Extracellular Matrix Function Research Articles

The Use of Newly Synthesized Composite Scaffolds for Bone Regeneration - A Review of Literature

Abstract Bone tissue engineering is a multidisciplinary concept that combines biological and engineering principles to repair bone defects. Three elements that have a fundamental role in bone tissue engineering are scaffolds, stem cells, and bioactive components. Scaffolds mimic extracellular matrix functions and provide mechanical support for the new tissue formation. They are made of different natural and synthetic materials that can be categorized into three main groups: ceramics, metals, and polymers. Among them, synthetic polyesters and their combination with bioceramics, have been the most frequently used for scaffold fabrication. They could be potentially applied in clinical practice in the future as an alternative to the standard use of bone grafts but more studies are needed to assess their performance in the challenging conditions of human bone defects.

Theranostic Applications of Glycosaminoglycans in Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators.

A bio-inspired nano-material recapitulating the composition, ultra-structure, and function of the glycosaminoglycan-rich extracellular matrix of nucleus pulposus

The nucleus pulposus (NP) of intervertebral disc represents a soft gel consisting of glycosaminoglycans (GAGs)-rich extracellular matrix (ECM). Significant loss of GAGs and normal functions are the most prevalent changes in degenerated disc. Attempts targeted to incorporate GAGs into collagen fibrous matrices have been made but the efficiency is very low, and the resulting structures showed no similarity with native NP. Inspired by the characteristic composition and structures of the ECM of native NP, here, we hypothesize that by chemically modifying the collagen (Col) and hyaluronic acid (HA) and co-precipitating with GAGs, a bio-inspired nano-material recapitulating the composition, ultra-structure and function of the GAG-rich ECM will be fabricated. Compositionally, the bio-inspired nano-material namely Aminated Collagen-Aminated Hyaluronic Acid-GAG (aCol-aHA-GAG) shows a record high GAG/hydroxyproline ratio up to 39.1:1 in a controllable manner, out-performing that of the native NP. Ultra-structurally, the nano-material recapitulates the characteristic ‘nano-beads’ (25 nm) and ‘bottle-brushes’ (133 nm) features as those found in native NP. Functionally, the nano-material supports the viability and maintains the morphological and phenotypic markers of bovine NP cells, and shows comparable mechanical properties of native NP. This work contributes to the development of a compositionally, structurally, and functionally biomimetic nano-material for NP tissue engineering.

Biofabrication of Poly(glycerol sebacate) Scaffolds Functionalized with a Decellularized Bone Extracellular Matrix for Bone Tissue Engineering.

The microarchitecture of bone tissue engineering (BTE) scaffolds has been shown to have a direct effect on the osteogenesis of mesenchymal stem cells (MSCs) and bone tissue regeneration. Poly(glycerol sebacate) (PGS) is a promising polymer that can be tailored to have specific mechanical properties, as well as be used to create microenvironments that are relevant in the context of BTE applications. In this study, we utilized PGS elastomer for the fabrication of a biocompatible and bioactive scaffold for BTE, with tissue-specific cues and a suitable microstructure for the osteogenic lineage commitment of MSCs. In order to achieve this, the PGS was functionalized with a decellularized bone (deB) extracellular matrix (ECM) (14% and 28% by weight) to enhance its osteoinductive potential. Two different pore sizes were fabricated (small: 100-150 μm and large: 250-355 μm) to determine a preferred pore size for in vitro osteogenesis. The decellularized bone ECM functionalization of the PGS not only improved initial cell attachment and osteogenesis but also enhanced the mechanical strength of the scaffold by up to 165 kPa. Furthermore, the constructs were also successfully tailored with an enhanced degradation rate/pH change and wettability. The highest bone-inserted small-pore scaffold had a 12% endpoint weight loss, and the pH was measured at around 7.14. The in vitro osteogenic differentiation of the MSCs in the PGS-deB blends revealed a better lineage commitment of the small-pore-sized and 28% (w/w) bone-inserted scaffolds, as evidenced by calcium quantification, ALP expression, and alizarin red staining. This study demonstrates a suitable pore size and amount of decellularized bone ECM for osteoinduction via precisely tailored PGS elastomer BTE scaffolds.

