Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.

Immune metabolism is a result of many specific metabolic reactions, such as glycolysis, the tricarboxylic acid (TCA) pathway, the pentose phosphate pathway (PPP), mitochondrial oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), fatty acid biosynthesis (FAs) and amino acid pathways, which promote cell proliferation and maintenance with structural and pathological energy to regulate cellular signaling. The metabolism of macrophages produces many metabolic intermediates that play important regulatory roles in tissue repair and regeneration. The metabolic activity of proinflammatory macrophages (M1) mainly depends on glycolysis and the TCA cycle system, but anti-inflammatory macrophages (M2) have intact functions of the TCA cycle, which enhances FAO and is dependent on OXPHOS. However, the metabolic mechanisms of macrophages in tissue repair and regeneration have not been well investigated. Thus, we review how three main metabolic mechanisms of macrophages, glucose metabolism, lipid metabolism, and amino acid metabolism, regulate tissue repair and regeneration.

Discovery of bioactive peptides as therapeutic agents for skin wound repair.

Short sequences of amino acids called peptides have a wide range of biological functions and the potential to treat a number of diseases. Bioactive peptides can be derived from different sources, including marine organisms, and synthetic design, making them versatile candidates for production of therapeutic agents. Their therapeutic effects span across areas such as antimicrobial activity, cells proliferation and migration, synthesis of collagen, and more. This current review explores the fascinating realm of bioactive peptides as promising therapeutic agents for skin wound healing. This review focuses on the multifaceted biological effects of specific peptides, shedding light on their potential to revolutionize the field of dermatology and regenerative medicine. It delves into how these peptides stimulate collagen synthesis, inhibit inflammation, and accelerate tissue regeneration, ultimately contributing to the effective repair of skin wounds. The findings underscore the significant role several types of bioactive peptides can play in enhancing wound healing processes and offer promising insights for improving the quality of life for individuals with skin injuries and dermatological conditions. The versatility of peptides allows for the development of tailored treatments catering to specific wound types and patient needs. As continuing to delve deeper into the realm of bioactive peptides, there is immense potential for further exploration and innovation. Future endeavors may involve the optimization of peptide formulations, elucidation of underlying molecular and cellular mechanisms.

An Innovative Approach of Utilizing the Digastric Tendon for Lower Lip Soft Tissue Repair: A Case Report.

Lower lip reconstruction following oral and neck oncosurgery presents significant challenges in maintaining function and esthetics. This case report describes a novel application of the digastric tendon for repairing the soft tissue of the lower lip in a patient undergoing wide excision of a lesion, bilateral modified radical neck dissection, segmental mandibulectomy, and free fibula flap repair. This innovative approach aims to maintain oral competence, strengthen the flap, and enhance esthetics. The digastric tendon was chosen due to its accessibility and effectiveness in strengthening the lower lip.

The Role of Platelet-Rich Plasma in the Management of Sensorineural Hearing Loss: Current Evidence and Emerging Trends.

Sensorineural hearing loss (SNHL) is a common form of hearing impairment characterized by damage to the inner ear or auditory nerve, resulting in significant communication difficulties and reduced quality of life. Current treatment options, including hearing aids, cochlear implants, and corticosteroids, primarily focus on symptom management and do not address the underlying pathophysiological damage. Platelet-rich plasma (PRP), an autologous concentrate rich in platelets and growth factors, has emerged as a potential regenerative therapy due to its ability to promote tissue repair and cellular regeneration. This review provides a comprehensive overview of the role of PRP in the management of SNHL, examining the current evidence from preclinical and clinical studies. We discuss the mechanisms through which PRP may promote auditory tissue regeneration and repair, analyze its efficacy and safety profile, and explore innovative approaches and future directions in its application for SNHL. Despite promising preliminary findings, further research is needed to optimize PRP protocols, establish standardized treatment guidelines, and conduct large-scale randomized controlled trials to validate efficacy. This review aims to highlight the potential of PRP as a novel therapeutic strategy in treating SNHL and its possible integration into current clinical practices, offering new hope for patients with this debilitating condition.

