Changes In Extracellular Matrix Composition Research Articles

Obesity Induces Temporally Regulated Alterations in the Extracellular Matrix That Drive Breast Tumor Invasion and Metastasis.

Obesity is associated with increased incidence and metastasis of triple-negative breast cancer, an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet (HFD)-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary fat pads of mice fed a control or HFD, assessing tumor growth and metastasis and evaluating the ECM composition of the mammary fat pads, lungs, and livers. Tumor growth was increased in obese mice after 12 weeks on HFD. Liver metastasis increased in obese mice only at 4 weeks, and elevated body weight correlated with increased metastasis to the lungs but not the liver. Whole decellularized ECM coupled with proteomics indicated that early stages of obesity were sufficient to induce changes in the ECM composition. Obesity led to an increased abundance of the proinvasive ECM proteins collagen IV and collagen VI in the mammary glands and enhanced the invasive capacity of cancer cells. Cells of stromal vascular fraction and adipose stem and progenitor cells were primarily responsible for secreting collagen IV and collagen VI, not adipocytes. Longer exposure to HFD increased the invasive potential of ECM isolated from the lungs and liver, with significant changes in ECM composition found in the liver with short-term HFD exposure. Together, these data suggest that changes in the breast, lungs, and liver ECM underlie some of the effects of obesity on triple-negative breast cancer incidence and metastasis. Significance: Organ-specific extracellular matrix changes in the primary tumor and metastatic microenvironment are mechanisms by which obesity contributes to breast cancer progression.

The prognostic effect of mechanical, ultrastructural, and ECM signatures in glioblastoma core and rim.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance.

Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism

The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2]. The impact of ECM orientation on breast cancer metabolism, however, is largely unknown. Here, we employ two non-invasive imaging techniques, fluorescence-lifetime imaging microscopy (FLIM) and intensity-based multiphoton microscopy, to assess the metabolic states of cancer cells cultured on ECM-mimicking nanofibers in a random and aligned orientation. By tracking the changes in the intrinsic fluorescence of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, as well as expression levels of metastatic markers, we reveal how ECM fiber orientation alters cancer metabolism and EMT progression. Our study indicates that aligned cellular microenvironments play a key role in promoting metastatic phenotypes of breast cancer as evidenced by a more glycolytic metabolic signature on nanofiber scaffolds of aligned orientation compared to scaffolds of random orientation. This finding is particularly relevant for subsets of breast cancer marked by high levels of collagen remodeling (e.g. pregnancy associated breast cancer), and may serve as a platform for predicting clinical outcomes within these subsets [3–6].

Effects of aging on the biomechanical properties of the lung extracellular matrix: dependence on tissular stretch.

Introduction: Aging induces functional and structural changes in the lung, characterized by a decline in elasticity and diminished pulmonary remodeling and regenerative capacity. Emerging evidence suggests that most biomechanical alterations in the lung result from changes in the composition of the lung extracellular matrix (ECM), potentially modulating the behavior of pulmonary cells and increasing the susceptibility to chronic lung diseases. Therefore, it is crucial to investigate the mechanical properties of the aged lung. This study aims to assess the mechanical alterations in the lung ECM due to aging at both residual (RV) and functional (FV) lung volumes and to evaluate their effects on the survival and proliferation of mesenchymal stromal cells (MSCs). Methods: The lungs from young (4-6-month-old) and aged (20-24-month-old) mice were inflated with optimal cutting temperature compound to reach FV or non-inflated (RV). ECM proteins laminin, collagen I and fibronectin were quantified by immunofluorescence and the mechanical properties of the decellularized lung sections were assessed using atomic force microscopy. To investigate whether changes in ECM composition by aging and/or mechanical properties at RV and FV volumes affects MSCs, their viability and proliferation were evaluated after 72h. Results: Laminin presence was significantly reduced in aged mice compared to young mice, while fibronectin and collagen I were significantly increased in aged mice. In RV conditions, the acellular lungs from aged mice were significantly softer than from young mice. By contrast, in FV conditions, the aged lung ECM becomes stiffer than that of in young mice, revealing that strain hardening significantly depends on aging. Results after MSCs recellularization showed similar viability and proliferation rate in all conditions. Discussion: This data strongly suggests that biomechanical measurements, especially in aging models, should be carried out in physiomimetic conditions rather than following the conventional non-inflated lung (RV) approach. The use of decellularized lung scaffolds from aged and/or other lung disease murine/human models at physiomimetic conditions will help to better understand the potential role of mechanotransduction on the susceptibility and progression of chronic lung diseases, lung regeneration and cancer.

