RESUMO
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell-autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing IL-17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
Assuntos
Folículo Piloso , Folículo Piloso/metabolismo , Animais , Camundongos , Epiderme/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Pele/metabolismo , Interleucina-17/metabolismo , HumanosRESUMO
Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
Assuntos
Glândulas Sebáceas , Pele , Diferenciação Celular , Folículo Piloso , Células EpiteliaisRESUMO
Keratins are key structural proteins found in skin and other epithelial tissues. Keratins also protect epithelial cells from damage or stress. Fifty-four human keratins were identified and classified into two families, type I and type II. Accumulating studies showed that keratin expression is highly tissue-specific and used as a diagnostic marker for human diseases. Notably, keratin 79 (KRT79) is type II cytokeratin that was identified as regulator of hair canal morphogenesis and regeneration in skin, but its role in liver remains unclear. KRT79 is undetectable in normal mouse but its expression is significantly increased by the PPARA agonist WY-14643 and fenofibrate, and completely abolished in Ppara-null mice. The Krt79 gene has functional PPARA binding element between exon 1 and exon 2. Hepatic Krt79 is regulated by HNF4A and HER2. Moreover, hepatic KRT79 is also significantly elevated by fasting- and high-fat diet-induced stress, and these increases are completely abolished in Ppara-null mice. These findings suggest that hepatic KRT79 is controlled by PPARA and is highly associated with liver damage. Thus, KRT79 may be considered as a diagnostic marker for human liver diseases.
Assuntos
Hepatopatias , Fígado , Humanos , Camundongos , Animais , Fígado/metabolismo , Queratinas/metabolismo , Hepatopatias/metabolismo , Cabelo/metabolismo , Jejum/metabolismo , Camundongos KnockoutRESUMO
The emergence of hair is a defining event during mammalian skin development, but the cellular mechanisms leading to the opening of the hair follicle canal remain poorly characterized. Our previous studies have shown that early hair buds possess a central column of differentiated keratinocytes expressing Keratin 79 (K79), which marks the future hair follicle opening. Here, we report that during late embryogenesis and early postnatal development, K79+ cells at the distal tips of these columns downregulate E-cadherin, change shape, recede and undergo cell death. These changes likely occur independently of sebaceous glands and the growing hair shaft, and serve to create an orifice for hair to subsequently emerge. Defects in this process may underlie phenomena such as ingrown hair or may potentially contribute to upper hair follicle pathologies including acne, hidradenitis suppurativa and infundibular cysts.
Assuntos
Folículo Piloso/crescimento & desenvolvimento , Queratinas/metabolismo , Glândulas Sebáceas/metabolismo , Fenômenos Fisiológicos da Pele , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Oil-secreting sebaceous glands (SGs) are critical for proper skin function; however, it remains unclear how different factors act together to modulate SG stem cells. Here, we provide functional evidence that each SG lobe is serviced by its own dedicated stem cell population. Upon ablating Notch signaling in different skin subcompartments, we find that this pathway exerts dual counteracting effects on SGs. Suppressing Notch in SG progenitors traps them in a hybrid state where stem and differentiation features become intermingled. In contrast, ablating Notch outside of the SG stem cell compartment indirectly drives SG expansion. Finally, we report that a K14:K5âK14:K79 keratin shift occurs during SG differentiation. Deleting K79 destabilizes K14 in sebocytes, and attenuates SGs and eyelid meibomian glands, leading to corneal ulceration. Altogether, our findings demonstrate that SGs integrate diverse signals from different niches and suggest that mutations incurred within one stem cell compartment can indirectly influence another.
Assuntos
Glândulas Sebáceas/citologia , Pele/citologia , Nicho de Células-Tronco , Células-Tronco/citologia , Animais , Diferenciação Celular , Feminino , Proteínas Hedgehog/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Queratinas/metabolismo , Masculino , Glândulas Tarsais/metabolismo , Camundongos Knockout , Mutação/genética , Receptores Notch/genéticaRESUMO
The uppermost aspect of the hair follicle, known as the infundibulum or hair canal, provides a passageway for hair shaft egress and sebum secretion. Recent studies have indicated that the infundibulum and sebaceous ducts are lined by molecularly distinct differentiated cells expressing markers including Keratin 79 and Gata6. Here, we ablated Gata6 from the skin and observed dilation of both the hair canal and sebaceous ducts, independent of gender and hair cycle stage. Constitutive loss of Gata6 yielded only a mild delay in depilation-induced entry into anagen, while unperturbed mutant mice possessed overtly normal skin and hair. Furthermore, we noted that Keratin 79 and Gata6 expression and localization did not depend upon each other. Our findings implicate Gata6 in maintaining the upper hair follicle and suggest that regulation of this transcription factor may be compromised in pathologies such as acne or infundibular cystic diseases that are characterized by abnormal expansion of this follicular domain.
Assuntos
Fator de Transcrição GATA6/genética , Folículo Piloso/patologia , Glândulas Sebáceas/patologia , Animais , Núcleo Celular/metabolismo , Dilatação Patológica/genética , Feminino , Fator de Transcrição GATA6/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Queratinas/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regeneração/genética , Glândulas Sebáceas/metabolismoRESUMO
The formation of epithelial tubes underlies the development of diverse organs. In the skin, hair follicles resemble tube-like structures with lumens that are generated through poorly understood cellular rearrangements. Here, we show that creation of the hair follicle lumen is mediated by early outward movement of keratinocytes from within the cores of developing hair buds. These migratory keratinocytes express keratin 79 (K79) and stream out of the hair germ and into the epidermis prior to lumen formation in the embryo. Remarkably, this process is recapitulated during hair regeneration in the adult mouse, when K79(+) cells migrate out of the reactivated secondary hair germ prior to formation of a new hair canal. During homeostasis, K79(+) cells line the hair follicle infundibulum, a domain we show to be multilayered, biochemically distinct and maintained by Lrig1(+) stem cell-derived progeny. Upward movement of these cells sustains the infundibulum, while perturbation of this domain during acne progression is often accompanied by loss of K79. Our findings uncover previously unappreciated long-distance cell movements throughout the life cycle of the hair follicle, and suggest a novel mechanism by which the follicle generates its hollow core through outward cell migration.