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The present study investigates the multiphasic nature of the mechanical behavior of human dermis. Motivated by experimental observations and by consideration of its composition, a quadriphasic model of the dermis is proposed, distinguishing solid matrix components, interstitial fluid and charged constituents moving within the fluid, i.e., anions and cations. Compression and tensile experiments with and without change of osmolarity of the bath are performed to characterize the chemo-mechanical coupling in the dermis. Model parameters are determined through inverse analysis. The computations predict a dominant role of the permeability in the determination of the temporal evolution of the mechanical response of the tissue. In line with the previous studies on other tissues, the analysis shows that an ideal model based on Donnan's equilibrium overestimates the osmotic pressure in skin for the case of very dilute solutions. The quadriphasic model is applied to predict changes in dermal cell environment and therefore alterations in what is called the "mechanome," associated with skin stretch. The simulations indicate that skin deformation causes a variation in several local variables, including in particular the electric field associated with a deformation-induced non-homogeneous distribution of fixed charges., (© 2024. The Author(s).)

The intact and healthy skin forms a barrier to the outside world and protects the body from mechanical impact. The skin is a complex structure with unique mechano-elastic properties. To better direct the design of biomimetic materials and induce skin regeneration in wounds with optimal outcome, more insight is required in how the mechano-elastic properties emerge from the skin's main constituents, collagen and elastin fibers. Here, we employed two-photon excited autofluorescence and second harmonic generation microscopy to characterize collagen and elastin fibers in 3D in 24 human dermis skin samples. Through uniaxial stretching experiments, we derive uni-directional mechanical properties from resultant stress-strain curves, including the initial Young's modulus, elastic Young's modulus, maximal stress, and maximal and mid-strain values. The stress-strain curves show a large variation, with an average Young's modules in the toe and linear regions of 0.1 MPa and 21 MPa. We performed a comprehensive analysis of the correlation between the key mechanical properties with age and with microstructural parameters, e.g., fiber density, thickness, and orientation. Age was found to correlate negatively with Young's modulus and collagen density. Moreover, real-time monitoring during uniaxial stretching allowed us to observe changes in collagen and elastin alignment. Elastin fibers aligned significantly in both the heel and linear regions, and the collagen bundles engaged and oriented mainly in the linear region. This research advances our understanding of skin biomechanics and yields input for future first principles full modeling of skin tissue., (© 2024. The Author(s).)

Skin aging is a multi-factorial process that affects nearly every aspect of skin biology and function. The processes developing in the skin during aging are based on fundamental molecular mechanisms associated with fibroblasts, the main cellular population of the dermis. It has been revealed that the amount of fibroblasts decreases markedly with age and their functional activity is also reduced. This inevitably leads to a decrease in the regenerative abilities of the skin and the progression of its aging. In this review we consider the mechanisms underlying these processes, mainly the changes observed with age in the stem/progenitor cells that constitute the fibroblastic differon of the dermis and form their microenvironment (niches). These changes lead to the depletion of stem cells, which, in turn, leads to a decrease in the number of differentiated (mature) dermal fibroblasts responsible for the production of the dermal extracellular matrix and its remodeling. We also describe in detail DNA damages, their cellular and systemic consequences, molecular mechanisms of DNA damage response, and also the role of fibroblast senescence in skin aging.

Dupuytren's disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex toward the palm with significant loss of function. Surgical treatments are limited; therefore, effective new therapies for DD are urgently required. To identify the key cellular and molecular pathways driving DD, we employed single-cell RNA sequencing, profiling the transcriptomes of 35,250 human single cells from DD, nonpathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN + /FAP + mesenchymal cells displaying an elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified, including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited the proliferation and altered the profibrotic gene expression of cultured human FAP + mesenchymal cells, demonstrating a functional role for these genes in DD. The power of single-cell RNA sequencing is utilized to identify the major pathogenic mesenchymal subpopulations driving DD and the key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of DD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Induction of new hair follicles (HFs) may be an ultimate treatment goal for alopecia; however, functional cells with HF inductivity must be expanded in bulk for clinical use. In vitro culture conditions are completely different from the in vivo microenvironment. Although fetal and postnatal dermal cells (DCs) have the potential to induce HFs, they rapidly lose this HF inductivity during culture, accompanied by a drastic change in gene expression. This suggests that epigenetic regulation may be involved. Of the various histone deacetylases (HDACs), Class I HDACs are noteworthy because they are ubiquitously expressed and have the strongest deacetylase activity. This study revealed that DCs from postnatal mice rapidly lose HF inductivity and that this reduction is accompanied by a significant decrease in histone H3 acetylation. However, MS-275, an inhibitor of class I HDACs, preserves HF inductivity in DCs during culture, increasing alkaline phosphatase activity and upregulating HF inductive genes such as BMP4, HEY1, and WIF1. In addition, the inhibition of class I HDACs activates the Wnt signaling pathway, the most well-described molecular pathway in HF development, via increased histone H3 acetylation within the promoter region of the Wnt transcription factor LEF1. Our results suggest that class I HDACs could be a potential target for the neogenesis of HFs., (© 2021. The Author(s).)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The use of DNA as a functional biomaterial for therapeutic, diagnostic, and drug delivery applications has been prominent in recent years, but its use as a scaffold for tissue regeneration is still limited. This study aimed to evaluate the biocompatibility and interaction of DNA-based polymeric films (DNA-PFs) with primary human fibroblasts (PHF) for regenerative medicine and wound healing purposes. The morphological characterization of the films was performed by scanning electron microscopy, SEM-energy-dispersive X-ray spectroscopy, and atomic force microscopy analysis. Cell viability, cell cycle kinetics, oxidative stress, and migration studies were carried out at 48 and 72 hr of incubation and compared to control cells. Cell adhesion was impaired in the first 24 hr, DNA-PFs with higher concentrations of DNA (1.0 and 2.0 g/L) this effect was not seen in DNA-PFs (0.5 g/L), explained by the difference in topography and roughness of DNA-PFs, but it was overcome after 48 hr of incubation. PHF seeded on DNA films showed higher proliferation and migration rates than the control after 48 hr of incubation, with the maintenance of cell morphology and lower cytotoxicity and oxidative stress during the evaluation time. Therefore, these results indicate that DNA-PFs are highly biocompatible and provide a suitable microenvironment for dermal fibroblasts to maintain their activity, helping build new and more complex biomaterials suitable for future tissue repair applications., (© 2021 Wiley Periodicals LLC.)

