Review of the Role of Mesenchymal Stem Cells and Exosomes Derived from Mesenchymal Stem Cells in the Treatment of Orthopedic Disease.

Exosomes can be derived from mesenchymal stem cells (MSCs) and have recently been used to treat defects in the tendons. They may also have applications in treating osteoporosis. MSC-derived exosomes communicate with mesenchymal and osteogenic cells through endocrine or paracrine mechanisms and contribute factors involved in physiological and pathological orthopedic conditions associated with hypoxia and bone tumors. Also, generalized medical conditions, such as obesity, hyperglycemia, and degenerative diseases, can inhibit the osteogenic effect of MSC-derived exosomes. This review aims to present an update on the roles of MSCs and exosomes derived from MSCs in treating orthopedic diseases, such as osteoporosis, and in the repair of cartilage, tendons, and bone fractures.

BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting TXNIP in cutaneous melanoma.

Treatment of advanced BRAFV600-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted TXNIP which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAFV600-mutant melanoma patients.

Peroxisome Proliferator-Activated Receptor-γ Knockdown Impairs Bone Morphogenetic Protein-2-Induced Critical-Size Bone Defect Repair.

The Food and Drug Administration-approved clinical dose (1.5 mg/mL) of bone morphogenetic protein-2 (BMP2) has been reported to induce significant adverse effects, including cyst-like adipose-infiltrated abnormal bone formation. These undesirable complications occur because of increased adipogenesis, at the expense of osteogenesis, through BMP2-mediated increases in the master regulatory gene for adipogenesis, peroxisome proliferator-activated receptor-γ (PPARγ). Inhibiting PPARγ during osteogenesis has been suggested to drive the differentiation of bone marrow stromal/stem cells toward an osteogenic, rather than an adipogenic, lineage. We demonstrate that knocking down PPARγ while concurrently administering BMP2 can reduce adipogenesis, but we found that it also impairs BMP2-induced osteogenesis and leads to bone nonunion in a mouse femoral segmental defect model. In addition, in vitro studies using the mouse bone marrow stromal cell line M2-10B4 and mouse primary bone marrow stromal cells confirmed that PPARγ knockdown inhibits BMP2-induced adipogenesis; attenuates BMP2-induced cell proliferation, migration, invasion, and osteogenesis; and escalates BMP2-induced cell apoptosis. More important, BMP receptor 2 and 1B expression was also significantly inhibited by the combined BMP2 and PPARγ knockdown treatment. These findings indicate that PPARγ is critical for BMP2-mediated osteogenesis during bone repair. Thus, uncoupling BMP2-mediated osteogenesis and adipogenesis using PPARγ inhibition to combat BMP2's adverse effects may not be feasible.

The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice.

Fractures are common, with an incidence of 13.7 per 1000 adults annually. Systemic agents have been widely used for enhancing bone regeneration; however, the efficacy of these therapeutics for the management and prevention of fracture remains unclear. NEL-like protein 1 (NELL-1) is a potent pro-osteogenic cytokine that has been modified with polyethylene glycol (PEG)ylation [PEGylated NELL-1 (NELL-PEG)] to enhance its pharmacokinetics for systemic therapy. Our aim was to investigate the effects of systemic administration of NELL-PEG on fracture healing in mice and on overall bone properties in uninjured bones. Ten-week-old CD-1 mice were subjected to an open osteotomy of bilateral radii and treated with weekly injections of NELL-PEG or PEG phosphate-buffered saline as control. Systemic injection of NELL-PEG resulted in improved bone mineral density of the fracture site and accelerated callus union. After 4 weeks of treatment, mice treated with NELL-PEG exhibited substantially enhanced callus volume, callus mineralization, and biomechanical properties. NELL-PEG injection significantly augmented bone regeneration, as confirmed by high expression of bone turnover rate, bone formation rate, and mineral apposition rate. Consistently, the immunohistochemistry results also confirmed a high bone remodeling activity in the NELL-PEG-treated group. Our findings suggest that weekly injection of NELL-PEG may have the clinical potential to accelerate fracture union and enhance overall bone properties, which may help prevent subsequent fractures.

