RESUMEN
Dermal papilla cells (DPCs) are a source of nutrients and growth factors, which support the proliferation and growth of keratinocytes as well as promoting the induction of new hair follicles and maintenance of hair growth. The protection from reactive oxygen species (ROS) and the promotion of angiogenesis are considered two of the basal mechanisms to preserve the growth of the hair follicle. In this study, a noncrosslinked hyaluronic acid (HA) filler (HYDRO DELUXE BIO, Matex Lab S.p.A.) containing several amino acids was tested with in vitro assays on human follicle dermal papilla cells (HFDPCs). The experiments were carried out to investigate the possible protection against oxidative stress and the ability to increase the vascular endothelial growth factor (VEGF) release. The results demonstrated the restoration of cell viability against UVB-induced cytotoxicity and an increase in the VEGF secretion. These data demonstrate the capability of the product to modulate human dermal papilla cells, suggesting a future use in mesotherapy, a minimally invasive local intradermal therapy (LIT), after further clinical investigations.
Asunto(s)
Dermis/metabolismo , Folículo Piloso/metabolismo , Ácido Hialurónico/farmacología , Células Cultivadas , Dermis/efectos de los fármacos , Dermis/crecimiento & desarrollo , Cabello/crecimiento & desarrollo , Folículo Piloso/efectos de los fármacos , Humanos , Ácido Hialurónico/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Recent studies clearly show that cell-derived extracellular vesicles (EVs, including exosomes) can promote hair growth. However, large-scale production of EVs remains a big hurdle. Recently, extracellular vesicle mimetics (EMs) engineered by extrusion through various membranes are emerging as a complementary approach for large-scale production. In this study, to investigate their ability to induce hair growth, we generated macrophage-engineered EMs (MAC-EMs) that activated the human dermal papilla (DP) cells in vitro. MAC-EMs intradermally injected into the skin of C57BL/6 mice were retained for up to 72 h. Microscopy imaging revealed that MAC-EMs were predominately internalized into hair follicles. The MAC-EMs treatment induced hair regrowth in mice and hair shaft elongation in a human hair follicle, suggesting the potential of MAC-EMs as an alternative to EVs to overcome clinical limitation.
Asunto(s)
Vesículas Extracelulares/metabolismo , Folículo Piloso/crecimiento & desarrollo , Folículo Piloso/metabolismo , Cabello/metabolismo , Macrófagos/metabolismo , Animales , Proliferación Celular/fisiología , Células Cultivadas , Dermis/crecimiento & desarrollo , Dermis/metabolismo , Dermis/fisiología , Exosomas/metabolismo , Cabello/crecimiento & desarrollo , Humanos , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Piel/metabolismo , Vía de Señalización Wnt/fisiologíaRESUMEN
Transcription factor p63 has critical functions in epidermal, hindgut/anorectal, and limb development. Human mutations in P63 correlate with congenital syndromes affecting the skin, anorectal, and limbs. Nevertheless, less are detected regarding networks and functions controlled by P63 mutations in dermal fibroblasts, which are closely related to skin physiology. To screen for new targets, we employed microarray technology to investigate the R226Q P63 mutation with regards to the resulting circular RNA (circRNA) profiles from P63 point mutations in human dermal fibroblasts (HDFs). In this study, we show that P63-mutant HDFs display reduced proliferation, collagen synthesis, and myofibroblast differentiation; circAMD1 was also downregulated in P63-mutant HDFs compared with wild-type HDFs. Furthermore, overexpressing circAMD1 rescued the functional and phenotypic alterations of p63-mutant HDFs. We as well determined that miR-27a-3p was circAMD1 target involved in effects of circAMD1 in P63-mutant HDFs. Collectively, our data show that circAMD1 functions as a miR-27a-3p sponge that inhibits the functional and phenotypical alteration of P63-mutant HDFs and may be a critical marker in pathogenesis regarding P63-associated traits.