Immunomodulatory Biomaterials: Tailoring Surface Properties to Mitigate Foreign Body Reaction and Enhance Tissue Regeneration.

The immune cells have demonstrated the ability to promote tissue repair by removing debris, breaking down the extracellular matrix, and regulating cytokine secretion profile. If the behavior of immune cells is not well directed, chronic inflammation and foreign body reaction (FBR) will lead to scar formation and loss of biomaterial functionality. The immunologic response toward tissue repair or chronic inflammation after injury and implantation can be modulated by manipulating the surface properties of biomaterials. Tailoring surface properties of biomaterials enables the regulation of immune cell fate such as adhesion, proliferation, recruitment, polarization, and cytokine secretion profile. This review begins with an overview of the role of immune cells in tissue healing and their interactions with biomaterials. It then discusses how the surface properties of biomaterials influence immune cell behavior. The core focus is reviewing surface modification methods to create innovative materials that reduce foreign body reactions and enhance tissue repair and regeneration by modulating immune cell activities. The review concludes with insights into future advancements in surface modification techniques and the associated challenges.

Developing fibrin-based biomaterials/scaffolds in tissue engineering.

Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologically active tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs. Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix. Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and good degradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation, and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widely recognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair. This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, the modification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissue engineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of the use and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future research directions for clinical treatment.

The influence of AHR on immune and tissue biology.

The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.

Differential effects of macrophage subtype-specific cytokines on fibroblast proliferation and endothelial cell function in co-culture system.

Macrophages are involved in several critical activities associated with tissue repair and regeneration. Current approaches in regenerative medicine are focusing on leveraging the innate immune response to accelerate tissue regeneration and improve long-term healing outcomes. Of particular interest in this regard are the currently known, four main M2 macrophage subtypes: M2interleukin (IL)-4,IL-13, M2IC, M2IL-10, M2non-selective adenosine receptor agonists (NECA) (M2IL-4,IL-13 → M2NECA). In this study, rat bone marrow-derived macrophages (M0) were polarized to each of the four subtypes M2IL-4,IL-13 → M2NECA and cultured for 72 h in vitro. Luminex assay results highlighted increased production of tissue inhibitor of metalloproteinases-1 (TIMP-1) for M2IL-4,IL-13, higher amounts of transforming growth factor-beta 1 (TGF-ß1) for M2IL-10, and elevated vascular endothelial growth factor A (VEGF-A) from M2NECA. Co-culture experiments performed with M2IL-10 macrophages and L929 fibroblasts highlighted the increased production of soluble collagen within the media as well as higher amounts of collagen in the extracellular matrix. Human umbilical vein endothelial cells (HUVECs) were co-cultured with M2NECA macrophages, which demonstrated an increase in intercellular adhesion molecule (ICAM) and platelet endothelial cell adhesion molecule (PECAM), as well as increased formation of endothelial tubes. The findings of this study emphasize a critical demand for further characterization and analyses of distinct M2 subtypes and careful selection of specific macrophage populations for regeneration of specific tissue types. The current, broad classification of "M2" may be sufficient in many general tissue engineering applications, but, as conditions are constantly in flux within the microenvironment in vivo, a higher degree of specificity and control over the initial M2 subtype could result in more consistent long-term outcomes where macrophages are utilized as part of an overall regenerative strategy.

Exosome Mediated Cell-Cell Crosstalk in Tissue Injury and Repair.

