Inhibition of BMP signaling in P-Cadherin positive hair progenitor cells leads to trichofolliculoma-like hair follicle neoplasias
© Kan et al; licensee BioMed Central Ltd. 2011
Received: 20 October 2011
Accepted: 14 December 2011
Published: 14 December 2011
Skin stem cells contribute to all three major lineages of epidermal appendages, i.e., the epidermis, the hair follicle, and the sebaceous gland. In hair follicles, highly proliferative committed progenitor cells, called matrix cells, are located at the base of the follicle in the hair bulb. The differentiation of these early progenitor cells leads to specification of a central hair shaft surrounded by an inner root sheath (IRS) and a companion layer. Multiple signaling molecules, including bone morphogenetic proteins (BMPs), have been implicated in this process.
To further probe the contribution of BMP signaling to hair follicle development and maintenance we employed a transgenic mouse that expresses the BMP inhibitor, Noggin, to disrupt BMP signaling specifically in subset of hair follicle progenitors under the control of neuron specific enolase (Nse) promoter. We then studied the skin tumor phenotypes of the transgenic mice through histology, immunohistochemistry and Western Blotting to delineate the underlying mechanisms. Double transgenic mice expressing BMP as well as noggin under control of the Nse promoter were used to rescue the skin tumor phenotypes.
We found that the transgene is expressed specifically in a subpopulation of P-cadherin positive progenitor cells in Nse-Noggin mice. Blocking BMP signaling in this cell population led to benign hair follicle-derived neoplasias resembling human trichofolliculomas, associated with down-regulation of E-cadherin expression and dynamic regulation of CD44.
These observations further define a critical role for BMP signaling in maintaining the homeostasis of hair follicles, and suggest that dysregulation of BMP signaling in hair follicle progenitors may contribute to human trichofolliculoma.
The skin is a barrier that protects against the physical, chemical, and thermal assaults of the environment. To serve these functions, epidermis generates an elaborate array of supportive appendages, including hair follicles (HFs), sebaceous glands, sweat glands, and nails . Many conserved signal molecules, such as WNT, NOTCH, FGF, Hedgehog and BMP, are involved in orchestrating the development and maintenance of this important organ. Not surprisingly, disruption of BMP signaling has been implicated in an array of skin disorders.
BMP signaling plays essential roles in many biological processes in numerous types of cells and tissues during embryonic development and adult life . BMP actions are regulated in vivo in a time and location-dependent manner by proteins such as noggin, gremlin, chordin and others that antagonize BMP signaling by directly binding BMPs and their immediate downstream mediators, thus blocking ligand activity . Not surprisingly, the phenotypes generated from disrupting BMP signaling through loss-of-function or gain-of-function mutations are temporally, spatially, and dosage-dependent. For example, germline mutation of BMP2 or BMP4 leads to embryonic lethality [9, 10], whereas inhibition of BMP signaling by overexpressing Noggin under control of different promoters, or by conditional knockout of BMP receptor subunits, leads to variable phenotypes. Many of these mutant animals show strong cutaneous phenotypes that resemble human skin disorders. Further study along this line will deepen our understanding of the normal role of BMP signaling in skin and supportive appendages.
Here we utilized transgenic mice that overexpress noggin under control of the neuron-specific enolase (Nse) promoter  to further probe the role of BMP signaling in orchestrating proliferation and differentiation of epidermal progenitors. We found that overexpression of Noggin in P-cadherin positive hair progenitor cells led to benign hair follicle-derived neoplasias resembling human trichofolliculomas.
Trichofolliculoma (also called folliculoma, or hair follicle nevus) is a benign highly structured hamartoma of the pilosebaceous unit. The morphologic features of trichofolliculoma are variable, reminiscent of the anagen, catagen, and telogen phases of a normal hair follicle in its cycle. However, the follicular epithelium usually exhibits a distinct granular cell layer similar to the normal follicular infundibulum. Follicles or follicle-like structures branch to form secondary or tertiary units. Trichokeratin, not real hair, may be found enclosed in the follicle matrix cells, and the stroma is moderately cellular and loosely organized similar to that found in the normal follicle. These characteristic histological features distinguish this disorder from similar skin disorders such as dilated pore of winer, trichoepithelioma, folliculosebaceous cystic hamartoma , pilomatricomas or sebaceous trichofolliculoma . However, the precise etiology of trichofolliculoma is still unknown.
Our current study of a trichofolliculoma-like phenotype in Nse-Noggin mice indicated that blocking BMP signaling in hair follicle progenitors is associated with down-regulation of E-cadherin expression and subsequent dosage dependent up-regulation of CD44. Complimentary to a previous report , we also observed dysregulation of β-catenin signaling in tumor cells. This study not only provides additional evidence of the importance of BMP signaling in maintaining the homeostasis of hair follicles, but also may help to further understand the pathophysiology of human skin disorders, especially trichofolliculomas.
