Search

Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands., Competing Interests: Declaration of Interests A provisional patent application has been filed by the President and Fellows of Harvard College based on this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Summary The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of T regs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs. [ABSTRACT FROM AUTHOR]

Although stem cells are subject to niche control, evidence is emerging that they also contribute to generating the niche through their offspring. Using the hair follicle as a model, Hsu at al. demonstrate that the transient-amplifying cells, downstream of stem cells and well-known cell producers, signal back to stem cells to maintain long-term regenerative capacity. [ABSTRACT FROM AUTHOR]

Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as a paradigm, we show that emerging TACs constitute a signaling center that orchestrates tissue growth. Whereas primed stem cells (SCs) generate TACs, quiescent SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but the TAC pool wanes if they can't produce SHH. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent SCs' special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent SCs, replenishment of primed SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrators of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Innocuous touch of the skin is detected by distinct populations of neurons, the low-threshold mechanoreceptors (LTMRs), which are classified as Aβ-, Aδ-, and C-LTMRs. Here, we report genetic labeling of LTMR subtypes and visualization of their relative patterns of axonal endings in hairy skin and the spinal cord. We found that each of the three major hair follicle types of trunk hairy skin (guard, awl/auchene, and zigzag hairs) is innervated by a unique and invariant combination of LTMRs; thus, each hair follicle type is a functionally distinct mechanosensory end organ. Moreover, the central projections of Aβ-, Aδ-, and C-LTMRs that innervate the same or adjacent hair follicles form narrow LTMR columns in the dorsal horn. These findings support a model of mechanosensation in which the activities of Aβ-, Aδ-, and C-LTMRs are integrated within dorsal horn LTMR columns and processed into outputs that underlie the perception of myriad touch sensations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

When surface epithelium was conditionally targeted for ablation of alpha-catenin, hair follicle development was blocked and epidermal morphogenesis was dramatically affected, with defects in adherens junction formation, intercellular adhesion, and epithelial polarity. Differentiation occurred, but epidermis displayed hyperproliferation, suprabasal mitoses, and multinucleated cells. In vitro, alpha-catenin null keratinocytes were poorly contact inhibited and grew rapidly. These differences were not dependent upon intercellular adhesion and were in marked contrast to keratinocytes conditionally null for another essential intercellular adhesion protein, desmoplakin (DP). KO keratinocytes exhibited sustained activation of the Ras-MAPK cascade due to aberrations in growth factor responses. Thus, remarkably, features of precancerous lesions often attributed to defects in cell cycle regulatory genes can be generated by compromising the function of alpha-catenin.

To explore the physiological roles of transforming growth factor alpha (TGF alpha), we disrupted the mouse gene by homologous recombination in embryonic stem cells. Homozygous mutant mice were viable and fertile, but displayed pronounced waviness of the whiskers and fur, accompanied by abnormal curvature, disorientation, and misalignment of the hair follicles. Homozygous and, to a lesser extent, heterozygous mice displayed eye abnormalities of variable incidence and severity, including open eyelids at birth, reduced eyeball size, and superficial opacity. Histological examination revealed eyelid and anterior segment dysgenesis, corneal inflammation and scarring, and lens and retinal defects. Although TGF alpha deficiency affected skin and eyes, wound healing in these tissues was not impaired. Similar hair and eye defects have been previously associated with the recessive mutation waved-1 (wa-1), and Northern analysis revealed reduced expression of TGF alpha in wa-1 mice. Crosses between wa-1 homozygotes and TGF alpha-targeted mice confirmed that wa-1 and TGF alpha are allelic.