The landscape of exosome research has undergone a significant paradigm shift, with a departure from early conceptions of exosomes as vehicles for cellular waste disposal towards their recognition as integral components of cellular communication with therapeutic potential. This chapter presents an exhaustive elucidation of exosome biology, detailing the processes of exosome biogenesis, release, and uptake, and their pivotal roles in signal transduction, tissue repair, regeneration, and intercellular communication. Additionally, the chapter highlights recent innovations and anticipates future directions in exosome research, emphasizing their applicability in clinical settings. Exosomes have the unique ability to navigate through tissue spaces to enter the circulatory system, positioning them as key players in tissue repair. Their contributory role in various processes of tissue repair, although in the nascent stages of investigation, stands out as a promising area of research. These vesicles function as a complex signaling network for intracellular and organ-level communication, critical in both pathological and physiological contexts. The chapter further explores the tissue-specific functionality of exosomes and underscores the advancements in methodologies for their isolation and purification, which have been instrumental in expanding the scope of exosome research. The differential cargo profiles of exosomes, dependent on their cellular origin, position them as prospective diagnostic biomarkers for tissue damage and regenerative processes. Looking ahead, the trajectory of exosome research is anticipated to bring transformative changes to biomedical fields. This includes advancing diagnostic and prognostic techniques that utilize exosomes as non-invasive biomarkers for a plethora of diseases, such as cancer, neurodegenerative, and cardiovascular conditions. Additionally, engineering exosomes through alterations of their native content or surface properties presents a novel frontier, including the synthesis of artificial or hybrid variants with enhanced functional properties. Concurrently, the ethical and regulatory frameworks surrounding exosome research, particularly in clinical translation, will require thorough deliberation. In conclusion, the diverse aspects of exosome research are coalescing to redefine the frontiers of diagnostic and therapeutic methodologies, cementing its importance as a discipline of considerable consequence in the biomedical sciences.

Synergistic potential of stem cells and microfluidics in regenerative medicine.

Regenerative medicine has immense potential to revolutionize healthcare by using regenerative capabilities of stem cells. Microfluidics, a cutting-edge technology, offers precise control over cellular microenvironments. The integration of these two fields provides a deep understanding of stem cell behavior and enables the development of advanced therapeutic strategies. This critical review explores the use of microfluidic systems to culture and differentiate stem cells with precision. We examined the use of microfluidic platforms for controlled nutrient supply, mechanical stimuli, and real-time monitoring, providing an unprecedented level of detail in studying cellular responses. The convergence of stem cells and microfluidics holds immense promise for tissue repair, regeneration, and personalized medicine. It offers a unique opportunity to revolutionize the approach to regenerative medicine, facilitating the development of advanced therapeutic strategies and enhancing healthcare outcomes.

Comparative Analysis of Commercially Available Extracellular Matrix Soft Tissue Bioscaffolds.

Decellularized extracellular matrix (dECM) products are widely established for soft tissue repair, reconstruction, and reinforcement. These regenerative biomaterials mimic native tissue ECM with respect to structure and biology and are produced from a range of tissue sources and species. Optimal source tissue processing requires a balance between removal of cellular material and the preservation of structural and biological properties of tissue ECM. Despite the widespread clinical use of dECM products there is a lack of comparative information on these products. This study provides a comparative analysis of 12 commercially available dECM products. One group of products consisted of materials intended for dermal repair including ovine forestomach matrix (OFMm), porcine peritoneum (PPN), porcine placenta (PPC), and porcine small intestinal submucosa (SISu). The second group, intended for load-bearing reconstruction, consisted of material derived from ovine forestomach matrix (OFMo), porcine urinary bladder matrix (UBM), porcine small intestinal submucosa (SISb and SISz), human dermis (ADM), porcine dermis (PADM), and fetal/neonatal bovine dermis (BADM). A minimally processed product consisting of human placental tissue was included as a control. Products were compared histologically and by agarose gel electrophoreses to assess structural features and decellularization. Structurally, some dECM products showed a well-preserved collagen architecture with a broad porosity distribution, whereas others showed a significantly altered structure compared with native tissue. Decellularization varied across the products. Some materials surveyed (OFMm, PPN, PPC, OFMo, UBM, SISz, ADM, PADM, and BADM) were essentially devoid of nuclear bodies (mean count of <5 cells per high-powered field [HPF]), whereas others (SISu and SISb) demonstrated an abundance of nuclear bodies (>50 cells per HPF). Pathology assessment of the products demonstrated that OFMm, OFMo, and PADM had the highest qualitative assessment score for collagen fiber orientation and arrangement, matrix porosity, decellularization efficiency, and residual vascular channels scoring 10.5 ± 0.8, 12.8 ± 1.0, and 9.7 ± 0.7 out of a maximum total score of 16, respectively. This analysis of commercially available dECM products in terms of their structure and cellularity includes 12 different commercial materials. The findings highlight the variability of the products in terms of matrix structure and the efficacy of decellularization.

Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling.

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.

Enhancing Wound Healing: A Comprehensive Review of Sericin and Chelidonium majus L. as Potential Dressings.

Wound healing, a complex physiological process orchestrating intricate cellular and molecular events, seeks to restore tissue integrity. The burgeoning interest in leveraging the therapeutic potential of natural substances for advanced wound dressings is a recent phenomenon. Notably, Sericin, a silk-derived protein, and Chelidonium majus L. (C. majus), a botanical agent, have emerged as compelling candidates, providing a unique combination of natural elements that may revolutionize conventional wound care approaches. Sericin, renowned for its diverse properties, displays unique properties that accelerate the wound healing process. Simultaneously, C. majus, with its diverse pharmacological compounds, shows promise in reducing inflammation and promoting tissue regeneration. As the demand for innovative wound care solutions increases, understanding the therapeutic potential of natural products becomes imperative. This review synthesizes current knowledge on Sericin and C. majus, envisioning their future roles in advancing wound management strategies. The exploration of these natural substances as constituents of wound dressings provides a promising avenue for developing sustainable, effective, and biocompatible materials that could significantly impact the field of wound healing.

Manufacturing Process Affects Coagulation Kinetics of Ortho-R, an Injectable Chitosan-Platelet-Rich Plasma Biomaterial for Tissue Repair.

Ortho-R (ChitogenX Inc., Kirkland, QC, Canada) is an injectable combination drug-biologic product that is used as an adjunct to augment the standard of care for the surgical repair of soft tissues. The drug product comprises lyophilized chitosan, trehalose and calcium chloride, and it is dissolved in platelet-rich plasma (PRP), a blood-derived biologic, prior to injection at the surgical site where it will coagulate. The first step of the Ortho-R manufacturing process involves dissolving the chitosan in hydrochloric acid. The purpose of this study was to investigate the effect of increasing the amount of acid used to dissolve the chitosan on final drug product performance, more specifically, on the chitosan-PRP coagulation kinetics. Chitosans were solubilized in hydrochloric acid, with concentrations adjusted to obtain between 60% and 95% protonation of the chitosan amino groups. Freeze-dried Ortho-R was solubilized with PRP, and coagulation was assessed using thromboelastography (TEG). The clotted mixtures were observed with histology. Clot reaction time (TEG R) increased and clot maximal amplitude (TEG MA) decreased with protonation levels as pH decreased. Chitosan distribution was homogeneous in chitosan-PRP clots at the lowest protonation levels, but it accumulated toward the surface of the clots at the highest protonation levels as pH decreased. These changes in coagulation kinetics, clot strength and chitosan distribution induced by high protonation of the chitosan amino groups were partially reversed by adding sodium hydroxide to the dissolved chitosan component in order to decrease pH. Careful control of manufacturing processes is critical, and it is important to consider the impact of each manufacturing step on product performance.

A novel suturing technique for natural tissue repair in cystocele treatment.