Asunto(s)
Dermis/crecimiento & desarrollo , MicroARNs/genética , ARN Circular/genética , Piel/crecimiento & desarrollo , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Diferenciación Celular/genética , Proliferación Celular/genética , Colágeno/biosíntesis , Colágeno/genética , Dermis/patología , Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Proteínas Mutantes/genética , Miofibroblastos/metabolismo , ARN Circular/clasificación , Piel/patologíaRESUMEN
Hair loss, including alopecia, is a common and distressing problem for men and women, and as a result, there is considerable interest in developing treatments that can prevent or reverse hair loss. Dermal papillae closely interact with epidermal cells and play a key role during hair follicle induction and hair morphogenesis. As dermal papilla cells (DPCs) lose their hairinducing ability in monolayer cultures in vitro, it is difficult to obtain de novo hair follicle structures following DPC transplantation in vivo. The present study aimed to explore culture conditions to maintain DPC characteristics using conditioned media (CM) from the supernatant of cultured HaCaT keratinocyte cells supplemented with other components. Initially, it was observed that during passaging of in vitro monolayer DPC cultures, the Wnt/ßcatenin pathway was repressed, while the TGFß/Smad pathway was activated, and that HaCaT cells cultivated in 1% fetal bovine serum had higher levels of expression of Wnt3a and Wnt10b compared with normal keratinocytes. Culturing of highpassage (P7) DPCs in CM from HaCaT cells (HaCaTCM) actively stimulated cell proliferation and maintained Sox2 and Versican expression levels. Supplementation of HaCaTCM with SB431542 (SB, a TGFß receptor inhibitor), CHIR99021, (CHIR, a GSK3α/ß inhibitor and activator of Wnt signaling) and plateletderived growth factor (PDGF)AA further increased the expression levels of Sox2, Versican and alkaline phosphatase (ALP) in P7 DPCs. Threedimensional culture of P7 DPCs using hanging drop cultures in HaCaTCM supplemented with SB, CHIR and PDGFAA resulted in larger cell aggregates and a further significant upregulation of Sox2, ALP and Versican expression levels. Taken together, these findings demonstrated that HaCaTCM supplemented with SB, CHIR and PDGFAA may preserve the hairinducing ability of highpassage DPCs and may therefore be useful in reconstructing new hair follicles in vivo.
Asunto(s)
Alopecia/genética , Desdiferenciación Celular/efectos de los fármacos , Dermis/crecimiento & desarrollo , Factor de Crecimiento Derivado de Plaquetas/genética , Alopecia/tratamiento farmacológico , Alopecia/patología , Benzamidas/farmacología , Técnicas de Cultivo de Célula , Medios de Cultivo Condicionados , Dermis/citología , Dioxoles/farmacología , Cabello/crecimiento & desarrollo , Cabello/metabolismo , Folículo Piloso/citología , Folículo Piloso/crecimiento & desarrollo , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The dermal papilla comprises mesenchymal cells in hair follicles, which play the main role in regulating hair growth. Maintaining the potential hair inductivity of dermal papilla cells (DPCs) and dermal sheath cells during cell culture is the main factor in in vitro morphogenesis and regeneration of hair follicles. Using common methods for the cultivation of human dermal papilla reduces the maintenance requirements of the inductive capacity of the dermal papilla and the expression of specific dermal papilla biomarkers. Optimizing culture conditions is therefore crucial for DPCs. Moreover, exosomes appear to play a key role in regulating the hair follicle growth through a paracrine mechanism and provide a functional method for treating hair loss. The present review investigated the biology of DPCs, the molecular and cell signaling mechanisms contributing to hair follicle growth in humans, the properties of the dermal papilla, and the effective techniques in maintaining hair inductivity in DPC cultures in humans as well as hair follicle bioengineering.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Dermis/citología , Dermis/crecimiento & desarrollo , Folículo Piloso/citología , Folículo Piloso/crecimiento & desarrollo , Dermis/metabolismo , Cabello/citología , Cabello/crecimiento & desarrollo , Cabello/metabolismo , Folículo Piloso/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Regeneración/fisiologíaRESUMEN
The hair follicle goes through repetitive cycles including anagen, catagen, and telogen. The interaction of dermal papilla cells (DPCs) and keratinocytes regulates the hair cycle and hair growth. Humanin was discovered in the surviving brain cells of patients with Alzheimer's disease. HNG, a humanin analogue, activates cell growth, proliferation, and cell cycle progression, and it protects cells from apoptosis. This study was performed to investigate the promoting effect and action mechanisms of HNG on hair growth. HNG significantly increased DPC proliferation. HNG significantly increased hair shaft elongation in vibrissa hair follicle organ culture. In vivo experiment showed that HNG prolonged anagen duration and inhibited hair follicle cell apoptosis, indicating that HNG inhibited the transition from the anagen to catagen phase mice. Furthermore, HNG activated extracellular signal-regulated kinase (Erk)1/2, Akt, and signal transducer and activator of transcription (Stat3) within minutes and up-regulated vascular endothelial growth factor (VEGF) levels on DPCs. This means that HNG could induce the anagen phase longer by up-regulating VEGF, which is a Stat3 target gene and one of the anagen maintenance factors. HNG stimulated the anagen phase longer with VEGF up-regulation, and it prevented apoptosis by activating Erk1/2, Akt, and Stat3 signaling.