Antibioflm effects of extracellular matrix degradative agents on the biofilm of different strains of multi-drug resistant Corynebacterium striatum

BackgroundCorynebacterium striatum is a microorganism with an excellent capacity for biofilm production and thus has been correlated with nosocomial transmission and invasive infections. However, little is known about the mechanism of biofilm formation of this commensal pathogen. In this study, we aimed to investigate the biofilm formation abilities of multidrug-resistant Corynebacterium striatum clinical isolates and the roles of extracellular proteins, exopolysaccharides and extracellular DNA in mediating more robust biofilm formation by the isolates of C. striatum.MethodsC. striatum isolates were identified using VITEK-2 ANC card, matrix-assisted laser desorption/ionization-time of flight mass spectrometry and 16S rRNA sequencing. The antibiotic susceptibility test was performed using the broth microdilution method. The distribution of spaDEF genes among C. striatum isolates was detected by polymerase chain reaction, and pulsed-field gel electrophoresis typing was employed to analyze the genotypes of the isolates. Crystal violet staining and scanning electron microscopy techniques were used to detect biofilm production by C. striatum isolates. Biofilm degradation assay was performed to observe the effects of extracellular matrix degradative agents (proteinase K, dispersin B, and DNase I) on C. striatum biofilms.ResultsTwenty-seven C. striatum isolates were enrolled in the study, and the resistance rates were the highest (100%, 27/27) against penicillin and ceftriaxone. Approximately 96.3% (26/27) C. striatum isolates were resistant to at least three different types of antimicrobial agents tested. All isolates were confirmed to be biofilm producers, and 74.07% (20/27) isolates presented moderate to strong biofilm production abilities. P7 genotype (44.4%, 12/27) was identified to as the predominant genotype, and all of isolates belonging to this genotype were multidrug-resistant and had stronger biofilm-forming abilities. Most C. striatum isolates (74.07%, 20/27) carry spaD, spaE, and spaF genes, which encode spa-type pili. However, the correlation between the expression of spa-type genes and the biofilm production abilities of the C. striatum isolates was not found. The biofilms of 80% (8/10), 90% (9/10), and 100% (10/10) C. striatum isolates with moderate to strong biofilm production abilities were significantly eliminated upon the treatment of dispersin B (20 μg/mL), DNase I (20 μg/mL), and proteinase K (20 μg/mL) (p < 0.05), respectively. For the combination groups with two kinds of biofilm-degradative agents, the combination of 20 μg/mL proteinase K/dispersin B showed the strongest biofilm-eliminating effects, when the biofilms of 90% (9/10) C. striatum isolates degraded more than 50%.ConclusionsThe C. striatum isolates that belonged to the predominant genotype showed a multidrug resistance (MDR) phenotype and strong biofilm formation abilities. Extracellular matrix seems to be an essential determinant in mediating biofilm formation of MDR C. striatum, since extracellular matrix degradative agents (proteinase K, dispersin B and DNase I) showed strong biofilm-eliminating effects toward multidrug-resistant C. striatum isolates. The findings of this study highlight new ideas/directions to explore the whole nature of biofilm formation of C. striatum and the function of extracellular matrix in this process.

Comprehensive bioinformatics analysis reveals biomarkers of DNA methylation-related genes in varicose veins.