How dermis maintains tissue homeostasis in cyclic growth and wounding is a fundamental unsolved question. Here, we study how dermal components of feather follicles undergo physiological (molting) and plucking injury-induced regeneration in chickens. Proliferation analyses reveal quiescent, transient-amplifying (TA) and long-term label-retaining dermal cell (LRDC) states. During the growth phase, LRDCs are activated to make new dermal components with distinct cellular flows. Dermal TA cells, enriched in the proximal follicle, generate both peripheral pulp, which extends distally to expand the epithelial-mesenchymal interactive interface for barb patterning, and central pulp, which provides nutrition. Entering the resting phase, LRDCs, accompanying collar bulge epidermal label-retaining cells, descend to the apical dermal papilla. In the next cycle, these apical dermal papilla LRDCs are re-activated to become new pulp progenitor TA cells. In the growth phase, lower dermal sheath can generate dermal papilla and pulp. Transcriptome analyses identify marker genes and highlight molecular signaling associated with dermal specification. We compare the cyclic topological changes with those of the hair follicle, a convergently evolved follicle configuration. This work presents a model for analyzing homeostasis and tissue remodeling of mesenchymal progenitors., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Lack of adult cells' ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the known effects on elastin post-menopause, thus have primarily included older mostly female populations. In this study, we examined the effects of female sex hormones on the synthesis of elastin by female and male human dermal fibroblasts in engineered dermal substitutes. Differences between the sexes were observed with 17β-estradiol treatment alone stimulating elastin synthesis in female substitutes but not male. TGF-β levels were significantly higher in male dermal substitutes than female dermal substitutes and the levels did not change with 17β-estradiol treatment. The male dermal substitutes had a 1.5-fold increase in cAMP concentration in the presence of 17β-estradiol compared to no hormone controls, while cAMP concentrations remained constant in the female substitutes. When cAMP was added in addition to 17β-estradiol and progesterone in the culture medium, the sex differences were eliminated, and elastin synthesis was upregulated by 2-fold in both male and female dermal substitutes. These conditions alone did not result in functionally significant amounts of elastin or complete elastic fibers. The findings presented provide insights into differences between male and female cells in response to female sex steroid hormones and the involvement of the cAMP pathway in elastin synthesis. Further explorations into the signaling pathways may identify better targets to promote elastic fiber synthesis in skin substitutes.

The dermis has disparate embryonic origins; abdominal dermis develops from lateral plate mesoderm, dorsal dermis from paraxial mesoderm and facial dermis from neural crest. However, the cell and molecular differences and their functional implications have not been described. We hypothesise that the embryonic origin of the dermis underpins regional characteristics of skin, including its response to wounding. We have compared abdomen, back and cheek, three anatomical sites representing the distinct embryonic tissues from which the dermis can arise, during homeostasis and wound repair using RNA sequencing, histology and fibroblast cultures. Our transcriptional analyses demonstrate differences between body sites that reflect their diverse origins. Moreover, we report histological and transcriptional variations during a wound response, including site differences in ECM composition, cell migration and proliferation, and re-enactment of distinct developmental programmes. These findings reveal profound regional variation in the mechanisms of tissue repair. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Tissue homeostasis is maintained through constant, dynamic and heterogeneous communication between cells and their microenvironment. Proteins that are at the same time active at the intracellular, cell periphery and deeper extracellular levels possess the ability to, on the individual molecular level, influence the cells and their microenvironment in a bidirectional manner. The transmembrane collagens are a family of such proteins, which are of notable interest for tissue development and homeostasis. In skin, expression of all transmembrane collagens has been reported and deficiency of transmembrane collagen XVII manifests with distinct skin phenotypes. Nevertheless, transmembrane collagens in skin remain understudied despite the association of them with epidermal wound healing and dermal fibrotic processes. Here, we present an overview of transmembrane collagens and put a spotlight on them as regulators of epidermal-dermal communication and as potential players in fibrinogenesis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermal fibroblast cell migration is a key process in a physiological wound healing. Therefore, the analysis of cell migration is crucial for wound healing research. In this study, lab-on-a-chip technology was used to investigate the effects of basic fibroblast growth factor (bFGF), mitomycin C (MMC), MEK1/2 inhibitor (U0126) and fetal calf serum (FCS) on human dermal fibroblast cell migration. The microdevice was fabricated consisting of microchannels, pneumatic lines and pneumatically-activated actuators by xurographic rapid prototyping. In contrast to current approaches in in vitro wound healing such as scratch assays and silicone inserts in wellplate format, which show high variability and poor reproducibility, the current system aims to automate the wounding procedure at high precision and reproducibility using lab-on-a-chip. Traumatic wounding was simulated on-chip on fibroblast cell monolayers by applying air pressure on the flexible circular membrane actuator. Wound closure was monitored using light microscopy and cell migration was evaluated using image analysis. The pneumatically controlled system generates highly reproducible wound sizes compared to the conventional wound healing assay. As proof-of-principle study wound healing was investigated in the presence of several stimulatory and inhibitory substances and culture including bFGF, MMC, U0126 MEK1/2 inhibitor as well as serum starvation to demonstrate the broad applicability of the proposed miniaturized culture microsystem.

We studied the effect of platelet lysate and platelet-poor plasma from patients with trophic ulcers with and without type 2 diabetes mellitus on proliferation, migration, and apoptosis of human dermal fibroblast, mesenchymal stem cells, and endothelial cells. It is shown that plasma obtained from patients with type 2 diabetes mellitus produced inhibitory effects.

Purpose: This study aims to assess the efficacy and safety of Pelnac dermal regeneration template assisted by vacuum sealing drainage (VSD) and a split-thickness skin graft to cover the large skin and soft-tissue defects at foot and ankle. Methods: This study began from March 2013, up to February 2017. A total of 16 patients met the inclusion and exclusion criteria and were included. For every patient, 2 separate operations were performed, the first being thorough debridement of necrotic tissues immediate coverage of VSD at continuous negative pressure suction, and the second being the autologous split-thickness skin graft. At each follow-up, relevant data were documented. Results: The average follow-up was 16.5 months (range, 12 to 42 months). No infections, hematoma, or seroma were observed. 13 out of 16 patients had a complete skin graft "take" (100%). Patients' satisfaction of esthetic appearance was 76.5 ± 5.2/100. The VSS value was 2.2 ± 2.1, representing a good result. Regarding the sensory recovery, the response "normal or near normal" could be obtained in 14/16 patients. Mean AROM for extension/flexion of the ankle was 48.5 ± 4.8° (range 35-62°), and 93.7% (15/16) of patient could obtain a satisfying functional result. Conclusions: Our report indicated Pelnac provided an effective method for management of complex wounds with underlying bone or tendons exposed.