Asunto(s)
Dermis/crecimiento & desarrollo , Folículo Piloso/crecimiento & desarrollo , Cabello/crecimiento & desarrollo , Péptidos y Proteínas de Señalización Intracelular/farmacología , Animales , Apoptosis , Ciclo Celular , Proliferación Celular , Células Cultivadas , Dermis/efectos de los fármacos , Dermis/metabolismo , Femenino , Cabello/efectos de los fármacos , Cabello/metabolismo , Folículo Piloso/efectos de los fármacos , Folículo Piloso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Wistar , Fenómenos Fisiológicos de la PielRESUMEN
Implantation of autologous fibroblasts is a method used to correct age-related changes in facial skin. The aim of this study was to establish the optimal population of cultured human fibroblasts according to the organization of the extracellular matrix in the dermis. Transcriptome profile analysis of cells derived from three consecutive passages indicated that fibroblasts after the second passage were the population with the greatest number of upregulated genes encoding the critical biological processes responsible for skin regeneration, such as extracellular matrix organization, collagen fibril organization, and cell adhesion. Furthermore, genes encoding proteinases responsible for the degradation of dermal extracellular matrix proteins were noticeably downregulated at this stage of culture. Autologous fibroblasts seem to be an optimal and safe biological filler for the renewal of all skin structures.
Asunto(s)
Dermis/crecimiento & desarrollo , Cara/fisiología , Desarrollo Maxilofacial/genética , Transcriptoma/genética , Dermis/metabolismo , Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/genética , Fibroblastos , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of this work was to examine the content of Piezo1 in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of Piezo1 in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. Piezo1, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for Piezo1 in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of Piezo1 positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of Piezo1 in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of Piezo1 in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.
Asunto(s)
Vasos Sanguíneos , Dermis , Fibroblastos , Canales Iónicos , Envejecimiento de la Piel , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vasos Sanguíneos/fisiología , Niño , Preescolar , Dermis/irrigación sanguínea , Dermis/citología , Dermis/embriología , Dermis/crecimiento & desarrollo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Lactante , Canales Iónicos/metabolismo , Masculino , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Embarazo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Envejecimiento de la Piel/fisiologíaRESUMEN
The regeneration of proliferation potential of dermal papilla (DP) cells contributes to the treatment of hair loss disorders. Ginkgolide B (GKB) and bilobalide (BB) are two functional components isolated from Ginkgo biloba that can promote hair growth. In the current study, the effect of GKB or BB on DP cell viability and the related signaling was assessed. Hair follicles were isolated from minks, and the growth of hair follicles was measured under the administration of GKB or BB. DP cells isolated from minks were also subjected to GKB or BB. The administration of GKB or BB induced the growth of hair follicles. The viability of DP cells was also increased by GKB or BB as illustrated by methyl thiazolyl tetrazolium and flow cytometry detection. Moreover, the secretion of VEGF was enhanced by GKB or BB. At molecular level, the activities of Akt, ERK1/2, and ß-catenin were induced by GKB, whereas BB only increased the activities of Akt and ß-catenin. In conclusion, although the two components influenced the ß-catenin signaling activity in distinct mechanisms, they both increased the viability of DP cells and promoted the cycle of hair follicles.