Anthropometric labial analysis of Han Chinese young adults.

BACKGROUND: Facial features vary in size and proportions between different races. This study aimed to measure the anthropometric variables of the labial region in Han Chinese young adults. MATERIALS AND METHODS: A total of 900 college students (475 male and 425 female) of Chinese Han ethnicity from the northern China were included. Measurements of the labial region included 14 linear items and seven proportions. RESULTS: All the linear measurements of the males were significantly higher than those of the females (all P < 0.001). Significant gender differences were found in the philtrum morphology, philtrum width, upper vermilion-cutaneous lip, lower vermilion-cutaneous lip, and vermilion. There are significant differences in the anthropometric variables of the labial region between male and female Han Chinese young adults. CONCLUSIONS: These data may be used as a reference standard for labial reconstructive and aesthetic surgery.

Surgical Treatment Strategy for Severe Rhinophyma With Bilateral Pedicled Nasolabial Flaps.

BACKGROUND: Rhinophyma is a rare disease characterized by chronic inflammation and hypertrophy of sebaceous glands, blood vessels, and fibrous tissue, associated with end-stage severe acne rosacea. There are multiple approaches to treatment and repair, including dermal shaving, secondary intention healing, free skin graft, and skin flaps. However, these methods have various disadvantages, such as prolonged healing, obvious scarring, and skin texture mismatch. Therefore, the authors adopted surgical excision with bilateral pedicled nasolabial flaps, which have better color, texture, thickness, and symmetry. METHODS: The authors present a case of severe nasal tip rhinophyma successfully treated by excision and repair with bilateral pedicled nasolabial flaps. This procedure combines deep excision of the focal lesion and coverage with bilateral nasolabial flaps. RESULTS: The bilateral pedicled nasolabial flaps were used for severe rhinophyma in a patient. After the operation, the flaps survived uneventfully in this study. Both functional and aesthetic results were satisfactory at 3 months. CONCLUSION: The authors offer an effective method for surgical treatment of rhinophyma. Excision of hypertrophic nasal tissue is an acknowledged effective treatment for patients with severe rhinophyma. After excision, reconstruction with nasolabial flaps results in satisfactory outcomes both functionally and aesthetically. Therefore, this approach should be considered an appropriate alternative in cases of severe rhinophyma.

Cyst-Like Osteolytic Formations in Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Augmented Sheep Spinal Fusion.

Multiple case reports using recombinant human bone morphogenetic protein-2 (rhBMP-2) have reported complications. However, the local adverse effects of rhBMP-2 application are not well documented. In this report we show that, in addition to promoting lumbar spinal fusion through potent osteogenic effects, rhBMP-2 augmentation promotes local cyst-like osteolytic formations in sheep trabecular bones that have undergone anterior lumbar interbody fusion. Three months after operation, conventional computed tomography showed that the trabecular bones of the rhBMP-2 application groups could fuse, whereas no fusion was observed in the control group. Micro-computed tomography analysis revealed that the core implant area's bone volume fraction and bone mineral density increased proportionately with rhBMP-2 dose. Multiple cyst-like bone voids were observed in peri-implant areas when using rhBMP-2 applications, and these sites showed significant bone mineral density decreases in relation to the unaffected regions. Biomechanically, these areas decreased in strength by 32% in comparison with noncystic areas. Histologically, rhBMP-2-affected void sites had an increased amount of fatty marrow, thinner trabecular bones, and significantly more adiponectin- and cathepsin K-positive cells. Despite promoting successful fusion, rhBMP-2 use in clinical applications may result in local adverse structural alterations and compromised biomechanical changes to the bone.

High temperature requirement factor A1 (HTRA1) regulates the activation of latent TGF-ß1 in keloid fibroblasts.

