Extracellular Matrix Degradation and Remodeling in Development and Disease

The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.The extracellular matrix (ECM) forms a milieu surrounding cells that reciprocally influences cellular function to modulate diverse fundamental aspects of cell biology (Hynes 2009). The diversity and sophistication of ECM components and their respective cell surface receptors are among the most salient features during metazoan evolution (Har-el and Tanzer 1993; Hutter et al. 2000; Whittaker et al. 2006; Engler et al. 2009; Huxley-Jones et al. 2009; Ozbek et al. 2010). The ECM is extremely versatile and performs many functions in addition to its structural role. As a major component of the microenvironment of a cell, the ECM takes part in most basic cell behaviors, from cell proliferation, adhesion and migration, to cell differentiation and cell death (Hynes 2009). This pleiotropic aspect of ECM function depends on the highly dynamic structure of ECM and its remodeling as an effective mechanism whereby diverse cellular behaviors can be regulated. This concept is particularly important when considering processes and cell behaviors that need to be deployed promptly and transiently and wherein cell–cell and cell–matrix interactions are constantly changing (Daley et al. 2008).ECM dynamics are a feature of tissues wherein radical remodeling occurs, such as during metamorphosis of insects and amphibians or remodeling of the adult bone and mammary gland, and in developmental processes, including neural crest migration, angiogenesis, tooth and skeletal development, branching morphogenesis, maturation of synapses, and the nervous system (Berardi et al. 2004; Fukumoto and Yamada 2005; Page-McCaw et al. 2007; Zimmermann and Dours-Zimmermann 2008).ECM dynamics can result from changes of ECM composition, for example, because of altered synthesis or degradation of one or more ECM components, or in architecture because of altered organization. Mounting evidence has shown how individual ECM components are laid down, cross-linked, and organized together via covalent and noncovalent modifications and how they can greatly influence the fundamental aspects of cell behavior (Lopez et al. 2008; Engler et al. 2009; Egeblad et al. 2010b). This higher level of ECM organization is also dynamic and subject to sustained remodeling as mediated by reciprocal interactions between the ECM and its resident cellular components (Daley et al. 2008). Understandably, ECM dynamics are tightly regulated to ensure normal development, physiology, and robustness of organ systems. This is achieved by redundant mechanisms to modulate the expression and function of ECM modifying enzymes at multiple levels. When such control mechanisms are corrupted, ECM dynamics become deregulated, leading to various human congenital defects and diseases, including cancer.Here, we examine the players involved in ECM remodeling and how they are tightly regulated to achieve a delicate balance between stability and remodeling of the ECM. We focus on the cellular and molecular mechanisms through which ECM dynamics influence cellular behaviors. We illustrate how a wide variety of cell behaviors can be deployed by exploiting the important roles of ECM dynamics to build vertebrate organs and maintain their functions, and how deregulation of ECM dynamics contributes to the initiation and progression of human cancer.     

Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice

Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM) remodeling in response to pressure overload (PO). Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO) and wild-type (WT) mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson’s trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects.     

Proteomics Analysis of Extracellular Matrix Remodeling During Zebrafish Heart Regeneration

1. Download : Download high-res image (99KB)
2. Download : Download full-size image

Highlights

• •We have developed a decellularization protocol for ECM protein enrichment.
• •We have characterized the proteome of adult zebrafish heart ECM.
• •We describe dynamic changes in heart ECM proteome during regeneration.
• •We describe changes in heart ECM stiffness during regeneration.