Transcultured human skin derived precursors (tSKPs) from adherent monolayer culture system have similar characteristics as traditional skin derived precursors (SKPs), making tSKPs a suitable candidate for regenerative medicine. tSKPs can differentiate into fibroblasts. However, little is known about the molecular mechanism of the transition from tSKPs to fibroblasts. Here, we compared the transcriptional profiles of human tSKPs and tSKPs-derived fibroblasts (tFBs) by RNA-Sequence aiming to determine the candidate genes and pathways involving in the differentiation process. A total of 1042 differentially expressed genes (DEGs) were identified between tSKPs and tFBs, with 490 genes up-regulated and 552 genes down-regulated. Our study showed that these DEGs were significantly enriched in tumor necrosis factor signaling pathway, focal adhesion, extracellular matrix-receptor interaction and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. A further transcription factors (TFs) analysis of DEGs revealed the significantly down-expressed TFs (p21, Foxo1and Foxc1) in tFBs were mostly the downstream nodes of PI3K-Akt signaling pathway, which suggested PI3K-Akt signaling pathway might play an important role in tSKPs differentiation. The results of our study are useful for investigating the molecular mechanisms in tSKPs differentiation into tFBs, making it possible to take advantage of their potential application in regenerative medicine.

Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness., Competing Interests: The authors declare no competing interest.

Innovative therapies combining gene-corrected stem cells and the production of bioengineered tissues to treat epidermolysis bullosa are emerging. However, quantitative tests to measure the adhesion forces between two highly viscoelastic substrates such as those found in bilayered bioengineered skin are needed and are still lacking. The objective of this study was to develop a mechanical test to measure the dermal-epidermal adhesion strength of our bilayered tissue-engineered skin substitute (TES) produced with the self-assembly method. We developed a peel test, which allows the displacement of both skin layers in a T configuration, based on the ASTM International standard. A MATLAB program was written to process and analyze raw data. The experimental setup was tested by measuring the dermal-epidermal adhesion strength in TESs produced with normal or collagen VII-deficient cells. Our peel testing method allowed us to detect the impact of the absence of collagen VII in the dermal-epidermal adhesion strength of TESs and also to examine the progression of the dermal-epidermal adhesion strength in relation to culture time in normal TES. Impact statement This study describes a method for assessing the adhesion strength at the dermal-epidermal junction of individual tissue-engineered skin substitute (TES). An ASTM standardized protocol of peel testing was designed to measure this important mechanical property. Our innovative approach will serve as a quality control in the production, improvement, and application of TESs for the treatment of pathologies affecting the dermal-epidermal adhesion such as epidermolysis bullosa. Data presented contribute to research on the interfaces between biological substrates and provide a reference factor for the characterization of products derived from tissue engineering.

Multicellular spheroids can mimic the in vivo microenvironment and maintain the unique functions of tissues, which has attracted great attention in tissue engineering. However, the traditional culture microenvironment with structural deficiencies complicates the culture and collection process and tends to lose the function of multicellular spheroids with the increase of cell passage. In order to construct efficient and functional multicellular spheroids, in this study, a chitosan/polyvinyl alcohol nanofiber sponge which has an open-cell cellular structure is obtained. The hair follicle (HF) regeneration model was employed to evaluate HF-inducing ability of dermal papilla (DP) multicellular spheroids which formed on the cellular structure nanofiber sponge. Through structural fine-tuning, the nanofiber sponge has appropriate elasticity for the creation of a three-dimensional dynamic microenvironment to regulate cellular behavior. The cellular structure nanofiber sponge tilts the balance of cell-substratum and cell-cell interactions to a state which is more conducive to the formation of controllable multicellular spheroids in a short time. More importantly, it improves the secretory activity of high-passaged dermal papilla cells and restores their intrinsic properties. Experiments using BALB/c nude mice show that cultured DP multicellular spheroids could effectively enhance HF-inducing ability. This novel system provides a simple and efficient strategy for multicellular spheroid formation and HF regeneration.

The skin is a multilayered and primary defensive organ. Intimate intercellular communication in the skin is necessary to ensure effective surveillance. Extracellular vesicles (EVs) are being explored for their involvement in intercellular skin communication. The aim of this study was to evaluate how human dermal fibroblasts (HDFs) accelerate EV production during senescence and the effects of senescence-associated EVs on epidermal homeostasis. Replicative senescent HDFs were assessed with senescence-associated β-galactosidase staining and the expression of senescence-related markers. Isolated EVs were characterized by dynamic light scattering and EV marker expression. EVs secreted from untreated young or senescent HDFs, or from those treated with a nSMase inhibitor, antioxidant, and lysosomal activity regulators, were determined by sandwich ELISA for CD81. Human epidermal keratinocytes were treated with young- and senescent HDF-derived EVs. Compared to young HDFs, senescent HDFs produced relatively high levels of EVs due to the increased nSMase activity, oxidative stress, and altered lysosomal activity. The nSMase inhibitor, antioxidant, and agents that recovered lysosomal activity reduced EV secretion in senescent HDFs. Relative to young HDF-derived EVs, senescent HDF-derived EVs were less supportive in keratinocyte differentiation and barrier function but increased proinflammatory cytokine IL-6 levels. Our study suggests that dermis-derived EVs may regulate epidermal homeostasis by reflecting cellular status, which provides insight as to how the dermis communicates with the epidermis and influences skin senescence., Competing Interests: All authors are employees of Amorepacific Corporation.

