that TSC-related cutaneous hamartomas remain susceptible to sirolimus years after initiation, development of resistance during prolonged mTOR inhibition has been reported in renal and thyroid cancer. 23, 24 …”

“…Similar to treatment naïve samples from our previous work 20 , TSC2 -null skin tumor fibroblasts grown from two angiofibromas and one ungual obtained during in vivo sirolimus treatment (5, 10 or 15 months after treatment initiation) demonstrated constituent expression of pS6 that was undetectable after treatment with sirolimus in vitro (Figure 2C). Prior genetic analysis demonstrated biallelic TSC2 mutations in two of these skin tumors (refer to samples P3T1 and P22T) 17 .…”

“…These findings were corroborated on the microscopic and molecular level. Immunohistochemical staining revealed that pS6 immunoreactivity in tumor fibroblast-like cells, the tumor-initiating cells 16, 20 , is substantially decreased for at least 10 months after treatment initiation. The absence of pS6 positive stromal cells in the treated tumor is not due to elimination of tumor cells, as cells with biallelic mutations in TSC2 could be grown from treated lesions.…”

What’s new in Birt–Hogg–Dubé syndrome?

“…Recently published data suggest an alternative explanation, with the keratinocyte proliferation being reactive and induced by fibroblasts. In a recent paper, it was reported that TSC2-null fibroblast-like cells grown from human TSC angiofibromas can induce normal human keratinocytes to form hair follicles and TSC-associated skin hamartomas in a murine xenograft model [40]. These findings strongly imply loss of heterozygosity in skin fibroblasts in tumorigenesis.…”

Morphogenesis of chimeric hair follicles in engineered skin substitutes with human keratinocytes and murine dermal papilla cells

“…Stabilized b-catenin in murine epithelium has been reported to induce ectopic hair and accelerate adult hair cycling (3)(4)(5). Fresh or newborn dermal papilla cells (DPC) as well as angiofibroma cells, with similar genetic profiles to DPC, have also been demonstrated to induce trichogenesis (6). Contrary to other mammals, human skin appendages are formed completely during embryogenesis and cannot be restored postnatally after full-thickness skin loss.…”