     

Proteomic Analysis of Altered Extracellular Matrix Turnover in Bleomycin-induced Pulmonary Fibrosis

Fibrotic disease is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Surprisingly, very little is known about the synthesis and degradation rates of the many proteins and proteoglycans that constitute healthy or pathological extracellular matrix. A comprehensive understanding of altered ECM protein synthesis and degradation during the onset and progression of fibrotic disease would be immensely valuable. We have developed a dynamic proteomics platform that quantifies the fractional synthesis rates of large numbers of proteins via stable isotope labeling and LC/MS-based mass isotopomer analysis. Here, we present the first broad analysis of ECM protein kinetics during the onset of experimental pulmonary fibrosis. Mice were labeled with heavy water for up to 21 days following the induction of lung fibrosis with bleomycin. Lung tissue was subjected to sequential protein extraction to fractionate cellular, guanidine-soluble ECM proteins and residual insoluble ECM proteins. Fractional synthesis rates were calculated for 34 ECM proteins or protein subunits, including collagens, proteoglycans, and microfibrillar proteins. Overall, fractional synthesis rates of guanidine-soluble ECM proteins were faster than those of insoluble ECM proteins, suggesting that the insoluble fraction reflected older, more mature matrix components. This was confirmed through the quantitation of pyridinoline cross-links in each protein fraction. In fibrotic lung tissue, there was a significant increase in the fractional synthesis of unique sets of matrix proteins during early (pre-1 week) and late (post-1 week) fibrotic response. Furthermore, we isolated fast turnover subpopulations of several ECM proteins (e.g. type I collagen) based on guanidine solubility, allowing for accelerated detection of increased synthesis of typically slow-turnover protein populations. This establishes the presence of multiple kinetic pools of pulmonary collagen in vivo with altered turnover rates during evolving fibrosis. These data demonstrate the utility of dynamic proteomics in analyzing changes in ECM protein turnover associated with the onset and progression of fibrotic disease.The extracellular matrix (ECM)¹ comprises an intricate network of cell-secreted collagens, proteoglycans, and glycoproteins providing structural and mechanical support to every tissue. The dynamic interplay between cells and ECM also directs cell proliferation, migration, differentiation, and apoptosis associated with normal tissue development, homeostasis, and repair (1, 2). Tissue repair following acute injury is typically characterized by the recruitment of inflammatory cells, enzymatic degradation of ECM immediately adjacent to the damaged tissue site, and subsequent infiltration of fibroblasts depositing new ECM. However, in the case of chronic tissue injury and inflammation, abnormal signaling pathways can stimulate uncontrolled ECM protein deposition, ultimately resulting in fibrosis and organ failure (3–6). In fact, fibrotic diseases including idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, and cardiovascular disease have been estimated to account for over 45% of deaths in the developed world (1).Despite the wide prevalence of fibrotic diseases, there is currently a paucity of anti-fibrotic drug treatments and diagnostic tests (7, 8). Median survival rates for idiopathic pulmonary fibrosis, for example, range from only two to five years following diagnosis (9, 10). Failure in the development of successful anti-fibrotic treatments can in part be attributed to a poor understanding of the active and dynamic role played by the ECM during various stages of fibrotic disease. ECM components influence myofibroblast differentiation not only through their modulation of fibrogenic growth factor activity (e.g. TGF-β), but also through mechanotransductive pathways whereby cells interpret altered ECM mechanical properties (3, 5, 11–13). The search for novel target pathways in the development of anti-fibrotic therapies would benefit from a better understanding of dynamic ECM synthesis and degradation associated with the various stages of fibrotic disease.The combination of stable isotope labeling and proteomic analysis provides a new approach for interrogating dynamic changes in ECM protein synthesis associated with fibrotic disease. We have developed a platform termed “dynamic proteomics,” whereby protein synthesis rates from tissue samples are measured following the administration of stable isotope tracers (e.g. ²H, ¹⁵N) (14). Label incorporation into newly synthesized proteins is assessed via LC/MS analysis of mass isotopomer distributions in peptides derived from parent proteins through enzymatic degradation, providing a means to quantify the fractional synthesis rate (FSR) of individual proteins over the labeling period. Unlike traditional static proteomic techniques, this strategy provides valuable information regarding which proteins are actively synthesized or degraded during any specific stage of the disease process. Moreover, as measurements of label incorporation do not fluctuate based on the amount or yield of protein isolated (14–16), dynamic proteomic strategies also offer additional robustness relative to traditional quantitative proteomic techniques.The detection of ECM components in highly cellular tissues such as liver and lung poses an additional stumbling block in the proteomic analysis of fibrotic ECM. The identification of less abundant matrix components is limited by the overwhelming number of cellular proteins present in standard homogenized tissue samples. Standard global protein fractionation techniques (e.g. gel electrophoresis) are inefficient at enriching targeted subsets of proteins. Tissue decellularization techniques commonly utilized in regenerative medicine offer a novel approach toward the enrichment of ECM proteins prior to proteomic analysis (17). Tissue samples are incubated under mechanical agitation in the presence of weak detergents that solubilize cell membranes, releasing cellular protein components into solution while keeping the surrounding structural ECM intact. This technique has recently been applied in the compositional proteomic analysis of cardiovascular, lung, and colon tissues, leading to the identification of ECM-related proteins previously not associated with those tissues (11, 18–20).We present here the first study to combine dynamic proteomics with tissue decellularization in order to analyze altered ECM protein synthesis associated with pulmonary fibrosis. Bleomycin and sham-dosed mice were labeled for up to three weeks with heavy water (²H₂O), and lung tissue was subsequently collected and fractionated into cellular and extracellular components. Further fractionation of ECM based on guanidine solubility resulted in the identification of protein fractions with kinetically distinct characteristics composed of a variety of collagens, basement membrane proteoglycans, and microfibrillar proteins. Label incorporation into ECM proteins in sham-dosed control lungs was generally faster in the guanidine-soluble fraction, suggesting that the insoluble pool reflected more stable, slower-turnover matrix components. In bleomycin-dosed lungs, however, there was a significant increase in the synthesis of both guanidine-soluble and insoluble ECM proteins. These labeling and fractionation methods should be easily adaptable to a variety of animal and human tissue types and could provide a new approach toward actively monitoring the dynamic changes in ECM synthesis and composition associated with fibrotic disease.     