BACKGROUND: Recently, natural tissue repair has become popular in the treatment of pelvic organ prolapsed. In this study, we compared patients who underwent cystocele repair with the rug-weaving plication technique, a natural tissue repair method implemented since 2022 for anterior prolapse, with those treated using conventional colporrhaphy. METHODS: We retrospectively reviewed the data of 65 patients who underwent anterior vaginal wall repair with the rug-weaving plication technique (n = 33, Group 1) or conventional colporrhaphy (n = 32, Group 2). We recorded the patients' clinicodemographic and surgical data. At the 6-month postoperative follow-up, we assessed patients' complaints, degree of prolapse (using the simplified Pelvic Organ Prolapse Quantification system), and pelvic floor muscle strength (using the Modified Oxford Score). Anterior vaginal wall thickness was measured using transvaginal ultrasonography. We compared clinicodemographic and surgical data and postoperative outcomes between the two groups. RESULTS: The two groups were comparable in terms of age (p = 0.326), number of pregnancies (p = 0.307), number of parities (p = 0.555), preoperative anterior wall simplified Pelvic Organ Prolapse Quantification grade (p = 0.380), preoperative apical prolapse simplified Pelvic Organ Prolapse Quantification grade (p = 0.518), postoperative Modified Oxford Score (p = 0.857), operation time (p = 0.809), postoperative haemoglobin (p = 0.674), and amount of bleeding (p = 0.951). Compared with Group 2, Group 1 had significantly higher postoperative anterior vaginal wall thickness (p < 0.001) and significantly lower postoperative anterior wall simplified Pelvic Organ Prolapse Quantification grade (p < 0.001). CONCLUSIONS: The rug-weaving plication technique may offer a viable alternative for cystocele repair without mesh, using natural tissue and potentially reducing mesh-related complications and recurrence rates. CLINICAL TRIAL NUMBER: NCT06410469 (03/05/2024).

Dynamic regulation of tissue fluidity controls skin repair during wound healing.

During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.

Osteomyelitis in Late-Stage Pressure Sore Patients: A Retrospective Analysis.

BACKGROUND: Late-stage pressure sore (PS) patients are particularly susceptible to osteomyelitis (OM), as bony prominences commonly constitute the focal point of the ulcer. There are lack of data regarding the associated factors and the clinical relevance of this diagnosis in the context of PS treatment. METHODS: This retrospective analysis investigated the clinical characteristics, blood markers indicative of infection in PS patients, and development of histologically evident OM. A total of 125 patient were included from 2014 to 2019. The patient records were especially scanned for histological diagnosis of OM. RESULTS: OM was detected in 39% (37/96) of the samples taken during the index procedure. OM prevalence increased to 56% (43/77) at the second and 70% (41/59) at the third debridement. Therefore, the diagnosis of OM was acquired during treatment in 35 cases. Patients diagnosed with initial OM presented significantly higher blood markers, indicative of infection upon admission. Only patients with consistent OM (three positive biopsies) showed higher flap revision rates. CONCLUSION: This study found no compelling evidence linking OM to worse clinical outcomes in PS patients. In the absence of elevated inflammatory markers, reducing bone biopsy frequency and adopting a less aggressive bone debridement approach may help prevent OM in PS patients.

Long-Term Outcomes (10 Years) of Sacrospinous Ligament Fixation for Pelvic Organ Prolapse Repair.

Vaginal vault prolapse is one of the main reasons for reoperation in patients with pelvic organ prolapse. Effective correction of the vaginal apex is essential for lasting repair for these women. Apical suspension of the sacrospinous ligament is probably one of the main vaginal treatments still offered to patients today. We proposed an evaluation of the functional and anatomical results of long-term sacrospinous ligament fixation. OBJECTIVE: The purpose of this study was to evaluate the 10-year results of sacrospinous ligament suspension as primary repair for apical prolapse and to evaluate long-term side effects. MATERIALS AND METHODS: A retrospective study analyzed 10-year follow-up after prolapse repair using sacrospinous ligament suspension. A subjective recurrence was identified as the postoperative occurrence of swelling symptoms based on a particular item on the Italian Prolapse Quality of Life (P-QoL) questionnaire. An objective recurrence was defined as a postoperative decline to stage II or below in any compartment based on the POP-Q system or the requirement for additional surgery. The assessment of postoperative subjective satisfaction was conducted using the Patient Global Impression of Improvement (PGI-I) score. RESULTS: In total, 40 patients underwent sacrospinous ligament fixation. Objective recurrence was remarkably high, as it was observed in 17 (56.7%) patients. Subjective recurrence was reported by ten (33.3%) women, and reintervention occurred in two (6.7%) of patients. From the point of view of quality of life, according to the PGI-I, twenty-three (76.7%) patients described some degree of improvement after surgery, four (13.3%) described their status as unmodified, and three (10%) reported some form of worsening after primary treatment. CONCLUSIONS: Transvaginal repair with sacrospinous fixation is a long-lasting option for prolapse repair, with improvement in every POP-q parameter. Some degree of anterior recurrence, recurrence of symptoms with swelling, or an overall worsening of quality of life after surgery is possible.