Scar treatments are considered a major issue in the plastic surgery field. Activation of the transforming growth factor-ß (TGF-ß)-mediated signaling pathway plays a key role in the scar pathogeneses, and high temperature requirement factor A1 (HTRA1) inhibits TGF-ß1 activation in tumor cells. Our study aims to investigate the role of HTRA1 in the pathogenesis of scars. The mRNA levels of HTRA1 was evaluated by real time PCR, HTRA1 protein expression was determined using western blot and immunohistochemistry, and a luciferase assay was applied to measure dynamic changes of TGF-ß1 activity. We found that the expression of HTRA1 was significantly elevated in keloid tissues, compared to normal skin, and TGF-ß1 mRNA levels slightly increase in the keloid tissue. Furthermore, active TGF-ß1 protein levels and Smad2 phosphorylation significantly increased in the keloid tissue. Treatment with the latent TGF-ß1 or recombinant human HTRA1 (rhHTRA1), alone or in combination, increased Smad2 phosphorylation levels in keloid fibroblasts and active TGF-ß1 contents of associated supernatants. Our results suggest that HTRA1 is involved in the pathogenesis of scars through regulating activation of latent TGF-ß1 in keloid fibroblasts, and our study reveals that HTRA1 is a novel target that regulates scar formation.

Novel analysis of functional relationship linking moyamoya disease to moyamoya syndrome.

Objective: The aim of this study was to elucidate the genetic pathways associated with Moyamoya disease (MMD) and Moyamoya syndrome (MMS), compare the functional activities, and validate relevant related genes in an independent dataset. Methods: We conducted a comprehensive search for genetic studies on MMD and MMS across multiple databases and identified related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analyses were performed for these genes. Commonly shared genes were selected for further validation in the independent dataset, GSE189993. The Sangerbox platform was used to perform statistical analysis and visualize the results. P＜0.05 indicated a statistically significant result. Results: We included 52 MMD and 51 MMS-related publications and identified 126 and 51 relevant genes, respectively. GO analysis for MMD showed significant enrichment in cytokine activity, cell membrane receptors, enzyme binding, and immune activity. A broader range of terms was enriched for MMS. KEGG pathway analysis for MMD highlighted immune and cellular activities and pathways related to MMS prominently featured inflammation and metabolic disorders. Notably, nine overlapping genes were identified and validated. The expressions of RNF213, PTPN11, and MTHFR demonstrated significant differences in GSE189993. A combined receiver operating characteristic curve showed high diagnostic accuracy (AUC = 0.918). Conclusions: The findings indicate a close relationship of MMD with immune activity and MMS with inflammation, metabolic processes and other environmental factors in a given genetic background. Differentiating between MMD and MMS can enhance the understanding of their pathophysiology and inform the strategies for their diagnoses and treatment.

A preliminary study of differentially expressed genes of the scallop Chlamys farreri against acute viral necrobiotic virus (AVNV).

The scallop Chlamys farreri is one of the most important aquaculture species in northern coastal provinces. However, the sustainable development of scallop industry is currently threatened by a notorious pathogen named as acute viral necrobiotic virus (AVNV), which often causes mass mortality of the animals. Despite that great attention has been focused on this novel pathogen, little knowledge about the host-virus interactions is available. In this study, suppression subtractive hybridization (SSH) was employed to identify the up-regulated differentially expressed genes in the hemocytes of C. farreri challenged by AVNV. A forward subtracted cDNA library was finally constructed and 288 positive colonies representing differentially genes were screened to perform sequencing. A total of 275 ESTs were used for further analysis using bioinformatics tools after vector screening, among which 167 ESTs could be finally identified, with significant match (E values <1 × 10(-3)) to the deposited genes (proteins) in the corresponding databases. These genes could be classified into ten categories according to their Gene Ontology annotations of biological processes and molecular functions, i.e. cell defense and homeostasis (13.82%), cellular protein metabolic process (14.90), cellular metabolism (13.09%), cytoskeletal or cellular component (5.82%), transcription regulation or RNA processing (2.18%), cell division (meiosis)/apoptosis (2.18%), DNA metabolic process and repair (1.45%), cell adhesion/signaling (1.09%), microsatellite (0.73%), and ungrouped or unknown functions (6.88). The possible biological significance of some novel genes (mainly immune and homeostasis related genes) in the host response to AVNV were discussed. This study is the first global analysis of differentially expressed genes in hemocytes from AVNV-infected C. farreri, and in addition to increasing our understanding of the molecular pathogenesis of this virus-associated scallop disease, the results presented here should provide new insights into the molecular basis of host-pathogen interactions in C. farreri.

