ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA.

Approximately 70% of treatment failures in nasopharyngeal carcinoma (NPC) patients are attributed to distant metastasis, yet the underlying mechanisms remain unclear. RNA 5-methylcytosine (m5C) is an emerging regulatory modification that controls gene expression and plays a critical role in tumor progression. However, there is little information on the potential roles of RNA m5C modification in NPC metastasis. In this study, we found that the m5C reader Aly/REF export factor (ALYREF) is significantly upregulated in NPC, whereby its high expression is associated with metastasis and poor prognosis. ALYREF overexpression was found to promote tumor metastasis of NPC cells in vitro and in vivo. Mechanistically, m5C-modified NOTCH1 mRNA was identified as a target of ALYREF. Moreover, ALYREF was found to upregulate NOTCH1 expression by enhancing its RNA stability in an m5C modification-dependent manner, thereby promoting the activation of the NOTCH signaling pathway and facilitating NPC metastasis. Overall, our data reveal the crucial role of ALYREF in NPC metastasis and provide a potential therapeutic target for NPC.

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches.

Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.

The influence of bone block graft position on bone dimensional changes in staged onlay horizontal ridge augmentation: A 6-month retrospective cohort study.

OBJECTIVES: To analyze changes in bone dimensions and their modulating factor in bone dimensions 6 months after horizontal ridge augmentation using autogenous bone grafts. MATERIALS AND METHODS: Thirty-eight patients with horizontally atrophic alveolar ridges of a single edentulous tooth at the maxillary anterior site were divided into two groups based on the fixation position of the bone block during ridge augmentation surgery (H0, vertical distance from the upper edge of the bone block to the alveolar crest). Patients were classified into a crestal level (CL) group if H0 ≤ 1 mm and a sub-crestal level (SCL) group if H0 > 1 mm. The width and height of the alveolar ridge were recorded using CBCT both before and 6 months after the augmentation procedure. RESULTS: The CL group comprised 20 patients with 23 implants, whereas the SCL group comprised 18 patients with 22 implants. All the augmentation sites exhibited vertical bone resorption. Vertical bone resorption in the SCL group (1.94 ± 2.11 mm) was significantly higher than that of the CL group (0.61 ± 0.64 mm). The SCL group showed significantly lower horizontal bone gain than the CL group (SCL: 1.02 ± 2.30 mm; CL: 3.19 ± 3.17 mm) at the cervical level. Peri-implant marginal bone loss increased significantly in the SCL group (1.00 ± 2.71 mm) compared to the CL group (0.64 ± 0.40 mm). CONCLUSION: The bone height decreased after horizontal ridge augmentation using autogenous onlay grafting. The fixation position of the bone block was a modulating factor. The SCL group showed more vertical bone loss, less horizontal bone gain 6 months after surgery, and more marginal bone loss after restoration.

Design and synthesis of sulfonamide phenothiazine derivatives as novel ferroptosis inhibitors and their therapeutic effects in spinal cord injury.

Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC50 = 0.001 µM) and demonstrated a low hERG inhibition activity (IC50 > 30 µM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.

NBR1-mediated autophagic degradation of caspase 8 protects vascular endothelial cells against arsenite-induced apoptotic cell death.

Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.

Single-cell transcriptome profiling reveals cell type-specific variation and development in HLA expression of human skin.

Skin, the largest organ of body, is a highly immunogenic tissue with a diverse collection of immune cells. Highly polymorphic human leukocyte antigen (HLA) molecules have a central role in coordinating immune responses as recognition molecules. Nevertheless, HLA gene expression patterns among diverse cell types within a specific organ, like the skin, have yet to be thoroughly investigated, with stromal cells attracting much less attention than immune cells. To illustrate HLA expression profiles across different cell types in the skin, we performed single-cell RNA sequencing (scRNA-seq) analyses on skin datasets, covering adult and fetal skin, and hair follicles as the skin appendages. We revealed the variation in HLA expression between different skin populations by examining normal adult skin datasets. Moreover, we evaluated the potential immunogenicity of multiple skin populations based on the expression of classical HLA class I genes, which were well represented in all cell types. Furthermore, we generated scRNA-seq data of developing skin from fetuses of 15 post conception weeks (PCW), 17 PCW, and 22 PCW, delineating the dynamic expression of HLA genes with cell type-dependent variation among various cell types during development. Notably, the pseudotime trajectory analysis unraveled the significant variance in HLA genes during the evolution of vascular endothelial cells. Moreover, we uncovered the immune-privileged properties of hair follicles at single-cell resolution. Our study presents a comprehensive single-cell transcriptomic landscape of HLA genes in the skin, which provides new insights into variation in HLA molecules and offers a clue for allogeneic skin transplantation.