Background: Chronological skin aging causes the modification of genetic material through enzymes and proteins changes. The process reduces cellular proliferation, along with loss of tissue elasticity, reduced ability to regulate aqueous exchanges, and inefficient tissue replication. Appearance is negatively affected by cumulative changes in coloration, texture, and elasticity over time. The increase in the population's average life expectancy boosts the search for cosmetic therapies that can delay aging, mostly for the noninvasive modalities. Among the various options, radiofrequency therapy is a technique that can help reduce the effects of skin aging., Aim: Therefore, this study aims to review clinical evidence provided by scientific literature on the benefits of using radiofrequency therapy in reducing skin aging effects., Methods: A review of the literature concerning skin aging, characteristics of radiofrequency therapy, and radiofrequency therapy in the treatment of skin laxity and mechanism of action was conducted using PubMed., Results: The included studies have suggested that the mechanism of radiofrequency action is heating the dermis while preserving the epidermis. This heating causes immediate collagen denaturation, which is followed by the formation of new collagen, naturally providing skin tightening and greater elasticity., Conclusion: Even when used as single therapeutic modality, radiofrequency seems to meet the expectations in reducing the effects of skin aging., (© 2019 Wiley Periodicals, Inc.)

Tissue homeostasis requires the balance of growth by cell production and regression through cell loss. In the hair cycle, during follicle regression, the niche traverses the skin through an unknown mechanism to reach the stem cell reservoir and trigger new growth. Here, we identify the dermal sheath that lines the follicle as the key driver of tissue regression and niche relocation through the smooth muscle contractile machinery that generates centripetal constriction force. We reveal that the calcium-calmodulin-myosin light chain kinase pathway controls sheath contraction. When this pathway is blocked, sheath contraction is inhibited, impeding follicle regression and niche relocation. Thus, our study identifies the dermal sheath as smooth muscle that drives follicle regression for reuniting niche and stem cells in order to regenerate tissue structure during homeostasis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Short peptides are applied for supporting skin function during ageing, because they can permeate the intact stratum corneum of the epidermis and affect the cells of the dermis. Short peptides are part of natural metabolism of cells and many of them have geroprotective properties. In the review we are considering the base sorts of peptides that are used for normalized skin fibroblasts function: matrikines, carnosine, collagen peptides, cytokine and growth factor analogs, defensins, immunoprotective peptides and polyfunctional peptides. Polyfunctional peptides (AcSDKP, KED, AEDG, AED) have geroprotective properties, slow apoptosis and stimulate skin cell proliferation, also increase functional activity of skin fibroblasts, normalize intracellular matrix hemostasis. Polyfunctional peptides are the antioxidants and immunoprotectors and can activate microcirculation in dermis. Peptide regulation of skin function during ageing are the fast-developing and prospective area in molecular gerontology.

Hair is a defining feature of mammals and has critical functions, including protection, production of sebum, apocrine sweat and pheromones, social and sexual interactions, thermoregulation, and provision of stem cells for skin homeostasis, regeneration, and repair. The hair follicle (HF) is considered a "mini-organ," consisting of intricate and well-organized structures which originate from HF stem and progenitor cells. Dermal papilla cells are the main components of the mesenchymal compartments in the hair bulb and are instrumental in generating signals to regulate the behavior of neighboring epithelial cells during the hair cycle. Mesenchymal-epithelial interactions within the dermal papilla niche drive HF embryonic development as well as the postnatal hair growth and regeneration cycle. This review summarizes the current understanding of HF development, repair, and regeneration, with special focus on cell signaling pathways governing these processes. In particular, we discuss emerging paradigms of molecular signaling governing the dermal papilla-epithelial cellular interactions during hair growth and maintenance and the recent progress made towards tissue engineering of human hair follicles., (© 2020 S. Karger AG, Basel.)

The tactile sensor lies at the heart of electronic skin and is of great importance in the development of flexible electronic devices. To date, it still remains a critical challenge to develop a large-scale capacitive tactile sensor with high sensitivity and controllable morphology in an economical way. Inspired by the interlocked microridges between the epidermis and dermis, herein, a highly sensitive capacitive tactile sensor by creating interlocked asymmetric-nanocones in poly(vinylidenefluoride-co-trifluoroethylene) film is proposed. Particularly, a facile method based on cone-shaped nanoporous anodized aluminum oxide templates is proposed to cost-effectively fabricate the highly ordered nanocones in a controllable manner and on a large scale. Finite-element analysis reveals that under vertical forces, the strain/stress can be highly strengthened and localized at the contact apexes, resulting in an amplified variation of film permittivity and thickness. Benefiting from this, the developed tactile sensor presents several conspicuous features, including the maximum sensitivity (6.583 kPa -1 ) in the low pressure region (0-100 Pa), ultralow detection limit (≈3 Pa), rapid response/recovery time (48/36 ms), excellent stability and reproducibility (10 000 cycles). These salient merits enable the sensor to be successfully applied in a variety of applications including sign language gesture detection, spatial pressure mapping, Braille recognition, and physiological signal monitoring., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Salamanders are capable of full-thickness skin regeneration where removal of epidermis, dermis and hypodermis results in scar-free repair. What remains unclear is whether regeneration of these tissues recapitulates the cellular events of skin development or occurs through a process unique to regenerative healing. Unfortunately, information on the post-embryonic development of salamander skin is severely lacking, having focused on compartments or cell types, but never on the skin as a complete organ. By examining coordinated development of the epidermis and dermis in axolotls we establish six distinct stages of skin development (I-VI): I-V for normally paedomorphic adults and a sixth stage following metamorphosis. Raising animals either in isolation (zero density pressure) or in groups (density pressure) we find that skin development progresses as a function of animal size and that density directly effects developmental rate. Using keratins, p63, and proliferative markers, we show that when the dermis transforms into the stratum spongiosum and stratum compactum, keratinocytes differentiate into at least three distinct phenotypes that reveal a cryptic stratification program uncoupled from metamorphosis. Lastly, comparing skin regeneration to skin development, we find that dermal regeneration occurs through a unique process, relying heavily on remodeling of the wound extracellular matrix, rather than proceeding through direct development of a dermal lamella produced by the epidermis. By preventing fibroblast influx into the wound bed using beryllium nitrate, we show that in the absence of fibroblast generated ECM production skin regeneration occurs through an alternate route that recapitulates development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Perioperative skin injury is a major issue; therefore, several preventative measures have been developed. However, no previous studies have visualized the effects of stromal edema caused by surgical invasion of skin tissue, and therefore, the details remain unknown. We used an ultrasonic diagnostic imaging device to clarify changes in the skin tissue structure of patients after open surgery., Materials and Methods: Twenty subjects who underwent open hepatectomy were enrolled. We selected the lateral abdomen, upper arms, and lower legs as ultrasonic imaging measurement sites. We performed measurements on the day before surgery and on postoperative days 1, 3, and 5. We calculated the epidermal/dermal tissue thickness, subcutaneous tissue thickness, and skin tissue thickness. We performed a one-way analysis of variance with repeated measurements for each of the postoperatively measured values on the basis of the preoperative values. Significantly different variables were subjected to the Bonferroni method. We evaluated ultrasonic imaging findings and skin injury., Results: Epidermal/dermal tissue thickness at all measurement sites exhibited sustained thickening on postoperative day 5 compared to that preoperatively. The lateral abdomen exhibited thickening of the subcutaneous tissue and skin tissue on postoperative day 1. In addition, increased echogenicity, increased opacity of the layer structure, and a cobblestone appearance occurred during the postoperative course. Postoperatively, 80% of subjects exhibited skin injury., Conclusion: We evaluated the effects of surgical invasion on skin tissue over time. Continual observation and protective skincare are necessary near the surgical wound, where significant invasiveness occurs. Prevention of skin injury due to skin tissue thickening requires further study., (© 2019 The Authors. Skin Research and Technology Published by John Wiley & Sons Ltd.)