Asunto(s)
Ciclopentanos/farmacología , Furanos/farmacología , Ginkgólidos/farmacología , Folículo Piloso/crecimiento & desarrollo , Lactonas/farmacología , Visón/crecimiento & desarrollo , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclopentanos/química , Dermis/efectos de los fármacos , Dermis/crecimiento & desarrollo , Furanos/química , Ginkgo biloba/química , Ginkgólidos/química , Folículo Piloso/efectos de los fármacos , Lactonas/química , Transducción de Señal/efectos de los fármacos , beta Catenina/genéticaRESUMEN
The lymphatic vascular system plays important roles in the control of tissue fluid homeostasis and immune responses. While VEGF-A-induced angiogenesis promotes hair follicle (HF) growth, the potential role of lymphatic vessels (LVs) in HF cycling has remained unknown. In this study, we found that LVs are localized in close proximity to the HF bulge area throughout the postnatal and depilation-induced hair cycle in mice and that a network of LVs directly connects the individual HFs. Increased LV density in the skin of K14-VEGF-C transgenic mice was associated with prolongation of anagen HF growth. Conversely, HF entry into the catagen phase was accelerated in K14-sVEGFR3 transgenic mice that lack cutaneous LVs. Importantly, repeated intradermal injections of VEGF-C promoted hair growth in mice. Conditioned media from lymphatic endothelial cells promoted human dermal papilla cell (DPC) growth and expression of IGF-1 and alkaline phosphatase, both activators of DPCs. Our results reveal an unexpected role of LVs in coordinating and promoting HF growth and identify potential new therapeutic strategies for hair loss-associated conditions.
Asunto(s)
Folículo Piloso/crecimiento & desarrollo , Linfangiogénesis/fisiología , Vasos Linfáticos/fisiología , Piel/crecimiento & desarrollo , Animales , Ciclo Celular/fisiología , Proliferación Celular/genética , Células Cultivadas , Dermis/citología , Dermis/crecimiento & desarrollo , Femenino , Folículo Piloso/citología , Folículo Piloso/metabolismo , Remoción del Cabello , Humanos , Linfangiogénesis/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regeneración/genética , Piel/citología , Piel/metabolismo , Factor C de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.
Asunto(s)
Alopecia/genética , Butirofenonas/farmacología , Folículo Piloso/crecimiento & desarrollo , Proteína Quinasa 3 Activada por Mitógenos/genética , Piperidinas/farmacología , Alopecia/tratamiento farmacológico , Alopecia/patología , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Dermis/efectos de los fármacos , Dermis/crecimiento & desarrollo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/genética , Regulación de la Expresión Génica/efectos de los fármacos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Folículo Piloso/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
Hair loss, also known as alopecia, is a common dermatological condition of psychosocial significance; development of therapeutic candidates for the treatment of this condition is, hence, important. Silibinin, a secondary metabolite from Silybum marianum, is an effective antioxidant that also prevents various cutaneous problems. In this study, we have investigated the effect of silibinin on hair induction using three-dimensional (3D) cultured, human dermal papilla (DP) spheroids. Silibinin was found to significantly increase viability through AKT serine/threonine kinase (AKT) activation in 3D DP spheroids. This was correlated with an increase in the diameter of the 3D DP spheroids. The activation of the wingless and INT-1 (Wnt)/ß-catenin signaling pathway, which is associated with hair growth induction in the DP, was evaluated using the T cell-specific transcription factor and lymphoid enhancer-binding factor (TCF/LEF) transcription factor reporter assay; results indicated significantly increased luciferase activity. In addition, we were able to demonstrate increased expression of the target genes, WNT5a and LEF1, using quantitative real-time PCR assay. Lastly, significantly elevated expression of signature genes associated with hair induction was demonstrated in the 3D DP spheroids treated with silibinin. These results suggest that silibinin promotes proliferation and hair induction through the AKT and Wnt/ß-catenin signaling pathways in 3D DP spheroids. Silibinin can be a potential candidate to promote hair proliferation.
