ALKBH5-mediated m6A demethylation ameliorates extracellular matrix deposition in cutaneous pathological fibrosis.

BACKGROUND: Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. METHODS: In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. RESULTS: ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner. CONCLUSIONS: Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.

Immunomodulation of wound healing leading to efferocytosis.

Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes-macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis-mediated immunomodulation plays a repair-promoting role in wound healing, providing new insights for patients suffering from various cutaneous wounds.

Advances in GPCR-targeted drug development in dermatology.

Achieving the efficacy and specificity of G-protein-coupled receptor (GPCR) targeting-drugs in the skin remains challenging. Understanding the molecular mechanism underlying GPCR dysfunction is crucial for developing targeted therapies. Recent advances in genetic, signal transduction, and structural studies have significantly improved our understanding of cutaneous GPCR functions in both normal and pathological states. In this review, we summarize recent discoveries of pathogenic GPCRs in dermal injuries, chronic inflammatory dermatoses, cutaneous malignancies, as well as the development of potent potential drugs. We also discuss targeting of cutaneous GPCR complexes via the transient receptor potential (TRP) channel and structure elucidation, which provide new opportunities for therapeutic targeting of GPCRs involved in skin disorders. These insights are expected to lead to more effective and specific treatments for various skin conditions.

Autologous Tissue Repair and Total Face Restoration.

Importance: Total face restoration remains a challenge in modern reconstructive surgery. After 17 years of experiments and preliminary clinical studies, a new concept of face prefabrication was developed for face restoration with autologous tissue. Objective: To evaluate the long-term results of face restoration with autologous tissue and report a finalized and standardized approach of face prefabrication. Design, Setting, and Participants: In this single-center long-term retrospective study, 32 patients who underwent total face restoration between 2005 and 2022 were reviewed. These patients underwent total facial reconstruction, which included flap prefabrication, 3-dimensional printing, tissue expansion, and flap transfer with aid of indocyanine green angiography (IGA). The flap first undergoes prefabrication by transferring vascularized fascia under the skin of the selected chest. A tissue expander is then placed under the fascia to create a large, thin, reliable skin flap after expansion. Once completed, the flap is transferred to the face during the second stage of the reconstruction. Intraoperative IGA is performed to guide the design of subsequent openings for facial fissures. Data were analyzed from July to September 2023. Main Outcomes and Measures: Flap healing, reconstructive outcome, and patient recovery were assessed during follow-up. Three questionnaires, including the 36-Item Short Form Health Survey (SF-36), Aesthetic and Functional Status Score of Facial Soft-Tissue Deformities/Defects, and the EuroQoL Health-Related Quality of Life (EQ-5D-5L), were used to evaluate the quality of life and satisfaction with facial aesthetic and functional status. Results: Of 24 included patients, 14 (58%) were male, and the mean (range) age was 32.9 (8-62) years. The mean (range) follow-up was 5.6 (2-12) years. All patients reported a significant improvement in quality of life (SF-36), especially in mean (SD) social functioning (preoperative score, 53.65 [34.51]; postoperative score, 80.73 [19.10]) and emotional stability (preoperative score, 56.67 [25.55]; postoperative score, 71.17 [18.51]). A total of 22 patients (92%) went back to work. Mean (SD) facial aesthetic status (preoperative score, 4.96 [3.26]; postoperative score, 11.52 [3.49]; P < .001) and functional status (preoperative score, 11.09 [3.51]; postoperative score, 15.78 [3.26]; P < .001) also improved. In addition, there was a significant increase in overall satisfaction and self-reported health status (preoperative score, 8.13 [1.52]; postoperative score, 3.58 [2.31]). Conclusions and Relevance: In this study, 5-year follow-up results suggested that this innovative approach to total face restoration offered a safe and valid option for indicated patients, with acceptable reconstructive and cosmetic outcomes.

Targeting the nuclear long noncoding transcript LSP1P5 abrogates extracellular matrix deposition by trans-upregulating CEBPA in keloids.

Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids.

Total Face Reconstruction with Flap Prefabrication and Soft-Tissue Expansion Techniques.

SUMMARY: Total facial deformities always lead to psychological and functional consequences, making plastic and reconstructive surgery a great challenge. The skin of the anterior chest area is matched in thickness, texture, and color to the head and face. The purpose of this article was to discuss and evaluate reconstructive surgeons' experiences with obtaining a monoblock flap from the anterior thoracic area for entire face reconstruction using flap prefabrication, soft-tissue expansion, and facial plastic surgery following skin flap transplantation. Two patients underwent prefabricated expanded anterior thoracic flap reconstructions for total facial deformities; data collection included face defect size, flap type, the shape of the expander, expansion time, and complications. All the face flaps that were transplanted survived without major complications. It is concluded that using a prefabricated expanded flap to reconstruct an entire facial soft-tissue defect can provide a high degree of matching, a wide enough covering area, and a thin enough skin thickness to cover the face. Autologous flap grafting is easy to implement and has a high application value.