Materials and Methods
Animal study procedures
Histology and immunohistochemistry
Hematoxylin and eosin staining was performed on fixed tissue sections using Harris Modified Hematoxylin and Eosin Y Solution (Sigma, St. Louis, MO), according to the manufacturer's instructions. Immunostaining was done using standard protocols . Briefly, sections were fixed with 4% paraformaldehyde in PBS. Non-specific binding was blocked with 10% normal serum diluted in 1% bovine serum albumin (BSA, Jackson Lab, USA) and 0.25% Triton X-100 for one hour in room temperature. The sections were then incubated with primary antibodies diluted with 1% BSA + 0.25% Triton X-100 at 4°C overnight. The sections were then incubated with appropriate secondary antibodies (Cy3 or Cy2 conjugated antibodies (Jackson Lab) diluted with 1% BSA + 0.25% Triton X-100 or Alexa Fluor 488, Alexa Fluor 594, and Alexa 647 (1:1000, Invitrogen)) in the dark at room temperature for 2 hours. Counterstaining was then performed with DAPI (1:5000). Fluorescent images were processed by Adobe Photoshop. Anti-Ki67 (Novus Biologicals), anti-total β-cat (Santa Cruz Biotechnology Inc), anti-phospho β-cat (Thr41/Ser45) (cell signaling), anti-active β-cat (clone 8E7, Millipore), and NSE (BioGenex), anti-K14 (covance) are used in this study.
Western blot analysis
Protein levels of CD44 and P-cad in tissue were measured by Western blotting. Tissues were homogenized in protein extract buffer (Roche) and homogenized samples (20 μg of protein) were subjected to 4-20% SDSPAGE gradient gel (Bio-Rad) under reducing conditions. The CD44 was identified by Rat anti-mouse CD44 (BD Bioscience) and P-cad was identified by mouse anti-p-cad antibody (BD Bioscience). The membranes were incubated with the secondary antibodies (Biotinylated goat anti-rat IgG and Biotinylated goat anti-mouse IgG1) (Santa Cruz Biotechnology Inc) for 1 hr at room temperature. Blots were developed by the ECL Western blotting detection reagents (Perkin-Elmer).
Values are expressed as means ± standard deviation of the mean, and p < 0.05 is considered to be statistical significance. Intergroup comparisons were made using two-way ANOVA. The photographs shown represent the results obtained from three independent experiments.
The noggin transgene is expressed in P-cadherin positive hair progenitor cells in Nse-Noggin mice
Noggin overexpression under different promoters leads to a spectrum of phenotypes due to differing temporal and spatial patterns of transgene expression [18–21]. We initially constructed transgenic animals that overexpress the BMP inhibitor noggin under control of the Nse promoter (Nse-noggin) to examine the role of BMP signaling in development of the brain. We noticed that Nse-Noggin mice have a dramatic hair phenotype  and that substantial numbers of adult Nse-noggin mice also developed skin tumors.
Blocking BMP signaling in hair progenitor cells induces benign hair follicle-derived neoplasias resembling trichofolliculomas
Nse-BMP4 rescued the tumor phenotype in Nse-Noggin mice
Mechanisms of Noggin induced tumorigenesis
Mammalian skin begins as a single sheet of multipotent ectodermal cells. The development of a hair follicle requires a series of coordinated changes in the behavior of the targeted cells within an epithelial sheet . The process must be accompanied by alterations in the proliferation, polarity, shape, and adhesiveness of selected cells. BMP signaling plays a major role in numerous stages of this process. Consequently loss-of-function mutations in BMP signaling at different developmental stages or locations within the epithelium leads to strikingly different phenotypes, consistent with many prior studies that have shown developmental changes in the functions of growth factors .
Conditional null mutation of the BMP type IA receptor (BMPRIA) through cre-mediated recombination driven by different promoters leads to different phenotypes. For example, knockout of BMPR-IA through K14-Cre mediated recombination leads to severe defects in the inner root sheath and hair shaft differentiation, retardation of catagen and formation of hair follicles-derived tumors with age . By contrast, knockout of BMPR-IA through Emx1-Cre mediated recombination, leads to defects in the inner root sheath differentiation, formation of cysts in the hair canal . Finally knockout of BMPR-IA through En1-Cre mediated recombination leads to severe defects in the inner root sheath and hair shaft formation in ventral hair follicles .