Exploration of N6-methyladenosine modification in ascorbic acid 2-glucoside constructed stem cell sheets.

The aim of this study was to explore the mechanism of bone marrow stem cells (BMSCs) sheets constructed with different doses of Ascorbic acid 2-glucoside (AA-2G) in conjunction with N6-methyladenosine (m6A)-associated epigenetic genes analysing transcriptome sequencing data. Experimental groups of BMSCs induced by different AA-2G concentrations were set up, and the tissue structures were observed by histological staining of cell slices and scanning electron microscopy. Expression patterns of DEGs were analysed using short-time sequence expression mining software, and DEGs associated with m6A were selected for gene ontology analysis and pathway analysis. The protein-protein interaction (PPI) network of DEGs was analysed and gene functions were predicted using the search tool of the Retrieve Interacting Genes database. There were 464 up-regulated DEGs and 303 down-regulated DEGs between the control and high-dose AA-2G treatment groups, and 175 up-regulated DEGs and 37 down-regulated DEGs between the low and high-dose AA-2G treatment groups. The profile 7 exhibited a gradual increase in gene expression levels over AA-2G concentration. In contrast, profile 0 exhibited a gradual decrease in gene expression levels over AA-2G concentration. In the PPI network of m6A-related DEGs in profile 7, the cluster of metallopeptidase inhibitor 1 (Timp1), intercellular adhesion molecule 1 (Icam1), insulin-like growth factor 1 (Igf1), matrix metallopeptidase 2 (Mmp2), serpin family E member 1 (Serpine1), C-X-C motif chemokine ligand 2 (Cxcl2), galectin 3 (Lgals3) and angiopoietin-1 (Angpt1) was the top hub gene cluster. The expression of all hub genes was significantly increased after AA-2G intervention (P < 0.05), and the expression of Igf1 and Timp1 increased with increasing intervention concentration. The m6A epigenetic modifications were involved in the AA-2G-induced formation of BMSCs. Igf1, Serpine1 and Cxcl2 in DEGs were enriched for tissue repair, promotion of endothelial and epithelial proliferation and regulation of apoptosis.

Lineage Mapping of Extracellular Vesicles: What Cells Do They Come from And Where Do They Go?

Significance: Release of extracellular vesicles (EVs) by various cell types has been shown to mediate the delivery of biologically active payloads from donor cells to recipient cells; however, it remains unclear what cell types these EVs come from. With a focus on fluorescent reporters to monitor the release of EVs, especially those under the control of cell type-specific promoters, we address the translational relevance of genetic tools in cultured cells, normal tissues, and in models of development, injury, cancer, and wound healing. Recent Advances: It is well established that EVs are released by many cell types in the body via fusion and release processes at the plasma membrane. Since there remains debate about what fraction of EVs are released through regulated endosomal trafficking pathways versus nonspecific mechanisms, the development and validation of novel molecular tools are important to address the cellular source of EVs. Critical Issues: There is a need to develop and characterize new cell type-specific reporter mouse models that build upon the examples detailed here to identify the cellular source of EVs with genetic approaches being useful in addressing these critical limitations. Future Directions: Advances in reporter systems will drive a better understanding of EV subsets to identify compartment-specific EV localization to guide the development of more translationally relevant models for the wound healing field.