MFAP4-Deficiency Aggravates Age-Induced Changes in Resistance Artery Structure, While Ameliorating Hypertension.

Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening. Mesenteric arteries were isolated from old (20-23 months) littermate Mfap4+/+ and Mfap4-/- mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate Mfap4+/+ and Mfap4-/- mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting. MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4+/+ mice relative to Mfap4-/- mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4-/- mouse mesenteric arteries in ex vivo myography recordings. MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.

Dynamic changes in mitral valve extracellular matrix, tissue mechanics and function in a mouse model of Marfan syndrome

ObjectiveMouse models of Marfan syndrome (MFS) with Fibrillin 1 (Fbn1) variant C1041G exhibit cardiovascular abnormalities, including myxomatous valve disease (MVD) and aortic aneurism, with structural extracellular matrix (ECM) dysregulation. In this study, we examine the structure-function-mechanics relations of the mitral valve related to specific transitions in ECM composition and organization in progressive MVD in MFS mice from Postnatal day (P)7 to 1 year-of-age. Approach and resultsMechanistic links between mechanical forces and biological changes in MVD progression were examined in Fbn1C1041G/+ MFS mice. By echocardiography, mitral valve dysfunction is prevalent at 2 months with a decrease in cardiac function at 6 months, followed by a preserved cardiac function at 12 months. Mitral valve (MV) regurgitation occurs in a subset of mice at 2–6 months, while progressive dilatation of the aorta occurs from 2 to 12 months. Mitral valve tissue mechanical assessments using a uniaxial Permeabilizable Fiber System demonstrate decreased stiffness of MFS MVs at all stages. Histological and microscopic analysis of ECM content, structure, and fiber orientation demonstrate that alterations in ECM mechanics, composition, and organization precede functional abnormalities in Fbn1C1041G/+MFS MVs. At 2 months, ECM abnormalities are detected with an increase in proteoglycans and decreased stiffness of the mitral valve. By 6–12 months, collagen fiber remodeling is increased with abnormal fiber organization in MFS mitral valve leaflets. At the same time, matrifibrocyte gene expression characteristic of collagen-rich connective tissue is increased, as detected by RNA in situ hybridization and qPCR. Together, these studies demonstrate early prevalence of proteoglycans at 2 months followed by upregulation of collagen structure and organization with age in MVs of MFS mice. ConclusionsAltogether, our data indicate dynamic regulation of mitral valve structure, tissue mechanics, and function that reflect changes in ECM composition, organization, and gene expression in progressive MVD. Notably, increased collagen fiber organization and orientation, potentially dependent on increased matrifibrocyte cell activity, is apparent with altered mitral valve mechanics and function in aging MFS mice.

Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation

During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization, DNA accessibility, and methylation between the two cellular states. Using integrative analyses, we identified sustained Yes-Associated Protein (YAP) transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization and likely to be coordinated by changes in extracellular matrix composition. Together, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation.

Extracellular matrix composition affects outgrowth of dendrites and dendritic spines on cortical neurons.

The composition of the extracellular matrix (ECM) in nervous tissue plays an important role in controlling neuronal outgrowth and synapse development. Changes in both protein and glycosaminoglycan components of the ECM occur with tissue injury and may affect neuron growth. To investigate neuron responses to alterations in fibronectin (FN), a major component of the wound ECM, we grew cortical neurons on cell-derived decellularized matrices composed of wild type FN (FN+/+) or of a mutant form of FN (FNΔ/+) from which the III13 heparin-binding site had been deleted by CRISPR-Cas 9 gene editing. The most significant effect of the mutant FN was a reduction in dendrite outgrowth. Not only were dendrites shorter on mutant FNΔ/+-collagen (COL) matrix than on wild type (FN+/+-COL) matrix, but the number of dendrites and dendritic spines per neuron and the spine densities were also dramatically reduced on FNΔ/+-COL matrices. Mass spectrometry and immunostaining identified a reduction in tenascin-C (TN-C) levels in the mutant matrix. TN-C is an ECM protein that binds to the III13 site of FN and modulates cell-matrix interactions and has been linked to dendrite development. We propose that TN-C binding to FN in the wound matrix supports dendrite and spine development during repair of damaged neural tissue. Overall, these results show that changes in ECM composition can dramatically affect elaboration of neurites and support the idea that the ECM microenvironment controls neuron morphology and connectivity.