Background: Patients with Varicose veins (VV) show no obvious symptoms in the early stages, and it is a common and frequent clinical condition. DNA methylation plays a key role in VV by regulating gene expression. However, the molecular mechanism underlying methylation regulation in VV remains unclear. Methods: The mRNA and methylation data of VV and normal samples were obtained from the Gene Expression Omnibus (GEO) database. Methylation-Regulated Genes (MRGs) between VV and normal samples were crossed with VV-associated genes (VVGs) obtained by weighted gene co-expression network analysis (WGCNA) to obtain VV-associated MRGs (VV-MRGs). Their ability to predict disease was assessed using receiver operating characteristic (ROC) curves. Biomarkers were then screened using a random forest model (RF), support vector machine model (SVM), and generalized linear model (GLM). Next, gene set enrichment analysis (GSEA) was performed to explore the functions of biomarkers. Furthermore, we also predicted their drug targets, and constructed a competing endogenous RNAs (ceRNA) network and a drug target network. Finally, we verified their mRNA expression using quantitative real-time polymerase chain reaction (qRT-PCR). Results: Total three VV-MRGs, namely Wnt1-inducible signaling pathway protein 2 (WISP2), Cysteine-rich intestinal protein 1 (CRIP1), and Odd-skipped related 1 (OSR1) were identified by VVGs and MRGs overlapping. The area under the curves (AUCs) of the ROC curves for these three VV-MRGs were greater than 0.8. RF was confirmed as the optimal diagnostic model, and WISP2, CRIP1, and OSR1 were regarded as biomarkers. GSEA showed that WISP2, CRIP1, and OSR1 were associated with oxidative phosphorylation, extracellular matrix (ECM), and respiratory system functions. Furthermore, we found that lncRNA MIR17HG can regulate OSR1 by binding to hsa-miR-21-5p and that PAX2 might treat VV by targeting OSR1. Finally, qRT-PCR results showed that the mRNA expression of the three genes was consistent with the results of the datasets. Conclusion: This study identified WISP2, CRIP1, and OSR1 as biomarkers of VV through comprehensive bioinformatics analysis, and preliminary explored the DNA methylation-related molecular mechanism in VV, which might be important for VV diagnosis and exploration of potential molecular mechanisms.

Protein disulfide isomerase A3 activity promotes extracellular accumulation of proteins relevant to basal breast cancer outcomes in human MDA-MB-A231 breast cancer cells.

Metastasis and recurrence of breast cancer remain major causes of patient mortality, and there is an ongoing need to identify new therapeutic targets relevant to tumor invasion. Protein disulfide isomerase A3 (PDIA3) is a disulfide oxidoreductase and isomerase of the endoplasmic reticulum that has known extracellular substrates and has been correlated with aggressive breast cancers. We show that either prior PDIA3 inhibition by the disulfide isomerase inhibitor 16F16 or depletion of heparin-binding proteins strongly reduces the activity of conditioned medium (CM) of MDA-MB-231 human breast cancer cells to support promigratory cell spreading and F-actin organization by newly adherent MDA-MB-231 cells. Quantitative proteomics to investigate effects of 16F16 inhibition on heparin-binding proteins in the CM of MDA-MB-231 cells identified 80 proteins reproducibly decreased at least twofold (at q ≤ 0.05) after 16F16 treatment. By Gene Ontology analysis, many of these have roles in extracellular matrix (ECM) structure and function and cell adhesion; ribosomal proteins that also correlate with extracellular vesicles were also identified. Protein-protein interaction analysis showed that many of the extracellular proteins have known network interactions with each other. The predominant types of disulfide-bonded domains in the extracellular proteins contained β-hairpin folds, with the knottin fold the most common. From human breast cancer data sets, the extracellular proteins were found to correlate specifically with the basal subtype of breast cancer and their high expression in tumors correlated with reduced distant metastasis-free survival. These data provide new evidence that PDIA3 may be a relevant therapeutic target to alter properties of the ECM-associated microenvironment in basal breast cancer.