Salvaging Complex Lower Extremity Injury with Laparoscopically Harvested Omental Flaps.

Background: Traumatic injuries to the lower extremities are frequently accompanied by extensive soft tissue loss, combined with vascular damage or exposure of bony tissues, making it difficult to reconstruct; consequently, patients are commonly at risk of amputation. Due to its superior anatomical and biochemical properties, the omental flap has been used to reconstruct soft tissue defects for decades. However, few studies have reported the omental flap's effectiveness in treating severe and complex lower extremity deformities. We attempted to use a laparoscopically harvested omental flap in conjunction with a second-stage skin graft to reduce infections during limb preservation, increase flap survival probability, and restore the aesthetic and functional integrity of the affected extremity. Methods: Seventeen patients with severe lower extremity wounds underwent omental flap transplantation and were followed up for 6 to 12 months to check for surgical complications, evaluate cosmetic results, and ensure proper limb function. Results: There were no complications, such as intestinal adhesion, intestinal volvulus, and peritonitis, with any of the omental grafts. The affected extremities were well-functioning and aesthetically pleasing. Conclusion: Laparoscopically harvested omental flap transplantation with skin grafting is an alternative reconstruction technique for severe lower extremity injuries with massive soft tissue loss and exposed bones and tendons.

Corrigendum: Editorial: Recent innovations to inhibit scar formation for better skin regeneration.

[This corrects the article DOI: 10.3389/fsurg.2023.1325832.].

Smart and versatile biomaterials for cutaneous wound healing.

The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation.

ALKBH5-mediated m6A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability.

BACKGROUND: Impaired wound re-epithelialization contributes to cutaneous barrier reconstruction dysfunction. Recently, N6-methyladenosine (m6A) RNA modification has been shown to participate in the determination of RNA fate, and its aberration triggers the pathogenesis of numerous diseases. Howbeit, the function of m6A in wound re-epithelialization remains enigmatic. METHODS: Alkbh5‒/‒ mouse was constructed to study the rate of wound re-epithelialization after ALKBH5 ablation. Integrated high-throughput analysis combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq was used to identify the downstream target of ALKBH5. In vitro and in vivo rescue experiments were conducted to verify the role of the downstream target on the functional phenotype of ALKBH5-deficient cells or animals. Furthermore, the interacting reader protein and regulatory mechanisms were determined through RIP-qPCR, RNA pull-down, and RNA stability assays. RESULTS: ALKBH5 was specifically upregulated in the wound edge epidermis. Ablation of ALKBH5 suppressed keratinocyte migration and resulted in delayed wound re-epithelialization in Alkbh5‒/‒ mouse. Integrated high-throughput analysis revealed that PELI2, an E3 ubiquitin protein ligase, serves as the downstream target of ALKBH5. Concordantly, exogenous PELI2 supplementation partially rescued keratinocyte migration and accelerated re-epithelialization in ALKBH5-deficient cells, both in vitro and in vivo. In terms of its mechanism, ALKBH5 promoted PELI2 expression by removing the m6A modification from PELI2 mRNA and enhancing its stability in a YTHDF2-dependent manner. CONCLUSIONS: This study identifies ALKBH5 as an endogenous accelerator of wound re-epithelialization, thereby benefiting the development of a reprogrammed m6A targeted therapy for refractory wounds.

Intraoperative Indocyanine Green Angiography Facilitates Flap Fenestration and Facial Organ Fabrication in Total Facial Restoration.

BACKGROUND: As effective measures to visualize flap vasculature and perfusion were unavailable, flap fenestration and facial organ fabrication could not be performed safely, preventing the transition from 2-D coverage to the restoration of the 3-D structure of facial organs. This study aims to evaluate the efficacy of indocyanine green angiography (ICGA) in guiding flap fenestration and facial organ fabrication in total facial restoration. METHODS: Ten patients with total facial scarring following burn injury were enrolled in the study. They were treated with pre-expanded, prefabricated monoblock flaps for total face restoration. The opening of nostrils, oral and palpebral orifices, together with organ fabrication, were conducted under the guidance of intraoperative ICGA via hemodynamic evaluation of flap perfusion. Postoperative follow-up parameters include vascular crisis, infection, flap necrosis and patients' aesthetic and functional recovery. RESULTS: The opening of facial organ orifices was performed at the stage of flap transfer in nine patients. To avoid damaging the major nourishing vessels, the left palpebral orifice was opened eight days after the flap transfer in one patient, as observed by ICGA. Based on ICGA evaluation, the decision to perform additional vascular anastomosis before flap fenestration was made in six patients. Hemodynamic analysis of flap perfusion following fenestration revealed no significant change. Follow-up showed satisfactory aesthetic recovery and well-restored 3-D structures of facial organs. CONCLUSION: This pilot study demonstrates how intraoperative ICGA can enhance the safety of flap fenestration, thereby transforming full facial restoration from the 2-D to the 3-D realm by facilitating facial organ fabrication.

Midface Prelamination by using a Three-dimensional Cervicothoracic Prefabricated Flap.