Changes in macrophage immunometabolism as a marker of skeletal muscle dysfunction across the lifespan.

One of the most pronounced changes in the elderly is loss of strength and mobility due to the decline of skeletal muscle function, resulting in a multifactorial condition termed sarcopenia. Although significant clinical changes begin to manifest at advanced ages, recent studies have shown that changes at the cellular and molecular level precede the symptomatology of sarcopenia. By utilizing a single-cell transcriptomic atlas of mouse skeletal muscle across the lifespan, we identified a clear sign of immune senescence that presents during middle age. More importantly, the change in macrophage phenotype in middle age may explain the changes in extracellular matrix composition, especially collagen synthesis, that contributes to fibrosis and overall muscle weakness with advanced age. Our results show a novel paradigm whereby skeletal muscle dysfunction is driven by alterations in tissue-resident macrophages before the appearance of clinical symptoms in middle-aged mice, providing a new therapeutic approach via regulation of immunometabolism.

Spatio-Temporal Changes of Extracellular Matrix (ECM) Stiffness in the Development of the Leech Hirudo verbana.

The invertebrate leech Hirudo verbana represents a powerful experimental animal model for improving the knowledge about the functional interaction between the extracellular matrix (ECM) and cells within the tissue microenvironment (TME), and the key role played by ECM stiffness during development and growth. Indeed, the medicinal leech is characterized by a simple anatomical organization reproducing many aspects of the basic biological processes of vertebrates and in which a rapid spatiotemporal development is well established and easily assessed. Our results show that ECM structural organization, as well as the amount of fibrillar and non-fibrillar collagen are deeply different from hatching leeches to adult ones. In addition, the changes in ECM remodelling occurring during the different leech developmental stages, leads to a gradient of stiffness regulating both the path of migratory cells and their fates. The ability of cells to perceive and respond to changes in ECM composition and mechanics strictly depend on nuclear or cytoplasmic expression of Yes-Associated Protein 1 (YAP1), a key mediator converting mechanical signals into transcriptional outputs, expression, and activation.

Control of Fibrotic Gene Expression in Cardiac Myocytes and Fibroblasts via the Rap1 GTPase

Fibrosis describes the excessive deposition of extracellular matrix components by cardiac myofibroblasts (CFs), a process which frequently promotes the adverse effects of pathological conditions damaging cardiac muscle, such as myocardial infarction and arrhythmogenic cardiomyopathy. Roughly 1 million Americans suffer a myocardial infarction each year, after which necrotic cardiac myocytes (CMs) are replaced by CF‐derived extracellular matrix (ECM), in response to (a) biochemical signaling cues from necrotic CMs and (b) mechanical cues from the contracting myocardium and ventricle cavity pressure. Accumulation of ECM proteins (such as collagen) within the infarct scar is initially critical to prevent further tissue damage, but chronic and excessive collagen deposition is detrimental to regeneration of CMs and healing of the myocardium. While the physiological outcomes of cardiac fibrosis are well studied, the biochemical and mechano‐responsive signaling mechanisms which regulate fibrotic gene expression remain poorly investigated. The RhoA GTPase signaling pathway has been shown to play a central role in regulating fibrotic gene expression and is activated via many different pro‐fibrotic signaling factors and biomechanical stimuli (i.e., changes in ECM composition, organization and rigidity). The GTPase Rap1 is also very well‐known to mediate both inside‐out and outside‐in signaling via attachment of integrins to ECM proteins. In certain contexts, Rap1 has also been shown to antagonize RhoA signaling, but very little is known about its role in fibrotic gene expression. We therefore hypothesized that expression of Rap1 would inhibit fibrotic gene expression in cardiac myocytes and fibroblasts. Expression of either wildtype (WT) or constitutively active (63E) GFP‐tagged Rap1A constructs in cardiac fibroblasts resulted in a dramatic decrease in mRNA levels of ACTA2 (smooth muscle alpha‐actin), a commonly used marker of myofibroblast activation. Further, expression of WT or 63E Rap1A in either cardiac myocytes or fibroblasts resulted in a significant decrease in mRNA levels of ECM proteins (such as COL1A1, COL3A1, COL4A1 and FN1), as well as other common markers of fibrotic gene expression (CTGF and EGR1). Taken together, these data indicate that Rap1 signaling inhibits fibrotic gene expression and myofibroblast activation. Interestingly, expression of WT or 63E Rap1A in cardiac fibroblasts caused a dramatic increase in inflammatory markers (such as TNF, IL6, NFKB1A) and matrix remodeling enzymes (MMP3 and MMP9), genes which have been shown to play a role in increasing collagen turnover, reducing ECM rigidity/stiffness and repair of damaged myocardial tissue. Altogether, these data point to a significant role for Rap1 GTPase in reducing fibrotic gene expression and myofibroblast activation and suggest possible new therapeutic strategies to combat the damaging effects of cardiac fibrosis.