Construction of Ti3C2 MXene based fire resistance nanocoating on flexible polyurethane foam for highly efficient photothermal conversion and solar water desalination.

In this work, a bilayer nanocoating was constructed on the surface of flexible polyurethane (FPU) foam with Ti3C2 MXene and polyethyleneimine-modified silica nanoparticles (mSiO2-NP@PEI) through layer-by-layer self-assembly technology, successfully obtaining modified flexible polyurethane composites (MFPU) with excellent flame retardancy, photothermal conversion and solar water desalination properties. The structure and morphology of MFPU foams were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Transmission electron microscope (TEM) and Scanning electron microscope (SEM). The MFPU with three coating cycles (MFPU3) had the best flame retardancy and smoke suppression performances, mainly in terms of decreased peak heat release rate (pHRR), peak smoke production rate (pSPR) and total smoke production (TSP) by 71.3 %, 62.1 % and 74.5 %, respectively, compared to those of neat FPU. In addition, MFPU foams exhibited extraordinary light-to-heat conversion and solar water desalination capabilities. MFPU3 could reach 120 °C in 138 s and its steam conversion efficiency η was as high as 89.6 %, which was 116.0 % higher than that of unmodified foam and had a 262.8 % increase over pure water. The flame retardant MFPU foams with excellent photothermal conversion efficiency will exhibit great application potential in solar water desalination and power generation.

Risk factors for wound healing complications after revascularization for MMD with complete Y-shaped incision.

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease that can be treated with revascularization. Surgery increases the risk of poor wound healing (PWH) due to the impact on the blood supply to the flap. We aimed to analyze risk factors for PWH in MMD with a complete Y-shaped incision. A total of 125 patients with MMD were enrolled in this prospective observational study. The wounds were assessed and measured on the third and seventh days after surgery. The mean age of these patients was 43.3 ± 10.0 years. The ratio of male to female was 1:1.3. 15 (12.0%) patients had incision complications. 5 patients (4.0%) had redness; 2 patients (1.6%) had swelling; 2 patients (1.6%) had fat necrosis; 3 patients (2.4%) had incision infection; and 3 patients (2.4%) had flap necrosis. Student's t test showed significant differences in BMI (P = 0.040) and fever time (P = 0.050). The standard chi-squared test showed significant differences in incision infection (P = 0.010), suture mode (P = 0.047), and cutting off large branch vessels in the flap (P < 0.001). Multivariate logistic regression analysis suggested that incision infection (P = 0.026, OR 12.958), using a skin stapler (P = 0.030, OR 4.335), cutting off large branch vessels in the flap (P = 0.009, OR 5.227), and BMI (P = 0.027, OR 1.204) were risk factors. The area under the curve for risk factors for PWH on a receiver operating characteristic curve was 0.853. Incision infection, using a skin stapler, higher BMI, and cutting off large branch vessels in the flap are risk factors for PWH.

Growth factors in the treatment of Achilles tendon injury.

