Gerd Lindner

Noggin is a mesenchymally derived stimulator of hair-follicle induction

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

Control of murine hair follicle regression (catagen) by TGF-β1 in vivo

The regression phase of the hair cycle (catagen) is an apoptosis‐driven process accompanied by terminal differentiation, proteolysis, and matrix remodeling. As an inhibitor of keratinocyte proliferation and inductor of keratinocyte apoptosis, transforming growth factor β1 (TGF‐β1) has been proposed to play an important role in catagen regulation. This is suggested, for example, by maximal expression of TGF‐β1 and its receptors during late anagen and the onset of catagen of the hair cycle. We examined the potential involvement of TGF‐β1 in catagen control. We compared the first spontaneous entry of hair follicles into catagen between TGF‐β1 null mice and age‐matched wild‐type littermates, and assessed the effects of TGF‐β1 injection on murine anagen hair follicles in vivo. At day 18 p.p., hair follicles in TGF‐β1 —/— mice were still in early catagen, whereas hair follicles of +/+ littermates had already entered the subsequent resting phase (telogen). TGF‐β1 — /— mice displayed more Ki‐67‐positive cells and fewer apoptotic cells than comparable catagen follicles from +/+ mice. In contrast, injection of TGF‐β1 into the back skin of mice induced premature catagen development. In addition, the number of proliferating follicle keratino‐cytes was reduced and the number of TUNEL + cells was increased in the TGF‐β1‐treated mice compared to controls. Double visualization of TGF‐β type II receptor (TGFRII) and TUNEL reactivity revealed colocalization of apoptotic nuclei and TGFRII in catagen follicles. These data strongly support that TGF‐β1 ranks among the elusive endogenous regulators of catagen induction in vivo, possibly via the inhibition of keratinocyte proliferation and induction of apoptosis. Thus, TGF‐βRII agonists and antagonists may provide useful therapeutic tools for human hair growth disorders based on premature or retarded catagen development (effluvium, alopecia, hirsutism).—Foitzik, K., Lindner, G., Mueller‐Roever, S., Maurer, M., Botchkareva, N., Botchkarev, V., Handjiski, B., Metz, M., Hibino, T., Soma, T., Dotto, G. P., Paus, R. Control of murine hair follicle regression (catagen) by TGF‐β1 in vivo. FASEB J. 14, 752–760 (2000)

Involvement of hepatocyte growth factor/scatter factor and Met receptor signaling in hair follicle morphogenesis and cycling

HGF/SF and its receptor (Met) are principal mediators of mesenchymal‐epithelial interactions in several different systems and have recently been implicated in the control of hair follicle (HF) growth. We have studied their expression patterns during HF morphogenesis and cycling in C57BL/6 mice, whereas functional hair growth effects of HGF/SF were assessed in vivo by analysis of transgenic mice and in skin organ culture. In normal mouse skin, follicular expression of HGF/SF and Met was strikingly localized: HGF/SF was found only in the HF mesenchyme (dermal papilla fibroblasts) and Met in the neighboring hair bulb keratinocytes. Both HGF/SF and Met expression peaked during the initial phases of HF morphogenesis, the stage of active hair growth (early and mid anagen), and during the apoptosis‐driven HF regression (cata‐gen). Met+ cells in the regressing epithelial strand appeared to be protected from undergoing apoptosis. Compared to wild‐type controls, transgenic mice overexpressing HGF/SF under the control of the MT‐1 promoter had twice as many developing HF and displayed accelerated HF development on postnatal day 3. They also showed significant catagen retardation on P17. In organ culture and in vivo, HGF/SF i.c. resulted in a significant catagen retardation. These results demonstrate an important role of HGF/SF and Met in murine hair growth control and suggest that Met‐mediated signaling might be exploited for therapeutic manipulation of human hair growth disorders.—Lindner, G., Menrad, A., Gherardi, E., Merlino, G., Welker, P., Handjiski, B., Roloff, B., Paus, R. Involvement of hepatocyte growth factor/scatter factor and Met receptor signaling in hair follicle morphogenesis and cycling. FASEB J. 14, 319–332 (2000)