Abstract 13166: Proteomic Pathways Across Ejection Fraction Categories in Heart Failure: An Exscel Substudy

Background: Ejection fraction (EF) is a key component of heart failure (HF) categorization, including the newly-proposed HF with mildly reduced EF (HFmrEF) category. The biologic basis of HFmrEF, as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF), has not been substantiated. Methods: The EXSCEL trial randomized participants with type 2 diabetes to once-weekly exenatide (EQW) vs. placebo. In participants with prevalent HF, we profiled ~5000 serum proteins. Principal component analysis (PCA) and ANOVA (FDR p&lt;0.1) were used to determine differences in factors and individual proteins between three EF groups, as documented in EXSCEL (EF&gt;55% [HFpEF], EF 40-55% [HFmrEF], EF&lt;40% [HFrEF]). Cox proportional hazards was used to assess relationships between baseline proteins and changes in protein level with incident HF hospitalization. Results: Of 1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the 3 groups. Levels of the majority of proteins (83.3%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, including the domain of extracellular matrix, e.g. COL28A1, tenascin C [TNC]; p&lt;0.0001. A minority of proteins (1%) were concordant between HFmrEF and HFrEF including matrix metalloproteinase-9 (p&lt;0.0001). Baseline levels of 94% of the 221 significant proteins were associated with incident HF including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NTpro-BNP), and renal function (cystatin-C). Change in levels of 18 of these proteins from baseline to 12 months (including increase in TNC) predicted subsequent HF (p&lt;0.05). TNC levels were reduced by EQW compared with placebo (p&lt;0.0001). Conclusions: In this large clinical trial, we found that most proteins were similar between HFmrEF and HFpEF. A key ECM protein, tenascin C, showed this relationship, and baseline level and change in tenascin C predicted HF and changed beneficially with EQW. These results suggest that HFmrEF is more biologically similar to HFpEF and highlight prognostic and modifiable biomarkers that vary by EF.

Butterfly Wing Color Pattern Modification Inducers May Act on Chitin in the Apical Extracellular Site: Implications in Morphogenic Signals for Color Pattern Determination.

Butterfly wing color patterns are modified by various treatments, such as temperature shock, injection of chemical inducers, and covering materials on pupal wing tissue. Their mechanisms of action have been enigmatic. Here, we investigated the mechanisms of color pattern modifications usingthe blue pansy butterfly Junoniaorithya. We hypothesized that these modification-inducing treatments act on the pupal cuticle or extracellular matrix (ECM). Mechanical load tests revealed that pupae treated with cold shock or chemical inducers were significantly less rigid, suggesting that these treatments made cuticle formation less efficient. A known chitin inhibitor, FB28 (fluorescent brightener 28), was discovered to efficiently induce modifications. Taking advantage of its fluorescent character, fluorescent signals from FB28 were observed in live pupae in vivo from the apical extracellular side and were concentrated at the pupal cuticle focal spots immediately above the eyespot organizing centers. It was shown that chemical modification inducers and covering materials worked additively. Taken together, various modification-inducing treatments likely act extracellularly on chitin or other polysaccharides to inhibit pupal cuticle formation or ECM function, which probably causes retardation of morphogenic signals. It is likely that an interactive ECM is required for morphogenic signals for color pattern determination to travel long distances.

Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses.

Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liver sinusoid, particularly liver sinusoidal endothelial cells (LSECs). Recently, it has been observed that LSECs may sustain injury before other fibrogenesis-associated cells of the sinusoid, implicating LSECs as key actors in the fibrotic cascade. A high-throughput cellular microarray platform was used to deconstruct the collective influences of defined combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors on primary human LSEC phenotype in vitro. We observed remarkable heterogeneity in LSEC phenotype as a function of stiffness, ECM, and soluble factor context. LYVE-1 and CD-31 expressions were highest on 1 kPa substrates, and the VE-cadherin junction localization was highest on 25 kPa substrates. Also, LSECs formed distinct spatial patterns of LYVE-1 expression, with LYVE-1+ cells observed in the center of multicellular domains, and pattern size regulated by microenvironmental context. ECM composition also influenced a substantial dynamic range of expression levels for all markers, and the collagen type IV was observed to promote elevated expressions of LYVE-1, VE-cadherin, and CD-31. These studies highlight key microenvironmental regulators of LSEC phenotype and reveal unique spatial patterning of the sinusoidal marker LYVE-1. Furthermore, these data provide insight into understanding more precisely how LSECs respond to fibrotic microenvironments, which will aid drug development and identification of targets to treat liver fibrosis.