CCL2促进肝再生中细胞外基质的形成

为阐明CC趋化因子配体2〔chemokine(C-C motif)ligand 2,CCL2〕对肝再生(liverregeneration,LR)的影响,构建CCL2的表达载体CCL2-N1及其干涉载体CCL2(255).为确定合适的转基因时间,观测内外源性CCL2的表达高峰.Rat Genome 230 2.0芯片、实时定量PCR和Western印迹显示,内源性CCL2的表达高峰在部分肝切除(partial hepatectomy,PH)后72 h.与CCL2融合表达的绿色荧光蛋白(green fluorescent protein,GFP)的表达和实时定量PCR显示,外源性CCL2的表达高峰在转基因后的24 h.所以,为使内源性和外源性CCL2的作用叠加,选择PH后48 h进行转基因.此时将CCL2-N1质粒转入大鼠体内,发现转基因后大鼠肝系数、增殖细胞核抗原(PCNA)表达量显著高于对照,透明质酸和层粘连蛋白含量显著升高.相反,干涉质粒CCL2(255)能降低肝系数,减少PCNA表达量,并且Ⅲ型前胶原肽、Ⅳ型胶原、透明质酸和层粘连蛋白含量与对照相比,有显著或极显著降低.综上所述,CCL2是肝再生相关基因,它能提高肝系数,可能通过调节细胞外基质(extracellular matrix,ECM)合成而促进肝脏再生.     