Cadherin-11 Influences Differentiation in Human Mesenchymal Stem Cells by Regulating the Extracellular Matrix Via the TGFβ1 Pathway

For regenerative medicine, directing stem cell fate is one of the key aims. Human mesenchymal stem cells (hMSCs) are versatile adult stem cells that have been proposed for several clinical applications, making directing their fate of utmost importance. For most clinical applications, their differentiation toward the adipogenic lineage is an undesired outcome. Understanding the mechanisms that regulate hMSC commitment toward the adipogenic lineage might help open up new avenues for fine-tuning implanted hMSCs for regenerative medicine applications. We know that cadherin-11 is required for hMSC commitment to the adipogenic lineage; therefore, we sought to investigate the mechanisms through which cadherin-11 regulates adipogenic differentiation. We observed that hMSCs lacking cadherin-11 had decreased expression of type VI collagen and increased expression of fibronectin. We provide evidence of increased transforming growth factor beta 1 and the subsequent translocation of phosphorylated SMAD2/3 into the nucleus by cells that lack cadherin-11, which could be attributed to the changes in extracellular matrix composition. Taken together, our study implicates cadherin-11 in regulating extracellular matrix production and thereby helping improve cell- and material-based regenerative medicine approaches.

Cardiac Fibroblasts Play Pathogenic Roles in Idiopathic Restrictive Cardiomyopathy.

Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation. Although several mutations were reported in some patients, no mutations were identified in cardiomyocyte expressing genes of other patients, indicating that pathological mechanisms underlying RCM could not be determined by cardiomyocytes only. Cardiac fibroblasts (CFs) are a major cell population in the heart; however, the pathological roles of CFs in cardiomyopathy are not fully understood.Methods and Results:This study established 4 primary culture lines of CFs from RCM patients and analyzed their cellular physiology, the effects on the contraction and relaxation ability of healthy cardiomyocytes under co-culture with CFs, and RNA sequencing. Three of four patients hadTNNI3mutations. There were no significant alterations in cell proliferation, apoptosis, migration, activation, and attachment. However, when CFs from RCM patients were co-cultured with healthy cardiomyocytes, the relaxation velocity of cardiomyocytes was significantly impaired both under direct and indirect co-culture conditions. RNA sequencing revealed that gene expression profiles of CFs in RCM were clearly distinct from healthy CFs. The differential expression gene analysis identified that several extracellular matrix components and cytokine expressions were dysregulated in CFs from RCM patients. The comprehensive gene expression patterns were altered in RCM-derived CFs, which deteriorated the relaxation ability of cardiomyocytes. The specific changes in extracellular matrix composition and cytokine secretion from CFs might affect pathological behavior of cardiomyocytes in RCM.

Special Issue: Application of Extracellular Matrix in Regenerative Medicine

The present Special Issue comprises a collection of articles addressing the many ways in which extracellular matrix (ECM), or its components parts, can be used in regenerative medicine applications. ECM is a dynamic structure, composed of a three-dimensional architecture of fibrous proteins, proteoglycans, and glycosaminoglycans, synthesized by the resident cells. Consequently, ECM can be considered as nature’s ideal biologic scaffold material. The articles in this Special Issue cover a range of topics from the use of ECM components to manufacture scaffold materials, understanding how changes in ECM composition can lead to the development of disease, and how decellularization techniques can be used to develop tissue-derived ECM scaffolds for whole organ regeneration and wound repair. This editorial briefly summarizes the most interesting aspects of these articles.