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system.

A structural scaffold embedding brain cells and vasculature is known as extracellular matrix (ECM). The physical appearance of ECM in the central nervous system (CNS) ranges from a diffused, homogeneous, amorphous, and nearly omnipresent matrix to highly organized distinct morphologies such as basement membranes and perineuronal nets (PNNs). ECM changes its composition and organization during development, adulthood, aging, and in several CNS pathologies. This spatiotemporal dynamic nature of the ECM and PNNs brings a unique versatility to their functions spanning from neurogenesis, cell migration and differentiation, axonal growth, and pathfinding cues, etc., in the developing brain, to stabilizing synapses, neuromodulation, and being an active partner of tetrapartite synapses in the adult brain. The malleability of ECM and PNNs is governed by both intrinsic and extrinsic factors. Glial cells are among the major extrinsic factors that facilitate the remodeling of ECM and PNN, thereby acting as key regulators of diverse functions of ECM and PNN in health and diseases. In this review, we discuss recent advances in our understanding of PNNs and how glial cells are central to ECM and PNN remodeling in normal and pathological states of the CNS.

Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors.

Seizures are one of the most common symptoms of brain tumors. The incidence of seizures differs among brain tumor type, grade, location and size, but paediatric-type diffuse low-grade gliomas/glioneuronal tumors are often highly epileptogenic. The extracellular matrix (ECM) is known to play a role in epileptogenesis and tumorigenesis because it is involved in the (re)modelling of neuronal connections and cell-cell signaling. In this review, we discuss the epileptogenicity of brain tumors with a focus on tumor type, location, genetics and the role of the extracellular matrix. In addition to functional problems, epileptogenic tumors can lead to increased morbidity and mortality, stigmatization and life-long care. The health advantages can be major if the epileptogenic properties of brain tumors are better understood. Surgical resection is the most common treatment of epilepsy-associated tumors, but post-surgery seizure-freedom is not always achieved. Therefore, we also discuss potential novel therapies aiming to restore ECM function.

Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO.

Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression.

Consequences of PDGFRα+ fibroblast reduction in adult murine hearts.

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE-infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.

Electrospun non-wovens potential wound dressing material based on polyacrylonitrile/chicken feathers keratin nanofiber

Electrospinning nanofibers have a tremendous interest in biomedical applications such as tissue engineering, drug administration, and wound healing because of their ability to replicate and restore the function of the natural extracellular matrix found in tissues. The study’s highlight is the electrospinning preparation and characterization of polyacrylonitrile with chicken feather keratin as an additive. In this study, keratin was extracted from chicken feather waste using an environmentally friendly method and used to reinforce polymeric nanofiber mats. Scanning electron microscopy, energy dispersive spectroscopy, and transmission electron microscopy were used to examine the morphology and the structure of the prepared nanofiber mats. The effect of keratin on the porosity and the tensile strength of reinforcing nanofibers is investigated. The porosity ratio of the nanofiber mats goes up from 24.52 ± 2.12 for blank polyacrylonitrile (PAN (NF)) to 90.89 ± 1.91% for polyacrylonitrile nanofiber with 0.05 wt% keratin (PAN/0.05% K). Furthermore, keratin reinforcement improves the nanofiber's mechanical properties, which are important for wound dressing application, as well as its antibacterial activity without causing hemolysis (less than 2%). The best antibacterial activities were observed against Pseudomonas aeruginosa (30 ± 0.17 mm inhibition zone) and Staphylococcus aureus (29 ± 0.31 mm inhibition zone) for PAN/0.05% K sample, according to the antibacterial test. This research has a good potential to broaden the use of feather keratin-based nanofibers in wound healing.

The Neuroprotection Effects of Exosome in Central Nervous System Injuries: a New Target for Therapeutic Intervention.