Emerging Role of Syndecans in Extracellular Matrix Remodeling in Cancer

The extracellular matrix (ECM) offers a structural basis for regulating cell functions while also acting as a collection point for bioactive molecules and connective tissue cells. To perform pathological functions under a pathological condition, the involved cells need to regulate the ECM to support their altered functions. This is particularly common in the development of cancer. The ECM has been recognized as a key driver of cancer development and progression, and ECM remodeling occurs at all stages of cancer progression. Thus, cancer cells need to change the ECM to support relevant cell surface adhesion receptor–mediated cell functions. In this context, it is interesting to examine how cancer cells regulate ECM remodeling, which is critical to tumor malignancy and metastatic progression. Here, we review how the cell surface adhesion receptor, syndecan, regulates ECM remodeling as cancer progresses, and explore how this can help us better understand ECM remodeling under these pathological conditions     

Microfibril-associated Glycoprotein-1, an Extracellular Matrix Regulator of Bone Remodeling

MAGP1 is an extracellular matrix protein that, in vertebrates, is a ubiquitous component of fibrillin-rich microfibrils. We previously reported that aged MAGP1-deficient mice (MAGP1Δ) develop lesions that are the consequence of spontaneous bone fracture. We now present a more defined bone phenotype found in MAGP1Δ mice. A longitudinal DEXA study demonstrated age-associated osteopenia in MAGP1Δ animals and μCT confirmed reduced bone mineral density in the trabecular and cortical bone. Further, MAGP1Δ mice have significantly less trabecular bone, the trabecular microarchitecture is more fragmented, and the diaphyseal cross-sectional area is significantly reduced. The remodeling defect seen in MAGP1Δ mice is likely not due to an osteoblast defect, because MAGP1Δ bone marrow stromal cells undergo osteoblastogenesis and form mineralized nodules. In vivo, MAGP1Δ mice exhibit normal osteoblast number, mineralized bone surface, and bone formation rate. Instead, our findings suggest increased bone resorption is responsible for the osteopenia. The number of osteoclasts derived from MAGP1Δ bone marrow macrophage cells is increased relative to the wild type, and osteoclast differentiation markers are expressed at earlier time points in MAGP1Δ cells. In vivo, MAGP1Δ mice have more osteoclasts lining the bone surface. RANKL (receptor activator of NF-κB ligand) expression is significantly higher in MAGP1Δ bone, and likely contributes to enhanced osteoclastogenesis. However, bone marrow macrophage cells from MAGP1Δ mice show a higher propensity than do wild-type cells to differentiate to osteoclasts in response to RANKL, suggesting that they are also primed to respond to osteoclast-promoting signals. Together, our findings suggest that MAGP1 is a regulator of bone remodeling, and its absence results in osteopenia associated with an increase in osteoclast number.     

人类心房纤维性颤动变化的分子机制

近年来确认了心房纤维性颤动(AF)以促进心房的发生和维持的方式修饰了心房的电特征.并确立了节律紊乱发生的电生理变化.主要描述了功能的快变化和蛋白质表达的慢变化的分子机制,这种慢变化会引起心房纤维性颤动的电改变和收缩异常.心房纤维性颤动的一个重要分子特征是L型钙离子通道功能和蛋白质表达的减少.这种减少可能有助于保护细胞抵制由于心房纤维性颤动的激活率增加产生的潜在致死钙离子超载.对蛋白水解系统的可能作用也进行了讨论,其中重点讨论了钙蛋白酶作为一种与钙离子超载导致蛋白表达减少相联系的机制.     

Stromal Fibroblasts Mediate Extracellular Matrix Remodeling and Invasion of Scirrhous Gastric Carcinoma Cells

Scirrhous gastric carcinoma (SGC) has the worst prognosis of all gastric cancers, owing to its rapid expansion by invasion and frequent peritoneal dissemination. Due to the increased proliferation of stromal fibroblasts (SFs) that occurs within SGC lesions and the peritoneal metastatic sites, SFs have been proposed to support the progression of this disease. However, the biological and molecular basis and the pathological role of the intercellular interaction between SGC cells and SFs remain largely unknown. In this study, we investigated the role of SFs in the invasion of the extracellular matrix (ECM) by SGC cells. When SGC cells were cocultured with SFs derived from SGC tissue on three-dimensional (3D) Matrigel, they were attracted together to form large cellular aggregates that invaded within the Matrigel. Time-lapse imaging revealed that this process was associated with extensive contraction and remodeling of the ECM. Immunofluorescence and biochemical analysis showed that SGC cells stimulate phosphorylation of myosin light chain and actomyosin-mediated mechanical remodeling of the ECM by SFs. By utilizing this assay system for inhibitor library screening, we have identified several inhibitors that potently suppress the cooperation between SGC cells and SFs to form the invasive structures. Among them, a Src inhibitor dasatinib impaired the interaction between SGC cells and SFs both in vitro and in vivo and effectively blocked peritoneal dissemination of SGC cells. These results indicate that SFs mediate mechanical remodeling of the ECM by SGC cells, thereby promoting invasion and peritoneal dissemination of SGC.     