Asunto(s)
Antioxidantes/farmacología , Dermis/efectos de los fármacos , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Silibina/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dermis/citología , Dermis/crecimiento & desarrollo , Dermis/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Folículo Piloso/citología , Folículo Piloso/metabolismo , Humanos , Factor de Unión 1 al Potenciador Linfoide/genética , Fosforilación , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Proteína Wnt-5a/genéticaRESUMEN
Norgalanthamine has been shown to possess hair-growth promoting effects, including increase in hair-fiber length in cultured rat vibrissa follicles and increase in dermal papilla cell (DPC) proliferation. However, the intracellular mechanisms that underlie the action of norgalanthamine in DPCs have not been investigated. In this study, we addressed the ability of norgalanthamine to trigger anagen-activating signaling pathways in DPCs. Norgalanthamine significantly increased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at 0.1 µM, a concentration at which DPC proliferation was also induced. Furthermore, the increases in norgalanthamine-induced ERK 1/2 activation and subsequent DPC proliferation were suppressed by the mitogen-activated protein kinase/ERK kinase (MEK) 1/2 inhibitor, U0126. A 0.1 µM dose of norgalanthamine also increased phosphorylation of AKT, which was followed by an increase in glycogen synthase kinase 3ß phosphorylation and nuclear translocation of ß-catenin. In addition, LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, blocked the effect of norgalanthamine on DPC proliferation. These results suggest that norgalanthamine can stimulate the anagen phase of the hair cycle in DPCs via activation of the ERK 1/2, PI3K/AKT, and Wnt/ß-catenin pathways.
Asunto(s)
Dermis/efectos de los fármacos , Dermis/crecimiento & desarrollo , Galantamina/análogos & derivados , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Transformada , Proliferación Celular/efectos de los fármacos , Galantamina/farmacología , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Ratas , Transducción de Señal/fisiología , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/fisiologíaRESUMEN
Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed in vivo live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue-scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration.
Asunto(s)
Linaje de la Célula/genética , Dermis/crecimiento & desarrollo , Piel/crecimiento & desarrollo , Cicatrización de Heridas/genética , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Dermis/metabolismo , Matriz Extracelular/genética , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Ratones , Piel/metabolismoRESUMEN
Human hair dermal papilla (DP) cells are specialized mesenchymal cells that play a pivotal role in hair regeneration and hair cycle activation. The current study aimed to first develop three-dimensional (3D) DP spheroids (DPS) with or without a silk-gelatin (SG) microenvironment, which showed enhanced DP-specific gene expression, resulting in enhanced extracellular matrix (ECM) production compared with a monolayer culture. We tested the feasibility of using this DPS model for drug screening by using minoxidil, which is a standard drug for androgenic alopecia. Minoxidil-treated DPS showed enhanced expression of growth factors and ECM proteins. Further, an attempt has been made to establish an in vitro 3D organoid model consisting of DPS encapsulated by SG hydrogel and hair follicle (HF) keratinocytes and stem cells. This HF organoid model showed the importance of structural features, cell-cell interaction, and hypoxia akin to in vivo HF. The study helped to elucidate the molecular mechanisms to stimulate cell proliferation, cell viability, and elevated expression of HF markers as well as epithelial-mesenchymal crosstalks, demonstrating high relevance to human HF biology. This simple in vitro DP organoid model system has the potential to provide significant insights into the underlying mechanisms of HF morphogenesis, distinct molecular signals relevant to different stages of the hair cycle, and hence can be used for controlled evaluation of the efficacy of new drug molecules.