De-aberration for transcranial photoacoustic computed tomography through an adult human skull.

Noninvasive transcranial photoacoustic computed tomography (PACT) of the human brain, despite its clinical potential, remains impeded by the acoustic distortion induced by the human skull. The distortion, which is attributed to the markedly different material properties of the skull relative to soft tissue, results in heavily aberrated PACT images -- a problem that has remained unsolved in the past two decades. Herein, we report the first successful experimental demonstration of the de-aberration of PACT images through an ex-vivo adult human skull using a homogeneous elastic model for the skull. Using only the geometry, position, and orientation of the skull, we accurately de-aberrate the PACT images of light-absorbing phantoms acquired through an ex-vivo human skull, in terms of the recovered phantom features, for different levels of phantom complexity and positions. Our work addresses the longstanding challenge of skull-induced aberrations in transcranial PACT and advances the field towards unlocking the full potential of transcranial human brain PACT.

The three-dimensional stability and accuracy of 3D printing surgical templates: An In Vitro study.

OBJECTIVE: To evaluate the three-dimensional (3D) stability and accuracy of additively manufactured surgical templates fabricated using two different 3D printers and materials. MATERIALS AND METHODS: Forty surgical templates were designed and printed using two different 3D printers: the resin group (n = 20) used a digital light processing (DLP) 3D printer with photopolymer resin, and the metal group (n = 20) employed a selective laser melting (SLM) 3D printer with titanium alloy. All surgical templates were scanned immediately after production and re-digitalized after one month of storage. Similarly, the implant simulations were performed twice. Three-dimensional congruency between the original design and the manufactured surgical templates was quantified using the root mean square (RMS), and the definitive and planned implant positions were determined and compared. RESULTS: At the postproduction stage, the metal templates exhibited higher accuracy than the resin templates (p < 0.001), and these differences persisted after one month of storage (p < 0.001). The resin templates demonstrated a significant decrease in three-dimensional stability after one month of storage (p < 0.001), whereas the metal templates were not affected (p > 0.05). No significant differences in implant accuracy were found between the two groups. However, the resin templates showed a significant increase in apical and angular deviations after one month of storage (p < 0.001), whereas the metal templates were not affected (p > 0.05). CONCLUSION: Printed metal templates showed higher fabrication accuracy than printed resin templates. The three-dimensional stability and implant accuracy of printed metal templates remained unaffected by one month of storage. CLINICAL SIGNIFICANCE: With superior three-dimensional stability and acceptable implant accuracy, printed metal templates can be considered a viable alternative technique for guided surgery.

Artificial intelligence-based MRI radiomics and radiogenomics in glioma.

The specific genetic subtypes that gliomas exhibit result in variable clinical courses and the need to involve multidisciplinary teams of neurologists, epileptologists, neurooncologists and neurosurgeons. Currently, the diagnosis of gliomas pivots mainly around the preliminary radiological findings and the subsequent definitive surgical diagnosis (via surgical sampling). Radiomics and radiogenomics present a potential to precisely diagnose and predict survival and treatment responses, via morphological, textural, and functional features derived from MRI data, as well as genomic data. In spite of their advantages, it is still lacking standardized processes of feature extraction and analysis methodology among different research groups, which have made external validations infeasible. Radiomics and radiogenomics can be used to better understand the genomic basis of gliomas, such as tumor spatial heterogeneity, treatment response, molecular classifications and tumor microenvironment immune infiltration. These novel techniques have also been used to predict histological features, grade or even overall survival in gliomas. In this review, workflows of radiomics and radiogenomics are elucidated, with recent research on machine learning or artificial intelligence in glioma.

Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.

PURPOSE: To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. METHODS: Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. RESULTS: A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. CONCLUSION: In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically.

Draft genome sequence analysis of a mcr-1-producing Klebsiella pneumoniae ST661 isolated from a mink in China.