For successful intra-articular injection therapy, it is essential to accurately position the tip of the injection needle into the target joint area while administering the drug into the affected tissue. In this study, we investigated the feasibility of a monopolar injection needle and lock-in amplifier (LIA)-based impedance measurement system for detecting the tissue type where the needle tip is located. After positioning the monopolar injection needle tip into the dermis, hypodermis, or muscle layer of pork tissue, the electrical impedance was measured in the frequency range of 10 Hz to 10 kHz. We observed a difference in the results based on the tissue type where the needle was positioned ( p -value < 0.01). Therefore, the monopolar injection needle with electrical impedance measurement can be used to improve intra-articular injection therapy through non-destructive and real-time monitoring of the needle position in the tissues., Competing Interests: The author declares that there is no conflict of interest regarding the publication of this paper.

The fibrotic encapsulation, which is mainly accompanied by an excessive proliferation of fibroblasts, is an undesired phenomenon after the implantation of various medical devices. Beside the surface chemistry, the topography plays also a major role in the fibroblast-surface interaction. In the present study, one-dimensional aluminium oxide (1D Al 2 O 3 ) nanostructures with different distribution densities were prepared to reveal the response of human fibroblasts to the surface topography. The cell size, the cell number and the ability to form well-defined actin fibres and focal adhesions were significantly impaired with increasing distribution density of the 1D Al 2 O 3 nanostructures on the substratum.

The structure and function of the skin relies on the complex expression pattern and organisation of extracellular matrix macromolecules, of which collagens are a principal component. The fibrillar collagens, types I and III, constitute over 90% of the collagen content within the skin and are the major determinants of the strength and stiffness of the tissue. However, the minor collagens also play a crucial regulatory role in a variety of processes, including cell anchorage, matrix assembly, and growth factor signalling. In this article, we review the expression patterns, key functions and involvement in disease pathogenesis of the minor collagens found in the skin. While it is clear that the minor collagens are important mediators of normal tissue function, homeostasis and repair, further insight into the molecular level structure and activity of these proteins is required for translation into clinical therapies., (© 2017 Anatomical Society.)

Dermal regeneration template (DRT) has been well widely implicated in the reconstruction of full-thickness injury. We present our experience and our clinical application of Pelnac® to achieve wound closure with complex acute, upper limb, full-thickness defect post-trauma. A 22-year-old boy presented a soft tissues loss of the back of the hand and forearm with tendon's involvement and exposure. The wound was treated with Pelnac®; the silicone layer was removed at postoperative day 30 and dermal regeneration template was reapplied at the level of the residual tendon exposure; a split-thickness skin graft (0.2 to 0.3 mm) was inserted. Clinically, the reconstructed areas demonstrated good granulation tissue at 14 days with a good take of the skin graft. There were no major acute graft loss, rejection or associated infections cells through downregulating TLR4 expression.

The biomechanical properties of the collagenous dermal matrix are well described but responses to mechanical force by the hair follicles have not been characterised so far. We applied a pulling force on hair follicles to visualise and quantify changes in the keratin-14 and involucrin-positive cell layers of the follicles using nuclear dimensions as an indicator of tissue deformation. Moreover, we used second-harmonic generation imaging to visualise changes in the dermal collagen. We report how the anatomical regions of the follicle respond to the force. Nuclei of the isthmus region were most affected. The nuclei in both K14-positive outer root sheath cells and in involucrin-positive cells were significantly compressed, whereas the response in the infundibulum and suprabulbar regions was more variable. The deformation of the nuclei did not correlate with lamin A/C expression. The changes in the collagenous matrix were distinct at different depths of the dermis as collagen fibrils were compressed closer to each other in the region adjacent to upper suprabulbar follicle and pulled apart near the infundibulum. Thus, the responses to the force are locally defined and the cells in the permanent and cycling parts of the follicle behave differently., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermal papillae (DP) play key roles in hair growth and regeneration by regulating follicular cell activity. Owing to the established roles of exosomes (Exos) in the regulation of cell functions, we investigated whether DP-derived Exos, especially those from three-dimensional (3D)-cultured DP cells, affect hair growth, cycling and regeneration. Exos derived from 3D DP (3D DP-Exos) promoted the proliferation of DP cells and outer root sheath (ORS) cells and increased the expression of growth factors (IGF-1, KGF and HGF) in DP cells. 3D DP-Exo treatment also increased hair shaft elongation in cultured human hair follicles. In addition, local injections of 3D DP-Exos induced anagen from telogen and also prolonged anagen in mice. Moreover, Exo treatment in human DP spheres augmented hair follicle neogenesis when the DP spheres were implanted with mouse epidermal cells. Similar results were obtained using Exos derived from 2D-cultured DP cells (2D DP-Exo). Collectively, our data strongly suggest that Exos derived from DP cells promote hair growth and hair regeneration by regulating the activity of follicular dermal and epidermal cells; accordingly, these findings have implications for the development of therapeutic strategies for hair loss., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