Asunto(s)
Folículo Piloso/crecimiento & desarrollo , Cabello/crecimiento & desarrollo , Células Madre Mesenquimatosas/citología , Organoides/crecimiento & desarrollo , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Dermis/citología , Dermis/crecimiento & desarrollo , Transición Epitelial-Mesenquimal/genética , Femenino , Cabello/citología , Folículo Piloso/citología , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Organoides/citología , Regeneración/genéticaRESUMEN
Versican, a large chondroitin sulfate (CS) proteoglycan, serves as a structural macromolecule of the extracellular matrix (ECM) and regulates cell behavior. We determined the function of versican in dermal development using VcanΔ3/Δ3 mutant mice expressing versican with deleted A-subdomain of the N-terminal G1 domain. The mutant versican showed a decreased hyaluronan (HA)-binding ability and failed to accumulate in the ECM. In the early developmental stage, VcanΔ3/Δ3 dermis showed a decrease in versican expression as compared with WT. As development proceeded, versican expression further decreased to a barely detectable level, and VcanΔ3/Δ3 mice died at the neonatal period (P0). At P0, VcanΔ3/Δ3 dermis exhibited an impaired ECM structure and decreased cell density. While the level of collagen deposition was similar in both genotypes, collagen biosynthesis significantly decreased in VcanΔ3/Δ3 fibroblasts as compared with that in wild type (WT). Transforming growth factor ß (TGFß) signaling mediated through the Smad2/3-dependent pathway was down-regulated in VcanΔ3/Δ3 fibroblasts and a reduced TGFß storage in the ECM was observed. Microarray analysis revealed a decrease in the expression levels of transcription factors, early growth response (Egr) 2 and 4, which act downstream of TGFß signaling. Thus, our results suggest that A-subdomain is necessary for adequate versican expression in dermis and that versican is involved in the formation of the ECM and regulation of TGFß signaling.
Asunto(s)
Dermis/crecimiento & desarrollo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Transducción de Señal , Versicanos/metabolismo , Animales , Células Cultivadas , Dermis/citología , Matriz Extracelular/genética , Fibroblastos/citología , Ratones , Mutación , Dominios Proteicos , Versicanos/genética , Versicanos/farmacologíaRESUMEN
Zinc (Zn), which is an essential trace element, is involved in numerous mammalian physiological events; therefore, either a deficiency or excess of Zn impairs cellular machineries and influences physiological events, such as systemic growth, bone homeostasis, skin formation, immune responses, endocrine function, and neuronal function. Zn transporters are thought to mainly contribute to Zn homeostasis within cells and in the whole body. Recent genetic, cellular, and molecular studies of Zn transporters highlight the dynamic role of Zn as a signaling mediator linking several cellular events and signaling pathways. Dysfunction in Zn transporters causes various diseases. This review aims to provide an update of Zn transporters and Zn signaling studies and discusses the remaining questions and future directions by focusing on recent progress in determining the roles of SLC39A/ZIP family members in vivo.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/metabolismo , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Dermis/crecimiento & desarrollo , Dermis/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Transducción de Señal , Zinc/metabolismoRESUMEN
The skin surface area varies flexibly in response to body shape changes. Skin homeostasis is maintained by stem cells residing in the basal layer of the interfollicular epidermis. However, how the interfollicular epidermal stem cells response to physiological body shape changes remains elusive. Here, we identify a highly proliferative interfollicular epidermal basal cell population in the rapidly expanding abdominal skin of pregnant mice. These cells express Tbx3 that is necessary for their propagation to drive skin expansion. The Tbx3+ basal cells are generated from Axin2+ interfollicular epidermal stem cells through planar-oriented asymmetric or symmetric cell divisions, and express transit-amplifying cell marker CD71. This biased division of Axin2+ interfollicular epidermal stem cells is induced by Sfrp1 and Igfbp2 proteins secreted from dermal cells. The Tbx3+ basal cells promote wound repair, which is enhanced by Sfrp1 and Igfbp2. This study elucidates the interfollicular epidermal stem cell/progeny organisation during pregnancy and suggests its application in regenerative medicine.The abdominal skin expands rapidly during pregnancy. Here the authors show that a population of highly proliferative stem cell progenies expressing the transcription factor Tbx3 is required for abdominal skin expansion in pregnant mice.