OBJECTIVES: Klebsiella pneumoniae is a major opportunistic pathogen that is a member of the Enterobacteriaceae. Klebsiella pneumoniae causes pneumonia in mink and has become the primary infectious disease that limits mink farming. In this study, we report the draft genome sequence of a multidrug-resistant (MDR) strain of K. pneumoniae that harbours the mcr-1 gene isolated from a mink in China. METHODS: The agar microdilution method was used to determine the minimum inhibitory concentration of the strain. The entire genomic DNA was sequenced using an Illumina MiSeq platform. A multilocus sequence type (MLST) and a core genome SNP phylogenetic tree analysis with a heatmap of the resistance genes and virulence genes were performed. RESULTS: The size of the genome was 5451.826 kb, and it included one chromosome and one plasmid. The draft genome of K. pneumoniae indicated that the isolate was a member of MLST 661. Four types of virulence genes were detected. The results of antimicrobial susceptibility testing showed multiple drug resistance, and 17 resistance genes were identified. CONCLUSION: The genome sequence reported in this study will help to reveal the key role of antibiotic resistance and pathogenic mechanisms. It will provide useful information for the role of mobile genetic elements in the adaptive translocation and spread of antimicrobial resistance.

The role of tumor parenchyma and brain cortex signal intensity ratio in differentiating solitary fibrous tumors and meningiomas.

BACKGROUND: Solitary fibrous tumors (SFT) and meningiomas (MA) have similar clinical and radiographic presentations but require different treatment approaches and have different prognoses. This emphasizes the importance of a correct preoperative diagnosis of SFT versus MA. OBJECTIVE: In this study, investigated the differences in imaging characteristics between SFT and MA to improve the accuracy of preoperative imaging diagnosis of SFT. METHODS: The clinical and imaging data of 26 patients with SFT and 104 patients with MA who were pathologically diagnosed between August 2017 and December 2022, were retrospectively analyzed. The clinical and imaging differences between SFT and MA, as well as between the various pathological grades of SFT, were analyzed. RESULTS: Age, gender, cystic change, flow void phenomenon, yin-yang sign, lobulation, narrow base, tumor/cortex signal ratio (TCSR) > 1.0 in T1-weighted imaging (T1WI), TCSR ≥ 1.1 in T2-weighted imaging (T2WI), peritumoral edema, and absence of dural tail sign varied between SFT and MA. As per the receiver operating characteristic (ROC) curve analysis, TCSR > 1 in T1WI has the maximum diagnostic accuracy for SFT. Cranial or venous sinus invasion had a positive effect on SFT (Grade III, World Health Organization (WHO) grading). CONCLUSION: Among the many radiological and clinical distinctions between SFT and MA, TCSR ≥ 1 exhibits the highest predictive efficacy for SFT; while cranial or venous sinus invasion may be a predictor of WHO grade III SFT.

Natural Sequential Collapse Method: A Common Technique to Identify the Intersegmental Plane.

The natural sequential collapse method (NSCM) can be employed during surgery to reduce the duration of segmentectomy. This method avoids inflating the lung by rapidly blocking vessels within the tumor basin. It is important to note that the color of the lungs should be used to determine the surgical procedure. The NSCM is efficient and straightforward in revealing the intersegmental plane.

Blueberry anthocyanins improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7 to affect ferroptosis of hepatic stellate cells.

This study aims to investigate the role and molecular mechanism of anthocyanin in improving liver fibrosis through ferroptosis, providing a basis for drug development and targeted therapy. In this study, a mouse model of liver fibrosis was established using CCl4, and the anthocyanin treatment groups were administered 100 mg/kg anthocyanin daily via gavage. Furthermore, real-time fluorescent quantitative PCR (qRT-PCR), Western blotting (WB), and enzyme-linked immunosorbent assay were used to assess liver fibrosis indicators and liver injury markers. Histopathological methods were used to confirm the morphology of liver injury in different treatment groups. The effects of anthocyanins on ferroptosis markers, NCOA4 and FTH1 expression, were examined through qRT-PCR, WB, and Co-IP. Confocal microscopy was used to validate the colocalization of ferritin and lysosomes. A differential expression model of TRIM7 was constructed to verify its impact on the progression of liver fibrosis. The present study demonstrates the hepatoprotective effects of anthocyanins in liver fibrosis, highlighting their ability to enhance hepatic stellate cell (HSC) ferroptosis and regulate ferritin autophagy. Moreover, TRIM7 is identified as a key mediator of anthocyanin-induced regulation of hepatic stellate cells activation for liver fibrosis treatment through modulation of ferroautophagy. Mechanistic investigations further reveal that TRIM7 exerts its influence on the process of ferroautophagy by controlling NCOA4 ubiquitination. Our study discovered that anthocyanins could improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7, thereby affecting hepatic stellate cells' ferroptosis levels.NEW & NOTEWORTHY This was the first study to demonstrate that anthocyanins can improve the progression of liver fibrosis by promoting hepatic stellate cell (HSC) ferroptosis. Anthocyanins could affect the content of Fe2+ by promoting ferroautophagy in HSCs, thereby promoting the level of ferroptosis. This study demonstrates for the first time that anthocyanins can inhibit the expression of TRIM7 and then affect the ubiquitination of NCOA4 to regulate the level of ferritin autophagy and ferroptosis.