Achilles tendon (AT) injury is one of the most common tendon injuries, especially in athletes, the elderly, and working-age people. In AT injury, the biomechanical properties of the tendon are severely affected, leading to abnormal function. In recent years, many efforts have been underway to develop effective treatments for AT injuries to enable patients to return to sports faster. For instance, several new techniques for tissue-engineered biological augmentation for tendon healing, growth factors (GFs), gene therapy, and mesenchymal stem cells were introduced. Increasing evidence has suggested that GFs can reduce inflammation, promote extracellular matrix production, and accelerate AT repair. In this review, we highlighted some recent investigations regarding the role of GFs, such as transforming GF-ß(TGF-ß), bone morphogenetic proteins (BMP), fibroblast GF (FGF), vascular endothelial GF (VEGF), platelet-derived GF (PDGF), and insulin-like GF (IGF), in tendon healing. In addition, we summarized the clinical trials and animal experiments on the efficacy of GFs in AT repair. We also highlighted the advantages and disadvantages of the different isoforms of TGF-ß and BMPs, including GFs combined with stem cells, scaffolds, or other GFs. The strategies discussed in this review are currently in the early stages of development. It is noteworthy that although these emerging technologies may potentially develop into substantial clinical treatment options for AT injury, definitive conclusions on the use of these techniques for routine management of tendon ailments could not be drawn due to the lack of data.

In vitro enzymatic degradation of the PTMC/cross-linked PEGDA blends.

Introduction: Poly(1,3-trimethylene carbonate) (PTMC) is a flexible amorphous polymer with good degradability and biocompatibility. The degradation of PTMC is critical for its application as a degradable polymer, more convenient and easy-to-control cross-linking strategies for preparing PTMC are required. Methods: The blends of poly(trimethylene carbonate) (PTMC) and cross-linked poly(ethylene glycol) diacrylate (PEGDA) were prepared by mixing photoactive PEGDA and PTMC and subsequently photopolymerizing the mixture with uv light. The physical properties and in vitro enzymatic degradation of the resultant PTMC/cross-linked PEGDA blends were investigated. Results: The results showed that the gel fraction of PTMC/cross-linked PEGDA blends increased while the swelling degree decreased with the content of PEGDA dosage. The results of in vitro enzymatic degradation confirmed that the degradation of PTMC/cross-linked PEGDA blends in the lipase solution occurred under the surface erosion mechanism, and the introduction of the uv cross-linked PEGDA significantly improved the resistance to lipase erosion of PTMC; the higher the cross-linking degree, the lower the mass loss. Discussion: The results indicated that the blends/cross-linking via PEGDA is a simple and effective strategy to tailor the degradation rate of PTMC.

Bioinformatics analysis reveals the landscape of immune cell infiltration and novel immune-related biomarkers in moyamoya disease.

Objective: This study aimed to identify immune infiltration characteristics and new immunological diagnostic biomarkers in the cerebrovascular tissue of moyamoya disease (MMD) using bioinformatics analysis. Methods: GSE189993 and GSE141022 were downloaded from the GEO database. Differentially expressed gene and PPI analysis were performed. After performing WGCNA, the most significant module associated with MMD was obtained. Next, functional pathways according to GSEA, GO, and KEGG were enriched for the aforementioned core genes obtained from PPI and WGCNA. Additionally, immune infiltration, using the CIBERSORT deconvolution algorithm, immune-related biomarkers, and the relationship between these genes, was further explored. Finally, diagnostic accuracy was verified with ROC curves in the validation dataset GSE157628. Results: A total of 348 DEGs were screened, including 89 downregulated and 259 upregulated genes. The thistlel module was detected as the most significant module associated with MMD. Functional analysis of the core genes was chiefly involved in the immune response, immune system process, protein tyrosine kinase activity, secretory granule, and so on. Among 13 immune-related overlapping genes, 4 genes (BTK, FGR, PTPN11, and SYK) were identified as potential diagnostic biomarkers, where PTPN11 showed the highest specificity and sensitivity. Meanwhile, a higher proportion of eosinophils, not T cells or B cells, was demonstrated in the specific immune infiltration landscape of MMD. Conclusion: Immune activities and immune cells were actively involved in the progression of MMD. BTK, FGR, PTPN11, and SYK were identified as potential immune diagnostic biomarkers. These immune-related genes and cells may provide novel insights for immunotherapy in the future.

Corrigendum: Effect of composite biodegradable biomaterials on wound healing in diabetes.

[This corrects the article DOI: 10.3389/fbioe.2022.1060026.].

Effect of composite biodegradable biomaterials on wound healing in diabetes.