There are many studies on certain skin cell specifications and their contribution to wound healing. In this review, we provide an overview of dermal cell heterogeneity and their participation in skin repair, scar formation, and in the composition of skin substitutes. The papillary, reticular, and hair follicle associated fibroblasts differ not only topographically, but also functionally. Human skin has a number of particular characteristics that are different from murine skin. This should be taken into account in experimental procedures. Dermal cells react differently to skin wounding, remodel the extracellular matrix in their own manner, and convert to myofibroblasts to different extents. Recent studies indicate a special role of papillary fibroblasts in the favorable outcome of wound healing and epithelial-mesenchyme interactions. Neofolliculogenesis can substantially reduce scarring. The role of hair follicle mesenchyme cells in skin repair and possible therapeutic applications is discussed. Participation of dermal cell types in wound healing is described, with the addition of possible mechanisms underlying different outcomes in embryonic and adult tissues in the context of cell population characteristics and extracellular matrix composition and properties. Dermal white adipose tissue involvement in wound healing is also overviewed. Characteristics of myofibroblasts and their activity in scar formation is extensively discussed. Cellular mechanisms of scarring and possible ways for its prevention are highlighted. Data on keloid cells are provided with emphasis on their specific characteristics. We also discuss the contribution of tissue tension to the scar formation as well as the criteria and effectiveness of skin substitutes in skin reconstruction. Special attention is given to the properties of skin substitutes in terms of cell composition and the ability to prevent scarring.

Rationale: Degloving injury of the upper limb often extends to underlying tendons and bone, which is at high risk of treatment failure if only simple reattachment of defatted avulsed skins was performed. Pelnac dermal regeneration template could be used as a treatment choice for necrosis of the reattached avulsed skins in a degloving injury., Patient Concerns: A 48-year-old woman with a degloving injury of the right forearm, wrist, and hand received initial treatment by reattachment of the defatted avulsed skins over the wound bed. However, 17 days postoperatively, the reattached skins developed complete necrosis, leaving large size of tissue defects and tendon/bone exposure., Diagnosis: Failure to reconstruct the skin and soft-tissue envelop by reattachment of the defatted avulsed skins in a severe degloving injury of the upper limb., Interventions: We decided to use a 2-stage procedure of Pelnac dermal regeneration template and secondary skin graft to solve this issue, in consideration of these conditions and the patient' demanding of limb function and aesthetic appearance., Outcomes: At the final follow-up, this patient obtained an excellent result, in term of scar quality, aesthetic appearance, and the ability to perform the daily activities., Lessons: We believe this could become an interesting option in patients who needed revision procedure for management of complex wounds with tendon/bone exposure following the necrosis of reattached skins in degloving injuries.

Effective bleeding control and wound healing are very important and can be life saving. However, traditional wound dressings with structural deficiencies are not effective in controlling bleeding and promoting the regeneration of functional tissues. In this study, a three-dimensional (3D) layered nanofiber sponge was obtained by expanding two-dimensional (2D) nanofiber membranes into the third dimension. This sponge has a layered nanofiber structure, which increases the interfacial interaction between the sponge and blood cells to accelerate hemostasis. Through fine-tuning of structure, the 3D nanofiber sponge acquires properties beneficial to wound healing such as good elasticity and high permeability and fluid absorption ratio. The 3D nanofiber sponges are both highly compressible and resilient, providing tamponade for deep wounds and creating a good 3D dynamic microenvironment to regulate cellular behavior. Further research has demonstrated that the layered nanofiber structure could promote the regeneration of functional dermis and the restoration of differentiated adipocytes during the early repair phase. Experiments using model mice with full-thickness skin defects have shown that the layered nanofiber structure could effectively accelerate wound healing and reduce scar formation. This layered 3D nanofiber sponge design is easy to produce. Due to its excellent wound healing property, this porous nanofiber sponge has great potential for future clinical application as wound dressings., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The dermis is primarily composed of the extracellular matrix (ECM) and fibroblasts. During the aging process, the dermis undergoes significant changes. Collagen, which is a major component of ECM, becomes fragmented and coarsely distributed, and its total amount decreases. This is mainly due to increased activity of matrix metalloproteinases, and impaired transforming growth factor-β signaling induced by reactive oxygen species generated during aging. The reduction in the amount of collagen hinders the mechanical interaction between fibroblasts and the ECM, and consequently leads to the deterioration of fibroblast function and further decrease in the amount of dermal collagen. Other ECM components, including elastic fibers, glycosaminglycans (GAGs), and proteoglycans (PGs), also change during aging, ultimately leading to a reduction in the amount of functional components. Elastic fibers decrease in intrinsically aged skin, but accumulate abnormally in photoaged skin. The changes in the levels of GAGs and PGs are highly diverse, and previous studies have reported conflicting results. A reduction in the levels of functional dermal components results in the emergence of clinical aging features, such as wrinkles and reduced elasticity. Various antiaging approaches, including topicals, energy-based procedures, and dermal fillers, can restore the molecular features of dermal aging with clinical efficacy. This review summarizes the current understanding of skin aging at the molecular level, and associated treatments, to put some of the new antiaging technology that has emerged in this rapidly expanding field into molecular context.

Human autologous bioengineered skin has been successfully developed and used to treat skin injuries in a growing number of cases. In current clinical studies, the biomaterial used is fabricated via plastic compression of collagen hydrogel to increase the density and stability of the tissue. To further facilitate clinical adoption of bioengineered skin, the fabrication technique needs to be improved in terms of standardization and automation. Here, we present a one-step mixing technique using highly concentrated collagen and human fibroblasts to simplify fabrication of stable dermal equivalents. As controls, we prepared cellularized dermal equivalents with three varying collagen compositions. We found that the dermal equivalents produced using the simplified mixing technique were stable and pliable, showed viable fibroblast distribution throughout the tissue, and were comparable to highly concentrated manually produced collagen gels. Because no subsequent plastic compression of collagen is required in the simplified mixing technique, the fabrication steps and production time for dermal equivalents are consistently reduced. The present study provides a basis for further investigations to optimize the technique, which has significant promise in enabling efficient clinical production of bioengineered skin in the future.