细胞外间质

细胞外间质由四大家族组成,胶原蛋白,蛋白多糖。弹性蛋白和细胞外间质糖蛋白。细胞外间质成分不仅仅是细胞的惰性支持物,它具有活性的生物功能,例如细胞粘附及迁移,甚至涉及基因表达。细胞外间质研究是一个十分活跃的生物学领域。     

Mapping Molecular Differences and Extracellular Matrix Gene Expression in Segmental Outflow Pathways of the Human Ocular Trabecular Meshwork

Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, and lowering IOP remains the only effective treatment for glaucoma. The trabecular meshwork (TM) in the anterior chamber of the eye regulates IOP by generating resistance to aqueous humor outflow. Aqueous humor outflow is segmental, but molecular differences between high and low outflow regions of the TM are poorly understood. In this study, flow regions of the TM were characterized using fluorescent tracers and PCR arrays. Anterior segments from human donor eyes were perfused at physiological pressure in an ex vivo organ culture system. Fluorescently-labeled microspheres of various sizes were perfused into anterior segments to label flow regions. Actively perfused microspheres were segmentally distributed, whereas microspheres soaked passively into anterior segments uniformly labeled the TM and surrounding tissues with no apparent segmentation. Cell-tracker quantum dots (20 nm) were localized to the outer uveal and corneoscleral TM, whereas larger, modified microspheres (200 nm) localized throughout the TM layers and Schlemm’s canal. Distribution of fluorescent tracers demonstrated a variable labeling pattern on both a macro- and micro-scale. Quantitative PCR arrays allowed identification of a variety of extracellular matrix genes differentially expressed in high and low flow regions of the TM. Several collagen genes (COL16A1, COL4A2, COL6A1 and 2) and MMPs (1, 2, 3) were enriched in high, whereas COL15A1, and MMP16 were enriched in low flow regions. Matrix metalloproteinase activity was similar in high and low regions using a quantitative FRET peptide assay, whereas protein levels in tissues showed modest regional differences. These gene and protein differences across regions of the TM provide further evidence for a molecular basis of segmental flow routes within the aqueous outflow pathway. New insight into the molecular mechanisms of segmental aqueous outflow may aid in the design and delivery of improved treatments for glaucoma patients.     

肝纤维化发病机制中细胞和分子机制的研究进展

关于肝纤维化形成的复杂的细胞和分子联系已经有了相当多的研究进展。最近的数据表明,纤维化进程的终止和纤维分解途径的恢复可以逆转晚期肝纤维化甚至肝硬化。因此,需要更好地阐明参与肝纤维化的细胞和分子机制。HSC(肝星状细胞)的激活是肝纤维化发生的中心事件,此外还有产生基质的其他细胞来源,包括肝门区的成纤维细胞,纤维细胞和骨髓来源的肌纤维母细胞。这些细胞与其邻近细胞通过多种联系聚集产生纤维疤痕并造成持续性损伤。阐明不同类型的细胞的相互作用,揭示细胞因子对这些细胞的影响,理清活化HSC基因表达的调控,将有助于我们探索新的肝纤维化治疗靶点。此外,不同的病因有不同的致病途径,弄清这一点有助于针对特异性疾病治疗方法的发现。本文概述了肝纤维化的细胞和分子机制的最新研究进展,可能为未来治疗方法带来新的突破。     