The repair of diabetic wounds has always been a job that doctors could not tackle quickly in plastic surgery. To solve this problem, it has become an important direction to use biocompatible biodegradable biomaterials as scaffolds or dressing loaded with a variety of active substances or cells, to construct a wound repair system integrating materials, cells, and growth factors. In terms of wound healing, composite biodegradable biomaterials show strong biocompatibility and the ability to promote wound healing. This review describes the multifaceted integration of biomaterials with drugs, stem cells, and active agents. In wounds, stem cells and their secreted exosomes regulate immune responses and inflammation. They promote angiogenesis, accelerate skin cell proliferation and re-epithelialization, and regulate collagen remodeling that inhibits scar hyperplasia. In the process of continuous combination with new materials, a series of materials that can be well matched with active ingredients such as cells or drugs are derived for precise delivery and controlled release of drugs. The ultimate goal of material development is clinical transformation. At present, the types of materials for clinical application are still relatively single, and the bottleneck is that the functions of emerging materials have not yet reached a stable and effective degree. The development of biomaterials that can be further translated into clinical practice will become the focus of research.

Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration.

Recent investigations into mechanisms behind the development of osteoporosis suggest that suppressing PPARγ-mediated adipogenesis can improve bone formation and bone mineral density. In this study, we investigated a co-treatment strategy to enhance bone formation by combining NELL-1, an osteogenic molecule that has been extensively studied for its potential use as a therapeutic for osteoporosis, with two methods of PPARγ suppression. First, we suppressed PPARγ genetically using lentiviral PPARγ-shRNA in immunocompromised mice for a proof of concept. Second, we used a PPARγ antagonist to suppress PPARγ pharmacologically in immunocompetent senile osteopenic mice for clinical transability. We found that the co-treatment strategy significantly increased bone formation, increased the proliferation stage cell population, decreased late apoptosis of primary mouse BMSCs, and increased osteogenic marker mRNA levels in comparison to the single agent treatment groups. The addition of PPARγ suppression to NELL-1 therapy enhanced NELL-1's effects on bone formation by upregulating anabolic processes without altering NELL-1's inhibitory effects on osteoclastic and adipogenic activities. Our findings suggest that combining PPARγ suppression with therapeutic NELL-1 may be a viable method that can be further developed as a novel strategy to reverse bone loss and decrease marrow adiposity in age-related osteoporosis.

Propranolol in the Treatment of Infantile Hemangiomas.

Propranolol, as the first generation of ß-blocker family, was initially introduced in the clinical application for tachycardia and hypertension in the 1960s. However, the occasional discovery of propranolol in the involution of infantile hemangiomas (IHs) brought us a new perspective. IHs are the most common infantile tumor, affecting 4-10% newborns. So far, oral propranolol is the first-line medication for IHs treatment. At the same time, local injection and topical propranolol are developing. Despite the worldwide application, the precise mechanism of propranolol of IHs has not been completely studied. In this article, we reviewed and summarized the current information on pharmacology, mechanism, efficacy, and adverse effects of propranolol. Novel design of biomaterials and bioactive molecules are needed for new treatment and ideal pathway to attain the minimal effective treatment concentration and eliminate the adverse effects.

Assessing the Bone-Forming Potential of Pericytes.

Human pericytes are a perivascular cell population with mesenchymal stem cell properties, present in all vascularized tissues. Human pericytes have a distinct immunoprofile, which may be leveraged for purposes of cell purification. Adipose tissue is the most commonly used cell source for human pericyte derivation. Pericytes can be isolated by FACS (fluorescence-activated cell sorting), most commonly procured from liposuction aspirates. Pericytes have clonal multilineage differentiation potential, and their potential utility for bone regeneration has been described across multiple animal models. The following review will discuss in vivo methods for assessing the bone-forming potential of purified pericytes. Potential models include (1) mouse intramuscular implantation, (2) mouse calvarial defect implantation, and (3) rat spinal fusion models. In addition, the presented surgical protocols may be used for the in vivo analysis of other osteoprogenitor cell types.