It is well known that advancing age is a factor that affects the normal course of wound healing. The population over the age of 65 years is increasing globally, and this may be accompanied by an increase in the number of individuals experiencing delayed wound healing. There is a breadth of research to show that age-related changes in the epidermis and dermis change the skin's ability to resist damage and injury. In particular, the dermoepidermal junction becomes flattened, which predisposes the tissue to shear and friction forces. Within the dermis, alterations in the amount and structure of collagen also mean that the tissue is much more rigid. Prompt assessment of the skin to identify existing conditions as well as preventive measures is therefore essential. This article discusses the anatomy of the skin and the effects of ageing on the tissues. It also offers some guidance on skin assessment and the basics of skin care.

Skin, the outermost layer of the body, fulfills a broad range of functions, protecting internal organs from damage and infection, while regulating the body's temperature and water content via the exchange of heat and fluids. It must be able to withstand and recover from extensive deformation and damage that can occur during growth, movement, and potential injuries. A detailed investigation of the evolution of the collagen architecture of the dermis as a function of deformation is conducted, which reveals new aspects that help us to understand the mechanical response of skin. Juvenile pig is used as a model material because of its similarity to human skin. The dermis is found to have a tridimensional woven structure of collagen fibers, which evolves with deformation. After failure, we observe that the fibers have straightened and aligned in the direction of tension. The effects of strain-rate change, cyclic loading, stress relaxation, and orientation are quantitatively established. Digital image correlation techniques are implemented to quantify skin's anisotropy; measurements of the Poisson ratio are reported. This is coupled with transmission electron microscopy which enables obtaining quantitative strain parameters evaluated through the orientation and curvature of the collagen fibers and their changes, for the first time in all three dimensions of the tissue. A model experiment using braided human hair in tension exhibits a similar J-curve response to skin, and we propose that this fiber configuration is at least partially responsible for the monotonic increase of the tangent modulus of skin with strain. The obtained results are intended to serve as a basis for structurally-based models of skin. STATEMENT OF SIGNIFICANCE: Our study reveals a new aspect of the dermis: it is comprised of a tridimensional woven structure of collagen fibers, which evolves with deformation. This is enabled by primarily two techniques, transmission electron microscopy on three perpendicular planes and confocal images with second harmonic generation fluorescence of collagen, captured at different intervals of depth. After failure, the fibers have straightened and aligned in the direction of tension. Digital image correlation techniques are implemented to quantify skin's anisotropy; measurements of the Poisson ratio are reported. A model experiment using braided human hair in tension exhibits a similar J-curve response to skin, and we propose that this fiber configuration is at least partially responsible for the monotonic increase of the tangent modulus of skin with strain., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We developed a novel skin regeneration therapy combining nevus tissue inactivated by high hydrostatic pressure (HHP) in the reconstruction of the dermis with a cultured epidermal autograft (CEA). The issue with this treatment is the unstable survival of CEA on the inactivated dermis. In this study, we applied collagen/gelatin sponge (CGS), which can sustain the release of basic fibroblast growth factor (bFGF), to the inactivated skin in order to accelerate angiogenesis. Murine skin grafts from C57BL6J/Jcl mice (8 mm in diameter) were prepared, inactivated by HHP and cryopreserved. One month later, the grafts were transplanted subcutaneously onto the back of other mice and covered by CGS impregnated with saline or bFGF. Grafts were harvested after one, two and eight weeks, at which point the engraftment was evaluated through the histology and angiogenesis-related gene expressions were determined by real-time polymerase chain reaction. Histological sections showed that the dermal cellular density and newly formed capillaries in the bFGF group were significantly higher than in the control group. The relative expression of FGF-2, PDGF-A and VEGF-A genes in the bFGF group was significantly higher than in the control group at Week 1. This study suggested that the angiogenesis into grafts was accelerated, which might improve the engraftment of inactivated dermis in combination with the sustained release of bFGF by CGSs., Competing Interests: The authors have declared that no competing interests exist.

The angiogenesis of an implanted construct is among the most important issues in tissue engineering. In this study, spermine was used to modify Bombyx mori silk fibroin (BSF) to synthesize cationized BSF (CBSF). BSF and CBSF were coated in sequence on the surface of polyethyleneimine (PEI)/vascular endothelial growth factor 165/angiopoietin-1 coexpression plasmid DNA (pDNA) complexes to form CBSF/BSF/PEI/pDNA quaternary complexes. BSF scaffolds loaded with carrier/pDNA complexes were prepared as dermal regeneration scaffolds by freeze-drying. In one set of experiments, scaffolds were used to cover a chick embryo chorioallantoic membrane (CAM) to investigate the influence of carrier/pDNA complexes on angiogenesis; in another set of experiments, scaffolds were implanted into dorsal full-thickness wounds in Sprague-Dawley rats to evaluate the effect of carrier/pDNA complex-loaded BSF scaffolds on neovascularization and dermal tissue regeneration. After modification with spermine, the surface zeta potential value of BSF rose to +11 mV from an initial value of -9 mV, and the isoelectric point of BSF increased from 4.20 to 9.04. The in vitro transfection of human umbilical vein endothelial cells (EA.hy926) with quaternary complexes revealed that the CBSF/BSF/PEI/pDNA complexes clearly exhibited lower cytotoxicity and higher transfection efficiency than the PEI/pDNA complexes. The CAM assay showed a more abundant branching pattern of blood vessels in BSF scaffolds loaded with CBSF/BSF/PEI/pDNA complexes than in BSF scaffolds without complexes or loaded with PEI/pDNA complexes. The in vivo experimental results demonstrated that the incorporation of CBSF/BSF/PEI/pDNA complexes could effectively enhance angiogenesis in the implanted BSF scaffolds, thereby promoting the regeneration of dermal tissue, providing a new scaffold for the regeneration of dermal tissue and other tissues containing blood vessels.

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.