Central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH), are the most common cause of death and disability around the world. As a key subset of extracellular vesicles (EVs), exosomes have recently attracted great attentions due to their functions in remodeling extracellular matrix and transmitting signals and molecules. A large number of studies have suggested that exosomes played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that exosomes could improve cognition function, inhibit apoptosis, suppress inflammation, regulate autophagy, and protect blood brain barrier (BBB) in CNS injuries via different molecules and pathways including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch1, and extracellular regulated protein kinases (ERK). Therefore, exosomes showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the applications of exosomes in CNS injuries. Hence, on the basis of these properties and effects, exosomes may be developed as therapeutic agents for CNS injury patients.

Basement Membrane of Tissue Engineered Extracellular Matrix Scaffolds Modulates Rapid Human Endothelial Cell Recellularization and Promote Quiescent Behavior After Monolayer Formation.

Off-the-shelf small diameter vascular grafts are an attractive alternative to eliminate the shortcomings of autologous tissues for vascular grafting. Bovine saphenous vein (SV) extracellular matrix (ECM) scaffolds are potentially ideal small diameter vascular grafts, due to their inherent architecture and signaling molecules capable of driving repopulating cell behavior and regeneration. However, harnessing this potential is predicated on the ability of the scaffold generation technique to maintain the delicate structure, composition, and associated functions of native vascular ECM. Previous de-cellularization methods have been uniformly demonstrated to disrupt the delicate basement membrane components of native vascular ECM. The antigen removal (AR) tissue processing method utilizes the protein chemistry principle of differential solubility to achieve a step-wise removal of antigens with similar physiochemical properties. Briefly, the cellular components of SV are permeabilized and the actomyosin crossbridges are relaxed, followed by lipophilic antigen removal, sarcomeric disassembly, hydrophilic antigen removal, nuclease digestion, and washout. Here, we demonstrate that bovine SV ECM scaffolds generated using the novel AR approach results in the retention of native basement membrane protein structure, composition (e.g., Collagen IV and laminin), and associated cell modulatory function. Presence of basement membrane proteins in AR vascular ECM scaffolds increases the rate of endothelial cell monolayer formation by enhancing cell migration and proliferation. Following monolayer formation, basement membrane proteins promote appropriate formation of adherence junction and apicobasal polarization, increasing the secretion of nitric oxide, and driving repopulating endothelial cells toward a quiescent phenotype. We conclude that the presence of an intact native vascular basement membrane in the AR SV ECM scaffolds modulates human endothelial cell quiescent monolayer formation which is essential for vessel homeostasis.

Thymic Extracellular Matrix in the Thymopoiesis: Just a Supporting?

The generation of T lymphocytes (thymopoiesis) is one of the major functions of the thymus that occurs throughout life. Thymic epithelial cells actively participate in this process. However, less attention has been paid to extracellular matrix (ECM) elements of thymus and their role in thymocyte differentiation. To clarify this topic, we selected some studies that deal with thymic ECM, its modulation, and its effects on thymopoiesis in different models. We emphasize that further studies are needed in order to deepen this knowledge and to propose new alternatives for thymic ECM functions during thymopoiesis.

ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus –infected chronic skin wound healing

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment–responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)–infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.

Molecular Mechanisms of Changes in Homeostasis of the Dermal Extracellular Matrix: Both Involutional and Mediated by Ultraviolet Radiation.

Skin aging is a multi-factorial process that affects nearly every aspect of skin biology and function. With age, an impairment of structures, quality characteristics, and functions of the dermal extracellular matrix (ECM) occurs in the skin, which leads to disrupted functioning of dermal fibroblasts (DFs), the main cells supporting morphofunctional organization of the skin. The DF functioning directly depends on the state of the surrounding collagen matrix (CM). The intact collagen matrix ensures proper adhesion and mechanical tension in DFs, which allows these cells to maintain collagen homeostasis while ECM correctly regulates cellular processes. When the integrity of CM is destroyed, mechanotransduction is disrupted, which is accompanied by impairment of DF functioning and destruction of collagen homeostasis, thereby contributing to the progression of aging processes in skin tissues. This article considers in detail the processes of skin aging and associated changes in the skin layers, as well as the mechanisms of these processes at the molecular level.