Asunto(s)
Dermis/metabolismo , Células Epiteliales/metabolismo , Embarazo/metabolismo , Células Madre/citología , Proteínas de Dominio T Box/metabolismo , Animales , Proteína Axina/genética , Proteína Axina/metabolismo , Proliferación Celular , Dermis/citología , Dermis/crecimiento & desarrollo , Células Epiteliales/citología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Embarazo/genética , Regeneración , Piel/citología , Piel/crecimiento & desarrollo , Piel/metabolismo , Células Madre/metabolismo , Proteínas de Dominio T Box/genéticaRESUMEN
To investigate sexual dimorphism and postnatal changes in skin collagen expression, mRNA levels of collagens and their regulatory factors in male and female skin were examined during the first 120 days of age by quantitative realtime PCR. Levels of mRNAs encoding extracellular matrices did not show any differences between male and female mice until day 15. Col1a1 and Col1a2 mRNAs noticeably increased at day 30 and remained at high levels until day 120 in male mice, while those in female mice remained at low levels during the period. Consistent with the mRNA expression, pepsin-soluble type I collagen contents in skin was very high in mature male as compared to female. Col3a1 mRNA in male mice also showed significantly high level at day 120 as compared to female. On the other hand, expression of mRNAs encoding TGF-ßs and their receptors did not show apparent sexual dimorphism although small significant differences were observed at some points. Castration at 60 days of age resulted in a significant decrease in type I collagen mRNA expression within 3 days, and noticeably decreased expression of all fibril collagen mRNAs examined within 14 days, while administration of testosterone tube maintained the mRNA expression at high levels. Despite the in vivo effect of testosterone, administration of physiological concentrations of testosterone did not affect fibril collagen mRNA expression in either human or mouse skin fibroblasts in vitro, suggesting that testosterone does not directly affect collagen expression in fibroblasts. In summary, present study demonstrated dynamic postnatal changes in expression of collagens and their regulatory factors, and suggest that testosterone and its effects on collagen expression are responsible for the skin sexual dimorphism but the effects of testosterone is not due to direct action on dermal fibroblasts.
Asunto(s)
Colágeno/genética , Regulación del Desarrollo de la Expresión Génica , Caracteres Sexuales , Piel/metabolismo , Animales , Animales Recién Nacidos , Castración , Colágeno/metabolismo , Reactivos de Enlaces Cruzados/metabolismo , Dermis/efectos de los fármacos , Dermis/crecimiento & desarrollo , Dermis/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Recién Nacido , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Piel/efectos de los fármacos , Testosterona/farmacologíaRESUMEN
One experiment was conducted to evaluate the effects of two incubation temperature profiles (TEM) and two trace mineral (TM) sources with their inclusion levels on performance and footpad skin development of Ross 708 chickens. A total of 1,000 eggs from 29-wk-old breeders were incubated following two TEM profiles: a standard (S) eggshell temperature (37.8±0.2°C) for 21 d of incubation and an early-low late-high (LH) TEM. The second profile had low (37.2±0.2°C) temperature for the first 3 d, and S until the last 3 d when eggshell temperature was 39.2±0.2°C. At hatch, 15 male and 15 female chicks from each TEM were selected, and footpads sampled. Additionally, 168 males per TEM were placed in 24 battery cages with 7 chickens each. The 48 cages were assigned to two TM dietary treatments: one with inorganic (ITM) sources of Zn (120 ppm), Cu (10 ppm), and Mn (120 ppm) and the other with chelated (CTM) mineral sources using lower inclusion levels of Zn (32 ppm), Cu (8 ppm), and Mn (32 ppm). At 7 and 21 d, BW gain and feed conversion ratio (FCR) were obtained and chicks sampled for footpads. Histological analysis assessed thickness and area ofstratus corneum(SC), epidermis, and dermis. Data were analyzed as a completely randomized block design in a 2×2 factorial arrangement of treatments with TEM and sex as main factors for hatch data and TEM and TM diets for 7 and 21 d data. The LH chicks were heavier than S chicks at hatch, but had more residual yolk. However, S TEM male chickens were heavier at 7 and 21 d. The S TEM had better FCR than LH TEM.Papillaedermis parameters at hatch were higher in the S TEM. At 7 d, SC height and area were increased by the S TEM. At 21 d CTM increased dermis height and area. In conclusion, TEM affected footpad skin development and broiler performance. Replacing ITM with reduced levels of CTM increased dermis development without affecting live performance or other skin layers.