Optical-resolution photoacoustic microscopy with a needle-shaped beam.

Optical-resolution photoacoustic microscopy (OR-PAM) can visualize wavelength-dependent optical absorption at the cellular level. However, OR-PAM suffers from a limited depth of field (DOF) due to the tight focus of the optical excitation beam, making it challenging to acquire high-resolution images of samples with uneven surfaces or high-quality volumetric images without z-scanning. To overcome this limitation, we propose needle-shaped beam photoacoustic microscopy (NB-PAM), which can extend the DOF to up to ~28-fold Rayleigh lengths via customized diffractive optical elements (DOEs). The DOE generate a needle beam with a well-maintained beam diameter, a uniform axial intensity distribution, and negligible sidelobes. The advantage of using NB-PAM is demonstrated by both histology-like imaging of fresh slide-free organs using a 266 nm laser and in vivo mouse brain vasculature imaging using a 532 nm laser. The approach provides new perspectives for slide-free intraoperative pathological imaging and in-vivo organ-level imaging.

A method for the geometric calibration of ultrasound transducer arrays with arbitrary geometries.

Geometric calibration of ultrasound transducer arrays is critical to optimizing the performance of photoacoustic computed tomography (PACT) systems. We present a geometric calibration method that is applicable to a wide range of PACT systems. We obtain the speed of sound and point source locations using surrogate methods, which results in a linear problem in the transducer coordinates. We characterize the estimation error, which informs our choice of the point source arrangement. We demonstrate our method in a three-dimensional PACT system and show that our method improves the contrast-to-noise ratio, the size, and the spread of point source reconstructions by 80±19%, 19±3%, and 7±1%, respectively. We reconstruct the images of a healthy human breast before and after calibration and find that the calibrated image reveals vasculatures that were previously invisible. Our work introduces a method for geometric calibration in PACT and paves the way for improving PACT image quality.

Single-shot 3D photoacoustic computed tomography with a densely packed array for transcranial functional imaging.

Photoacoustic computed tomography (PACT) is emerging as a new technique for functional brain imaging, primarily due to its capabilities in label-free hemodynamic imaging. Despite its potential, the transcranial application of PACT has encountered hurdles, such as acoustic attenuations and distortions by the skull and limited light penetration through the skull. To overcome these challenges, we have engineered a PACT system that features a densely packed hemispherical ultrasonic transducer array with 3072 channels, operating at a central frequency of 1 MHz. This system allows for single-shot 3D imaging at a rate equal to the laser repetition rate, such as 20 Hz. We have achieved a single-shot light penetration depth of approximately 9 cm in chicken breast tissue utilizing a 750 nm laser (withstanding 3295-fold light attenuation and still retaining an SNR of 74) and successfully performed transcranial imaging through an ex vivo human skull using a 1064 nm laser. Moreover, we have proven the capacity of our system to perform single-shot 3D PACT imaging in both tissue phantoms and human subjects. These results suggest that our PACT system is poised to unlock potential for real-time, in vivo transcranial functional imaging in humans.

Anthocyanins improve liver fibrosis in mice by regulating the autophagic flux level of hepatic stellate cells by mmu_circ_0000623.

