Hair follicle stem cells feel the pressure

The number of hair follicle stem cells decreases during aging and in hair-loss disorders, such as alopecia. In this issue of Cell Stem Cell, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar discover that the hair shaft serves as a physical niche component for the preservation of hair follicle stem cells. The number of hair follicle stem cells decreases during aging and in hair-loss disorders, such as alopecia. In this issue of Cell Stem Cell, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar discover that the hair shaft serves as a physical niche component for the preservation of hair follicle stem cells. Hair follicles are mini-organs that go through stem-cell-regulated cycles of growth and destruction. The terminal product, the hair shaft, provides thermal regulatory and protective functions. Hair thinning and loss are a common occurrence as we age. In general, aging is associated with a decrease in hair follicle stem cell (HFSC) numbers, likely explaining this phenomenon. A variety of mechanisms can cause HFSC loss during aging, such as decreased cell-substratum adhesion leading to differentiation, and loss of mesenchymal niche signals that are necessary for HFSC activation (Koester et al., 2021Koester J. Miroshnikova Y.A. Ghatak S. Chacón-Martínez C.A. Morgner J. Li X. Atanassov I. Altmüller J. Birk D.E. Koch M. et al.Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility.Nat. Cell Biol. 2021; 23: 771-781Crossref PubMed Scopus (17) Google Scholar; Matsumura et al., 2016Matsumura H. Mohri Y. Binh N.T. Morinaga H. Fukuda M. Ito M. Kurata S. Hoeijmakers J. Nishimura E.K. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis.Science. 2016; 351: aad4395Crossref PubMed Scopus (178) Google Scholar; Shin et al., 2020Shin W. Rosin N.L. Sparks H. Sinha S. Rahmani W. Sharma N. Workentine M. Abbasi S. Labit E. Stratton J.A. et al.Dysfunction of Hair Follicle Mesenchymal Progenitors Contributes to Age-Associated Hair Loss.Developmental Cell. 2020; 53: 185-198 e187Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). In this issue of Cell Stem Cell, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar present the surprising finding that hair shaft thinning or loss is sufficient to reduce stem cell numbers. This observation suggests that a positive reinforcing cycle—decreased HFSCs leading to smaller hair follicles, causing loss of additional HFSCs—may act to increase the rate of stem cell loss over time. Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar started by examining the response of mouse HFSCs to plucking, the physical removal of the shaft along with some associated cells. They found that plucking caused an increased rate of apoptosis in HFSCs. This effect was specific to the portion of the hair cycle where follicles were undergoing destruction (catagen) and returning to a resting phase (telogen). In an elegant experiment, the authors plucked hairs, removed associated cells, and re-inserted them into the hair follicle to distinguish between mechanical effects from the inert hair shaft or signaling by the cells removed. Remarkably, reintroducing hair shafts alone into hair follicles rescued the apoptosis of HFSCs, providing strong evidence for a mechanical role of the hair shaft. The authors suggested that the shaft serves as a physical scaffold for the HFSCs, and that its direct association with the niche may promote HFSC survival. Hair follicles thin with aging, raising the question of whether a thinner hair shaft, rather than outright removal, might have the same effect. Hair follicles from aged mice showed a similar apoptotic response that was limited to the catagen/telogen transition. Because aging and plucking are associated with numerous changes to the tissue, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar also used an additional mouse model to induce hair shaft thinning. Pure hair and nail ectodermal dysplasia is a genetic condition in which hair follicles form, but hair is largely absent. Loss of Hoxc13 causes this condition in humans (Lin et al., 2012Lin Z. Chen Q. Shi L. Lee M. Giehl K.A. Tang Z. Wang H. Zhang J. Yin J. Wu L. et al.Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia.Am. J. Hum. Genet. 