The ECM as a driver of heart development and repair.

The developing heart is formed of two tissue layers separated by an extracellular matrix (ECM) that provides chemical and physical signals to cardiac cells. While deposition of specific ECM components creates matrix diversity, the cardiac ECM is also dynamic, with modification and degradation playing important roles in ECM maturation and function. In this Review, we discuss the spatiotemporal changes in ECM composition during cardiac development that support distinct aspects of heart morphogenesis. We highlight conserved requirements for specific ECM components in human cardiac development, and discuss emerging evidence of a central role for the ECM in promoting heart regeneration.

Creation and grading of experimental corneal scars in mice models

PurposeTo develop a stromal wound healing model and a reliable scar classification score system that correlates photographic evaluation with changes in the structure and organization of the extracellular matrix. Materials and methodsWe tested three stromal injury techniques in adult C57BL/6 mice. Technique 1, a lineal partial thickness keratotomy in the horizontal axis. Technique 2, corneal epithelial and stromal debridement using a diamond burr in the horizontal axis, and technique 3, a combination of techniques 1 and 2. To assess intra-observer and inter-observer agreement between two examiners evaluating formed stromal scars, stereo microscopic photographs of anterior segment were scored by two masked examiners at around 1-month. Depending on the severity of opacification and the area of involvement, scars were classified on a scale from 0 to 3 based on a modified Fantes haze scale. Extracellular matrix composition as well as matrix organization, macrophage infiltration and neovascularization were evaluated with immunofluorescence and second harmonic generation (SHG) microscopy. ResultsTechnique 1 created mild scars, with a score of 0.5 ± 0.43, while techniques 2 (score 2.1 ± 0.45) and 3 (score 2 ± 0.66), created dense scars with a higher score. A significant difference in scar severity score was noted between the 3 techniques (one way ANOVA, p < 0.0001). Masked graders demonstrated excellent agreement (intraclass correlation = 0.927 [95% confidence interval: 0.87–0.96]). The severity of scars noted at stereo microscopy correlated with the severity of changes in extracellular matrix in the stroma as demonstrated by the expression of collagens I, IV and fibronectin and evaluation of matrix hierarchical organization. In contrast to mild scarring, moderate and severe scars had increased expression of CD31 and CD68, markers of vascular endothelial cells and macrophages, respectively. ConclusionMouse models of stromal scarring using simple surgical techniques are described. Corneal scars can be consistently classified by two observers. Grading of scar severity positively correlates with changes in extracellular matrix composition, disorganization and cell infiltration.

Mechanisms of Vascular Remodeling in Hypertension.

Hypertension is both a cause and a consequence of central artery stiffening, which in turn is an initiator and indicator of myriad disease conditions and thus all-cause mortality. Such stiffening results from a remodeling of the arterial wall that is driven by mechanical stimuli and mediated by inflammatory signals, which together lead to differential gene expression and concomitant changes in extracellular matrix composition and organization. This review focuses on biomechanical mechanisms by which central arteries remodel in hypertension within the context of homeostasis-what promotes it, what prevents it. It is suggested that the vasoactive capacity of the wall and inflammatory burden strongly influence the ability of homeostatic mechanisms to adapt the arterial wall to high blood pressure or not. Maladaptation, often reflected by inflammation-driven adventitial fibrosis, not just excessive intimal-medial thickening, significantly diminishes central artery function and disturbs hemodynamics, ultimately compromising end organ perfusion and thus driving the associated morbidity and mortality. It is thus suggested that there is a need for increased attention to controlling both smooth muscle phenotype and inflammation in hypertensive remodeling of central arteries, with future studies of the often adaptive response of medium-sized muscular arteries promising to provide additional guidance.

Engineering the Extracellular Matrix to Model the Evolving Tumor Microenvironment.