A New Role for Neurotrophin-3 : Involvement in the Regulation of Hair Follicle Regression (Catagen)

Nervous system and hair follicle epithelium share a common ectodermal origin, and some neurotrophins (NTs) can modulate keratinocyte proliferation and apoptosis. Therefore, it is reasonable to ask whether NTs are also involved in hair growth control. Here, we show that the expression of NT-3 and its high-affinity receptor, tyrosine kinase C, in the skin of C57BL/6 mice is strikingly hair cycle-dependent, with maximal transcript and protein expression seen during spontaneous hair follicle regression (catagen). During catagen, NT-3 and tyrosine kinase C are co-expressed by terminal deoxynucleotidyl transferase-mediated in situ nick end labeling-positive keratinocytes in the club hair and secondary germ. NT-3-overexpressing transgenic mice show precocious catagen development during the postnatal initiation of hair follicle cycling, whereas heterozygous NT-3 knockout (+/-) mice display a significant catagen retardation. Finally, NT-3 stimulates catagen development in organ culture of normal C57BL/6 mouse skin. These observations suggest that the hair follicle is both a source and target of NT-3 and that NT-3/tyrosine kinase C signaling is functionally important in the control of hair follicle regression. Therefore, tyrosine kinase C agonists and antagonists deserve systematic exploration for the management of hair growth disorders that are related to premature (alopecia/effluvium) or retarded catagen (hirsutism/hypertrichosis).

Alterations in Hair Follicle Morphology and Hair Shaft Production After Follicular Unit Transplantation.

Abstract:Follicular unit transplantation is the most commonly performed technique in modern restorative hair transplantation surgery. It relies on the acquisition of intact follicular units from microdissected scalp skin strips and their subsequent transplantation into the recipient regions affected by alopecia. Ideally, the translocation of follicular units from the balding-resistant areas of the scalp (usually the occipital region) to the recipient site should not result in any morphological change in the grafts. Nevertheless, the insults associated with surgical intervention present grafted follicles to mechanical and chemical cues differently from those of the physiological steady-state conditions in undamaged skin. This disruption of the normal follicular microenvironment might alter important aspects of hair biology in grafts, for example, hair cycle and pigmentation, and, in turn, could lead to differences in hair appearance, eventually culminating in a diminished esthetical outcome of the surgery. In this study, the authors analyzed native and grafted scalp hair follicles (HFs) from 2 patients who had undergone follicular unit transplantation surgeries formerly. Scanning electron microscopy and light microscopy-based histomorphometry revealed a marked enlargement of follicular structures in the grafts with a concomitant increase in hair shaft diameter. Immunohistological staining confirmed a thickening of the dermal sheath in transplanted HFs that also harbored a denser vascular network. Taken together, these results show that the grafted HFs analyzed were subjected to marked morphological changes during their residence in the recipient site and that this phenomenon is associated with a modulation of follicular vascularization.

Bioengineering of a Full-Thickness Skin Equivalent in a 96-Well Insert Format for Substance Permeation Studies and Organ-On-A-Chip Applications

The human skin is involved in protecting the inner body from constant exposure to outer environmental stimuli. There is an evident need to screen for toxicity and the efficacy of drugs and cosmetics applied to the skin. To date, animal studies are still the standard method for substance testing, although they are currently controversially discussed Therefore, the multi-organ chip is an attractive alternative to replace animal testing. The two-organ chip is designed to hold 96-well cell culture inserts (CCIs). Small-sized skin equivalents are needed for this. In this study, full-thickness skin equivalents (ftSEs) were generated successfully inside 96-well CCIs. These skin equivalents developed with in vivo-like histological architecture, with normal differentiation marker expressions and proliferation rates. The 96-well CCI-based ftSEs were successfully integrated into the two-organ chip. The permeation of fluorescein sodium salt through the ftSEs was monitored during the culture. The results show a decreasing value for the permeation over time, which seems a promising method to track the development of the ftSEs. Additionally, the permeation was implemented in a computational fluid dynamics simulation, as a tool to predict results in long-term experiments. The advantage of these ftSEs is the reduced need for cells and substances, which makes them more suitable for high throughput assays.