Interestingly, both pro- and anti-tumor effects of BMP signaling have been reported in the literature. For example, loss-of-function mutations in human of either MADH4 (which encodes SMAD4, the downstream transcription factor that mediates the BMP signaling) or BMPRIA are associated with juvenile polyposis syndrome . Further, conditional knockout of Smad4 through MMTV-Cre mediated recombination leads to squamous cell carcinoma formation . BMP signaling also exerts anti-tumor effects in cytokeratin IV-BMP-4 transgenic mice skin that resist the TPA (phorbol ester 12-O-tetradecanoylphorbol-13-acetate) induced papillomas and squamous cell carcinomas formation . By contrast, BMP proteins are highly over-expressed in human non-small cell lung carcinoma and recombinant BMP-2 enhances the growth of tumors formed from A549 cells injected subcutaneously into nude mice . Further, BMP-4 mRNA is preferentially overexpressed in poorly differentiated gastric cancer , and overexpression of BMP-2/4, -5 or BMPR-IA are all associated with malignancy of oral epithelium and may be involved in the metastasis of oral carcinoma cells . Thus, the biological responses to BMP signaling are cell type and/or context dependent.
More importantly, even overexpressing Noggin in skin under different promoters leads to a spectrum of phenotypes. For example, Msx2-Noggin transgenic mice lack external hairs due to severe alterations in hair shaft formation ; K5-Noggin transgenic mice have retarded epidermal differentiation and reduced apoptosis ; K14-Noggin transgenic mice have a thickened epidermis with formation of compound vibrissa hair follicles . Note that none of these studies reported tumorigenesis in these mice.
This study using the Nse-Noggin mouse model, as well as a prior study involving noggin overexpression in the skin , provides evidence that inhibition of BMP signaling may play a role in tumorigenesis. Specifically, we found that inhibition of BMP signaling by overexpression of Noggin in hair follicles resulted in formation of tumors that resemble trichofolliculomas, a relatively uncommon hair follicle-derived neoplasia.
Presumably the phenotype of Nse-Noggin mice is different from the other cutaneous Noggin transgenic mice because of differences in the expression patterns of the transgenes. In fact, in both K14-Noggin and K5-Noggin transgenic mice the transgene is overexpressed predominately in fully differentiated keratinocytes instead of hair follicle progenitors as in the Nse-Noggin mice. Similarly, in Msx2-Noggin transgene mice expression of transgene is also largely seen in differentiated epithelial cells of the precortex and hair shaft region. Our observations that hair progenitor cells overexpressing transgene remain in the cell cycle and down regulate E-cadherin expression (both are key events for tumorigenesis) further argue that this specific transgene pattern might be crucial for the tumorigenesis. Importantly, mating these mice with BMP4 transgenic mice under the same promoter rescued the tumor phenotype indicating that inhibition of BMP signaling mediated the effects of the noggin transgene.
More interestingly, significantly different phenotypes are even found in transgenic mice that used the same promoter. For example, both Plikus M et al.  and Sharov AA et al.  studied the phenotypes of K14-Noggin transgenic mice. Sharov AA et al. found that transgenic mice (on an FVB background) developed spontaneous hair follicle-derived tumors which resemble human trichofolliculomas. In contrast, Plikus et al. observed thickened skin epidermis, increased hair density, altered hair types, faster anagen re-entry, and formation of compound vibrissa follicles in their transgenic mice (C57BL/6J background). Mouse strain differences could have contributed to altered tumorigenicity of K14-Noggin, however, we observed similar tumorigenicity in both FVB and C57BL/6J backgrounds (data not shown).
Complementary to a previous study , we also observed dysregulation of β-catenin signaling in tumor cells, but our finding is significantly different from Gat U et al.'s report. Specifically, we found that both total β-catenin and phosphorylated β-catenin are down-regulated in the tumor, especially in the hair follicle derived cells. In contrast, even though no obvious change was found in majority of tumor cells, active/stable beta-catenin was dramatically up-regulated in dermal papillae. Both studies suggest that dysregulation of β-catenin can lead to hair follicle tumorigenesis, either directly or indirectly. However another study has found that noggin can promote skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways , so the precise molecular mechansims underlying tumor formation in our animals remain unclear. However the observation that Nse-Noggin develops a phenotype that closely resembles human trichofolliculomas, not other similar human skin disorders, suggests that disrupted BMP signaling in hair progenitors may specifically contribute to human trichofolliculomas.
Our observations indicate that inhibition of BMP signaling in P-cadherin positive progenitor cells leads to up-regulation of P-cadherin and down-regulation of E-cadherin with an associated inhibition of hair progenitor cell differentiation. Factors that affect cell migration, such as CD44, are also dynamically regulated which may enable newly generated cells to migrate to form tumors. Understanding the precise roles of BMP signaling in each cell type in the skin will hopefully lead to the development of new therapeutic approaches for using agonist or antagonists of BMP signaling in the treatment of skin and hair growth disorders, such as trichofolliculoma.
We appreciate the help from many members of the Kessler lab. JAK was supported by NIH grants NS20013 and NS20778. LK was supported in part by the Center for Research in FOP and Related Disorders at The Perelman School of Medicine of The University of Pennsylvania.
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