SUMMARY: The midface is an important area in aesthetics and function and a complex area to manage after burn injuries, trauma, and tumor resection. Traditional treatment to reconstruct midface defects involving the nose, lips and cheeks requires multiple sequential flap surgeries but results in a patch-like appearance, which remains a major challenge for head and neck reconstructive surgeons. This article describes how the authors perform prelamination using the prefabricated cervicothoracic flap on the anterior chest for midface reconstruction. The key point of the authors' procedure is to three-dimensionalize the cervicothoracic prefabricated flap with flap folding, flap rotation, and cartilage grafts for coverage, lining, and support of the nose and lips. This technique may be indicated for extensive midface defects involving total nose and lip loss. It provides a uniform matched facial appearance and significant functional improvement. Donor-site morbidity and the need for multiple flap procedures could be reduced.

Extracellular RNA in melanoma: Advances, challenges, and opportunities.

Melanoma, a malignant mass lesion that originates in melanocytes and has a high rate of malignancy, metastasis, and mortality, is defined by these characteristics. Malignant melanoma is a kind of highly malignant tumor that produces melanin and has a high mortality rate. Its incidence accounts for 1%-3% of all malignant tumors and shows an obvious upward trend. The discovery of biomolecules for the diagnosis and treatment of malignant melanoma has important application value. So far, the exact molecular mechanism of melanoma development relevant signal pathway still remains unclear. According to previous studies, extracellular RNAs (exRNAs) have been implicated in tumorigenesis and spread of melanoma. They can influence the proliferation, invasion and metastasis of melanoma by controlling the expression of target genes and can also influence tumor progression by participating in signal transduction mechanisms. Therefore, understanding the relationship between exRNA and malignant melanoma and targeting therapy is of positive significance for its prevention and treatment. In this review, we did an analysis of extracellular vesicles of melanoma which focused on the role of exRNAs (lncRNAs, miRNAs, and mRNAs) and identifies several potential therapeutic targets. In addition, we discuss the typical signaling pathways involved in exRNAs, advances in exRNA detection and how they affect the tumor immune microenvironment in melanoma.

The application of augmented reality in plastic surgery training and education: A narrative review.

Continuing problems with fewer training opportunities and a greater awareness of patient safety have led to a constant search for an alternative technique to bridge the existing theory-practice gap in plastic surgery training and education. The current COVID-19 epidemic has aggravated the situation, making it urgent to implement breakthrough technological initiatives currently underway to improve surgical education. The cutting edge of technological development, augmented reality (AR), has already been applied in numerous facets of plastic surgery training, and it is capable of realizing the aims of education and training in this field. In this article, we will take a look at some of the most important ways that AR is now being used in plastic surgery education and training, as well as offer an exciting glimpse into the potential future of this field thanks to technological advancements.

Positive feedback loops between fibroblasts and the mechanical environment contribute to dermal fibrosis.

Dermal fibrosis is characterized by excessive deposition of extracellular matrix in the dermis and affects millions of people worldwide and causes limited movement, disfigurement and psychological distress in patients. Fibroblast dysfunction of plays a central role in the pathogenesis of dermal fibrosis and is controlled by distinct factors. Recent studies support the hypothesis that fibroblasts can drive matrix deposition and stiffening, which in turn can exacerbate the functional dysregulation of fibroblasts. Ultimately, through a positive feedback loop, uncontrolled pathological fibrosis develops. This review aims to summarize the phenomenon and mechanism of the positive feedback loop in dermal fibrosis, and discuss potential therapeutic targets to help further elucidate the pathogenesis of dermal fibrosis and develop therapeutic strategies. In this review, fibroblast-derived compositional and structural changes in the ECM that lead to altered mechanical properties are briefly discussed. We focus on the mechanisms by which mechanical cues participate in dermal fibrosis progression. The mechanosensors discussed in the review include integrins, DDRs, proteoglycans, and mechanosensitive ion channels. The FAK, ERK, Akt, and Rho pathways, as well as transcription factors, including MRTF and YAP/TAZ, are also discussed. In addition, we describe stiffness-induced biological changes in the ECM on fibroblasts that contribute to the formation of a positive feedback loop. Finally, we discuss therapeutic strategies to treat the vicious cycle and present important suggestions for researchers conducting in-depth research.

Lean adipose tissue macrophage derived exosome confers immunoregulation to improve wound healing in diabetes.

Chronic non-healing wounds, a prevalent complication of diabetes, are associated with increased mortality in diabetic patients. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the ability to improve glucose tolerance and insulin sensitivity, as well as modulate inflammation. MicroRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we revealed that ATMs isolated from lean mice secrete miRs-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. The miRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ExosLean) revealed that miR-222-3p was up-regulated. Further analyses showed that inhibiting miR-222-3p using a miR inhibitor impaired the macrophage-reprogramming effect of ExosLean. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a connection between miR-222-3p, Bcl2l11/Bim, an inflammatory response effector, macrophage polarization, and diabetic wound healing. In summary, ExosLean act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing, and thus have important implications for wound management in diabetes.