2012; 91: 906-911Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), and a Hoxc13 knockout mouse model recapitulated the hair loss phenotype. Importantly, Hoxc13 is expressed in differentiating cells that form the hair shaft and not in the stem cells themselves. Remarkably, the authors could show that HFSCs in these mutant mice also undergo apoptosis at the catagen/telogen transition. After plucking, HFSCs became tall and rounded in comparison to their flattened and cuboidal control counterparts (Figure 1). These same changes were noted in HFSCs of both aged and Hoxc13 mutant mice. The authors also found evidence of altered membrane dynamics, consistent with changes in the mechanical microenvironment of HFSCs. In a number of contexts, mechanosensation relies on mechanically activated ion channels to transduce signals into the effected cell (Ranade et al., 2015Ranade S.S. Syeda R. Patapoutian A. Mechanically Activated Ion Channels.Neuron. 2015; 87: 1162-1179Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). To test whether plucking mechanically induced calcium signaling, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar employed intravital 2-photon calcium imaging. HFSCs showed increased intracellular calcium fluxes a few days after plucking. Further, both calcium chelators and inhibitors of mechanically gated ion channels blocked the calcium influx and the apoptosis of stem cells. Genetic analysis specifically implicated Piezo1 in producing the calcium influx and its loss protected stem cells from plucking-induced apoptosis. These data suggest that hair loss results in activation of mechanosensitive calcium signaling, leading to HFSC apoptosis. The authors then turned to a regulator of the apoptotic program in hair follicle cycling to probe the interaction between the Piezo1 mechanosensing pathway and apoptotic pathways in the hair follicle. Tumor necrosis factor alpha (TNFα) is expressed by apoptotic cells during the catagen stage (Pérez-Garijo et al., 2013Pérez-Garijo A. Fuchs Y. Steller H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway.eLife. 2013; 2: e01004Crossref PubMed Scopus (102) Google Scholar), thus it is present at the hair cycle stage where plucking-induced apoptosis occurs. Upon knockout of the TNFα receptor, apoptosis was substantially reduced in plucked catagen HFSCs. Interestingly, ectopic activation of TNFα and Piezo1 signaling together induced apoptosis in HFSCs of normal, un-plucked hair follicles, whereas activation of either one of the pathways alone did not (Figure 1). Through in vitro work in mouse keratinocytes, the authors found that Piezo1 and TNFα together are required for cleaved caspase expression through the mitochondrial depolarization pathway. Further study will be required to understand the molecular details of how these pathways converge to induce apoptosis in HFSCs. This work raises a number of questions about the plasticity of cells and the niche. For instance, it remains unclear whether stem cells can be expanded by increasing hair shaft diameter and/or pressure on stem cells. A successful expansion under these conditions would have important implications, as it would suggest that physical manipulation of an aging niche could restore stem cell numbers. In addition, the importance of this pathway in physiological aging also remains uncertain. Examination of aged Piezo1 mutant mice should directly address whether activation of this pathway is involved in HFSC and hair loss. In summary, Xie et al., 2021Xie Y. Chen D. Jiang K. Song L. Qian N. Du Y. Yang Y. Wang F. Chen T. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis.Cell Stem Cell. 2021; 29: 70-85Abstract Full Text Full Text PDF Scopus (12) Google Scholar reveal a previously unappreciated role for the hair shaft as a physical and mechanical niche component for HFSCs. This finding adds to the emerging literature highlighting ways in which stem cell progeny and the structures they generate can feed back on stem cell activity (Ning et al., 2021Ning W. Muroyama A. Li H. Lechler T. Differentiated Daughter Cells Regulate Stem Cell Proliferation and Fate through Intra-tissue Tension.Cell Stem Cell. 2021; 28: 436-452 e435Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Finally, the authors identify important cell shape and microenvironment requirements for maintaining HFSC homeostasis. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-α axisXie et al.Cell Stem CellOctober 7, 2021In BriefXie et al. demonstrate that hair shaft loss or a diameter decrease causes shrinkage of the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss in aging and disease. Piezo1 triggers calcium influx, causing sensitivity to TNF-α in otherwise resistant HFSCs to induce ectopic apoptosis. Full-Text PDF