Liver fibrosis is a key step in the progression of various chronic liver diseases to liver cirrhosis and even liver cancer, it is also an important link affecting prognosis. Therefore, this study aimed to investigate the therapeutic effect of anthocyanins on liver fibrosis and the molecular mechanism of mmu_circ_0000623 in anthocyanin therapy. In this study, CCL4 was used to build a mouse liver fibrosis model, and the treatment groups were treated with 100 and 200 mg/kg of anthocyanins daily by gavage. Liver fibrosis indicators, macrophage polarization markers, and liver injury markers were further detected by real-time quantitative PCR (qRT-PCR), western blotting (WB), and enzyme-linked immunosorbent assay. Morphological verification of liver injury in different treatment groups was performed by histopathological method. A mouse hepatic stellate cell (HSC) model and a mouse liver fibrosis model were constructed to verify the expression of circ_0000623, miR-351-5p, and TFEB. Transfected with mRFP-GFP-LC3 to detect the autophagic flux of HSCs. We found that 100 mg/kg or 200 mg/kg of anthocyanins could significantly reduce the degree of liver fibrosis in mice. In addition, anthocyanins can inhibit the proliferation, activation, and migration ability of HSCs. circ_0000623 was lowly expressed in mice with liver fibrosis, and anthocyanin treatment could promote its increased expression. Further testing found that anthocyanins could reverse the blocked autophagic flux induced by PDGF or CCL4. This effect is achieved by regulating the expression of TFEB by competitive adsorption of miR-351-5p. Anthocyanins could treat liver fibrosis by modulating circ_0000623/miR-351-5p/TFEB-mediated changes in HSC autophagic flux.

Implant Placement with Simultaneous Guided Bone Regeneration in the Anterior Region Close to the Periapical Lesion of Adjacent Teeth: A Combined Treatment Strategy to Prevent Complications.

PURPOSE: To evaluate the safety and performance of a potential novel strategy to resolve the above scenario by simultaneously performing implant-related surgery and endodontic microsurgery (EMS). MATERIALS AND METHODS: A total of 25 subjects requiring GBR during implant placement in anterior areas were allocated into two groups. In the experimental group (adjacent teeth with periapical lesions) with 10 subjects, implantation and GBR were performed for edentulous areas with simultaneous EMS for adjacent teeth. In the control group (adjacent teeth without periapical lesions) with 15 subjects, implantation and GBR were performed for edentulous areas. The clinical outcomes, radiographic bone remodeling, and patient-reported outcomes were assessed. RESULTS: Within a 1-year follow-up, the implant survival rate was 100% in both groups, with no significant difference regarding complications. All teeth achieved complete healing following EMS. Repeated analysis of variance (ANOVA) measurements revealed a significant change over time in horizontal bone widths and postoperative patient-reported outcomes, but no intergroup statistically significant differences (P > .05) in horizontal bone widths and visual analog scale scores of pain, swelling, and bleeding were observed. Likewise, the bone volumetric decrease (7.4% ± 4.5% in the experimental group and 7.1% ± 5.2% in the control group) from T1 (suture removal) to T2 (6 months after implantation) revealed no intergroup differences. The horizontal bone width gain at the implant platform was slightly lower in the experimental group (P < .05). Interestingly, the color-coded figures of both groups showed a facial reduction of grafted material in edentulous areas. However, the apical regions following EMS exhibited stable bone remodeling in the experimental group. CONCLUSION: This novel approach to address the problem involving implant-related surgery close to the periapical lesion of adjacent teeth appeared safe and reliable (no.: ChiCTR2000041153). Int J Oral Maxillofac Implants 2023;38:533-544. doi: 10.11607/jomi.9839.

Cooperation of TGF-ß and FGF signalling pathways in skin development.

The skin is a multi-layered structure composed of the epidermis, dermis and hypodermis. The epidermis originates entirely from the ectoderm, whereas the dermis originates from various germ layers depending on its anatomical location; thus, there are different developmental patterns of the skin. Although the regulatory mechanisms of epidermal formation are well understood, mechanisms regulating dermis development are not clear owing to the complex origin. It has been shown that several morphogenetic pathways regulate dermis development. Of these, transforming growth factor-ß (TGF-ß) and fibroblast growth factor (FGF) signalling pathways are the main modulators regulating skin cell induction, fate decision, migration and differentiation. Recently, the successful generation of human skin by modulating TGF-ß and FGF signals further demonstrated the irreplaceable roles of these pathways in skin regeneration. This review provides evidence of the role of TGF-ß and FGF signalling pathways in the development of different skin layers, especially the disparate dermis of different body regions. This review also provides new perspectives on the distinct developmental patterns of skin and explores new ideas for clinical applications in the future.