Thermoresponsive brushes based on linear poly(glycidyl ether)s (PGEs) have already shown to be functional coatings for cell sheet fabrication. In here, we introduce a method to functionalize polystyrene (PS) tissue culture substrates with thermoresponsive coatings comprising glycidyl ether-based bottlebrush architectures. Utilizing the UV-induced "grafting-from" approach, thermoresponsive oligo(glycidyl ether) acrylate (OGEA) macromonomers were polymerized from PS substrates under bulk conditions. Applying ellipsometry, water contact angle (CA), and atomic force microscopy (AFM) measurements, we found that OGEA coatings exhibit a complex, gel-like structure comprising nanosized roughness and exhibit a temperature-dependent phase transition in water through the reversible hydration of OGEA bottlebrush side chains. To assess the utility of the coatings as functional substrates for cell sheet fabrication, human dermal fibroblast (HDF) adhesion and detachment were investigated. By adjusting the bottlebrush properties via the grafting procedure and coating structure, we were able to harvest confluent HDF sheets from functionalized PS substrates in a temperature-triggered, controlled manner. As the first report on surface-grafted bottlebrushes comprising thermoresponsive side chains with molecular weight of up to 1 kDa, this study demonstrates the potential of OGEA-based coatings for cell sheet fabrication.

Finite element models in conjunction with adequate constitutive relations are pivotal in several physiological and medical applications related to both native and engineered tissues, allowing to predict the tissue response under various loading states. In order to get reliable results, however, the validation of the constitutive models is crucial. Therefore, the main purpose of this work is to provide an experimental-computational approach to the biomechanical investigation of soft tissues such as the dermis. This is accomplished by implementing and validating three widely adopted hyperelastic constitutive models (the Ogden, the Holzapfel, and the Gasser-Ogden-Holzapfel laws) supposed to be adequate to reproduce human reticular dermis mechanical behavior. Biaxial experimental data have represented the basis for the determination of the respective material parameters identified thanks to the definition of a cost function accounting for the discrepancy between experimental and predicted data. Afterwards, the experimental tests have been reproduced through finite element simulations. Hence, the constitutive laws have been validated comparing experimental and numerical outcomes in terms of displacements of four reference points and stress-strain relations. Hence, an experimental-numerical framework is proposed for the investigation of collagenous tissues, which could become more accurate with larger and independent experimental datasets. Graphical abstract ᅟ.

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts that are involved in a broad range of biological processes. Here, we examine the functional role of lncRNAs in feather regeneration. RNA-seq profiling of the regenerating feather blastema revealed that Wnt signaling is among the most active pathways during feather regeneration, with Wnt ligands and their inhibitors showing distinct expression patterns. Co-expression analysis identified hundreds of lncRNAs with similar expression patterns to either the Wnt ligands (the Lwnt group) or their downstream target genes (the Twnt group). Among these, we randomly picked two lncRNAs in the Lwnt group and three lncRNAs in the Twnt group to validate their expression and function. Members in the Twnt group regulated feather regeneration and axis formation, whereas members in the Lwnt group showed no obvious phenotype. Further analysis confirmed that the three Twnt group members inhibit Wnt signal transduction and, at the same time, are downstream target genes of this pathway. Our results suggest that the feather regeneration model can be utilized to systematically annotate the functions of lncRNAs in the chicken genome., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Monitoring oxygen saturation (SO2) in microcirculation is effective for understanding disease dynamics. We have developed an SO2 estimation method, sidestream dark-field (SDF) oximetry, based on SDF imaging. SDF imaging is a noninvasive and clinically applicable technique to observe microcirculation. We report the first in vivo experiment observing the changes in SO2 of microcirculation using SDF oximetry. First, heat from the light-emitting diodes used for the SDF imaging might affect hemodynamics in microcirculation, hence, we performed an experiment to evaluate the influence of that on the SDF oximetry. The result suggested that SDF oximetry had enough stability for long-term experiments. Then, to evaluate the sensitivity of SDF oximetry to alterations in the hemodynamics of the microcirculation, we observed the time-lapsed SO2 changes in the dermis microcirculation of rats under hypoxic stimulation. We confirmed that the SO2 estimated by SDF oximetry was in accordance with changes in the fraction of inspired oxygen (FiO2). Thus, SDF oximetry is considered to be able to observe SO2 changes that occur in accordance with alteration of the microcirculation.

Skin wrinkling is a typical symptom of cutaneous photoaging; however, the skin wrinkling depends on not only the actual age but also exposure history to ultraviolet B (UVB) rays in individuals. Therefore, there is considerable need for its assessment technique in vivo in skin cosmetics and antiaging dermatology. Wrinkles always appear as linear grooves in the skin, and dermal collagen fibers play an important role to determine the morphology and mechanical properties of the skin. Therefore, an optical probe sensitive to dermal collagen fiber and its orientation will be useful. Polarization-resolved second-harmonic-generation (SHG) microscopy is a promising approach for in vivo evaluation of collagen fiber orientation because the efficiency of SHG light is sensitive to collagen fiber orientation when the incident light is linearly polarized. We investigate orientation change of dermal collagen fiber in prewrinkled and wrinkled skins of the UVB-exposed mouse model using polarization-resolved SHG microscopy. A polarization anisotropic image of the SHG light indicates that the change of collagen fiber orientation starts in the prewrinkled skin of UVB-exposed mice, then the wrinkle appears. Furthermore, the dominant direction of collagen fiber orientation in the prewrinkled skin is significantly parallel to the wrinkle direction in the wrinkled skin. This result implies that the change of collagen fiber orientation is a trigger of wrinkling in cutaneous photoaging.

The spiny mouse, Acomys cahirinus, shows remarkable regenerative abilities after excisional skin wounding by regrowing hair, sebaceous glands, smooth muscle, skeletal muscle and dermis without scarring. We have asked here whether this same regeneration can be seen after full thickness thermal burn injuries. Using a brass rod thermal injury model we show that in contrast to the lab mouse, Mus musculus, which forms a thick scar covered by a hairless epidermis, the spiny mouse regenerates all the tissues injured - skeletal muscle, dermis, hairs, sebaceous glands such that the skin is externally indistinguishable from its original appearance. Re-epithelialization is faster in Acomys than in Mus but ingression and proliferation of dermal fibroblasts is the same in both species. After 3 weeks the wound epithelium of Acomys has developed a covering of new hair follicles in contrast to Mus. The skeletal muscle of the panniculus carnosus in Mus shows some regeneration but it is incomplete and fibrotic whereas the Acomys muscle is replaced perfectly. There are differences in the macrophage profiles which invade the damaged tissues such as the absence of F4/80 or MOMA-2 +ve cells in Acomys which likely reflect different cytokine profiles resulting from the same injury in these two species., (Copyright © 2018 Elsevier Ltd and ISBI. All rights reserved.)