CECMAtlas 1.0: 人类肿瘤相关的细胞外基质基因数据库

细胞外基质（extracellular matrix,ECM）是细胞微环境的重要组成部分,它不仅能为细胞提供物理支持,而且还参与了多种生物学过程。近年来,已经鉴定出来数百种与癌症相关的ECM（cancer-related ECM,C-ECM）基因,其中一些已作为潜在靶标。目前,有关于C-ECM基因的丰富信息还散布在成千上万的出版物中,并且它们在肿瘤发生过程中的作用也未被系统的整理。本文构建了CECMAtlas数据库（http://biokb.ncpsb.org.cn/CECMAtlas/）,该数据库使用文献挖掘和人工判读收集了225个C-ECM基因,以及相关生物学过程信息,该数据库将有助于研究肿瘤的发生机制和开展可能的临床应用。     

Molecular Evolution of Human Coronavirus Genomes

Download video (16MB)Help with mp4 files     

Modest Elevation in BNP in Asymptomatic Hypertensive Patients Reflects Sub-Clinical Cardiac Remodeling,Inflammation and Extracellular Matrix Changes

In asymptomatic subjects B-type natriuretic peptide (BNP) is associated with adverse cardiovascular outcomes even at levels well below contemporary thresholds used for the diagnosis of heart failure. The mechanisms behind these observations are unclear. We examined the hypothesis that in an asymptomatic hypertensive population BNP would be associated with sub-clinical evidence of cardiac remodeling, inflammation and extracellular matrix (ECM) alterations. We performed transthoracic echocardiography and sampled coronary sinus (CS) and peripheral serum from patients with low (n = 14) and high BNP (n = 27). Peripheral BNP was closely associated with CS levels (r = 0.92, p<0.001). CS BNP correlated significantly with CS levels of markers of collagen type I and III turnover including: PINP (r = 0.44, p = 0.008), CITP (r = 0.35, p = 0.03) and PIIINP (r = 0.35, p = 0.001), and with CS levels of inflammatory cytokines including: TNF-α (r = 0.49, p = 0.002), IL-6 (r = 0.35, p = 0.04), and IL-8 (r = 0.54, p<0.001). The high BNP group had greater CS expression of fibro-inflammatory biomarkers including: CITP (3.8±0.7 versus 5.1±1.9, p = 0.007), TNF-α (3.2±0.5 versus 3.7±1.1, p = 003), IL-6 (1.9±1.3 versus 3.4±2.7, p = 0.02) and hsCRP (1.2±1.1 versus 2.4±1.1, p = 0.04), and greater left ventricular mass index (97±20 versus 118±26 g/m², p = 0.03) and left atrial volume index (18±2 versus 21±4, p = 0.008). Our data provide insight into the mechanisms behind the observed negative prognostic impact of modest elevations in BNP and suggest that in an asymptomatic hypertensive cohort a peripheral BNP measurement may be a useful marker of an early, sub-clinical pathological process characterized by cardiac remodeling, inflammation and ECM alterations.     

细胞外基质的增龄性变化及分子机制的研究进展

人口老龄化及其伴随的各种疾病已成为全球性健康问题,细胞外基质在老化过程中发生的变化及对机体产生的影响逐渐成为研究衰老的热点。在机体发育和衰老过程中,细胞外基质不仅可以为细胞提供结构支架、组织连接,调节实质细胞的形态、增殖、分化、代谢、迁移等生理活动,并且其本身组成成分、合成、代谢、重构等变化也会对机体各系统的功能产生深刻影响,具体表现为骨骼肌僵硬、左心室功能受损、神经突触传导抑制等。本文通过介绍机体在衰老过程中,运动、循环、神经等系统细胞外基质的变化及相关机制的最新研究进展,从非细胞角度探讨老化的机制,了解衰老的过程。