SummaryClinical evidence supports a role for the extracellular matrix (ECM) in cancer risk and prognosis across multiple tumor types, and numerous studies have demonstrated that individual ECM components impact key hallmarks of tumor progression (e.g., proliferation, migration, angiogenesis). However, the ECM is a complex network of fibrillar proteins, glycoproteins, and proteoglycans that undergoes dramatic changes in composition and organization during tumor development. In this review, we will highlight how engineering approaches can be used to examine the impact of changes in tissue architecture, ECM composition (i.e., identity and levels of individual ECM components), and cellular- and tissue-level mechanics on tumor progression. In addition, we will discuss recently developed methods to model the ECM that have not yet been applied to the study of cancer.

Correlation of light microscopic findings with transmission electron microscopy within a vascular occlusion device

Host response to an implanted biomaterial is a complex process involving microscopic changes in extracellular matrix (ECM) composition. Reliable pathology analysis is imperative for accurate assessment of the tissue response to an implanted device. Plastic histology is commonly used for histology evaluation of medical devices to assess the device-tissue interface; however, this technique is prone to variable staining that can confound histology interpretation. Appropriately, we propose using transmission electron microscopy (TEM) to confirm histologic ECM findings in order to provide sufficient host-response data.Tissue response to an absorbable shape memory polymer intravascular occlusion device with a nitinol wire backbone was evaluated. Representative plastic-embedded, micro-ground sections from 30-day, 60-day, and 90-day timepoints were analyzed. ECM regions were selected, and ultrathin sections were created for TEM evaluation. Histological changes in ECM composition were compared for light microscopy (LM) and TEM findings; specifically, TEM fibrillary patterns for collagen and fibrin were used to confirm LM results.Throughout this study, LM reveals inconsistent staining in plastic-embedded sections. TEM, on the other hand, provides clear insight into the tissue response by morphologically discerning distinct fibrillary patterns within ECM structures; loose to dense collagen surrounds the implant as fibrin degrades, demonstrating progression of postimplant ECM maturation. Moreover, TEM serves as a definitive method for confirming tissue substrate morphology when LM findings prove ambiguous.

CeRNA Network Analysis Representing Characteristics of Different Tumor Environments Based on 1p/19q Codeletion in Oligodendrogliomas.

Simple SummaryOligodendroglioma (OD) is a subtype of glioma occurring in the central nervous system. The 1p/19q codeletion is a prognostic marker of OD with an isocitrate dehydrogenase (IDH) mutation and is associated with a clinically favorable overall survival (OS). The long non-coding RNAs (lncRNAs) protects the mRNA from degradation by binding with the same miRNA by acting as a competitive endogenous RNA (ceRNA). Recently, although there is an increasing interest in lncRNAs on glioma studies, however, studies regarding their effects on OD and the 1p/19q codeletion remain limited. In our study, we performed in silico analyses using low-grade gliomas from datasets obtained from The Cancer Genome Atlas to investigate the effects of ceRNA with 1p/19q codeletion on ODs. We constructed 16 coding RNA–miRNA–lncRNA networks and the ceRNA network participated in ion channel activity, insulin secretion, and collagen network and extracellular matrix (ECM) changes. In conclusion, our results can provide insights into the possibility in the different tumor microenvironments and OS following 1p/19q codeletion through changes in the ceRNA network.Oligodendroglioma (OD) is a subtype of glioma occurring in the central nervous system. The 1p/19q codeletion is a prognostic marker of OD with an isocitrate dehydrogenase (IDH) mutation and is associated with a clinically favorable overall survival (OS); however, the exact underlying mechanism remains unclear. Long non-coding RNAs (lncRNAs) have recently been suggested to regulate carcinogenesis and prognosis in cancer patients. Here, we performed in silico analyses using low-grade gliomas from datasets obtained from The Cancer Genome Atlas to investigate the effects of ceRNA with 1p/19q codeletion on ODs. Thus, we selected modules of differentially expressed genes that were closely related to 1p/19q codeletion traits using weighted gene co-expression network analysis and constructed 16 coding RNA–miRNA–lncRNA networks. The ceRNA network participated in ion channel activity, insulin secretion, and collagen network and extracellular matrix (ECM) changes. In conclusion, ceRNAs with a 1p/19q codeletion can create different tumor microenvironments via potassium ion channels and ECM composition changes; furthermore, differences in OS may occur. Moreover, if extrapolated to gliomas, our results can provide insights into the consequences of identical gene expression, indicating the possibility of tracking different biological processes in different subtypes of glioma.