Matrix Biology最新文献_第10页

Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood.

The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (Fbln5^-/-) mouse carotid arteries. Biomechanical testing demonstrated that Fbln5^-/- arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these Fbln5^-/- arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow Fbln5^-/- arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (Ctgf/Ccn2) was upregulated in vivo in ECs with aging, with stiffening in the Fbln5^-/- arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific Ctgf knockout (Ctgf^ecko). We identified that carotid arteries under disturbed flow and atherogenic conditions in male Ctgf^ecko, but not female, mice had decreased plaque area compared to WT control mice. We then tested the Ctgf expression in the carotid endothelium exposed to disturbed or stable flow in WT and Fbln5^-/- mice. Here we found that under disturbed flow male mice had greater Ctgf expression than female mice.

This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments.

动脉内皮细胞（ECs）生活在一个复杂的生物力学环境中。ECs感知并响应壁面剪应力。低且振荡的壁剪应力是血流紊乱的特征，常见于动脉分叉处和动脉粥样硬化斑块周围。血流紊乱对内皮细胞有促炎作用。动脉也会随着年龄的增长和/或血管疾病的发生而变硬。内皮细胞以促纤维化的方式感知和响应硬化。因此，血流和硬化紊乱引起EC反应，促进病理性动脉重塑。然而，在病理性硬化和血流紊乱的情况下，内皮细胞所引发的途径尚不清楚。这项工作的目的是发现和测试ECs关键通路的可修饰性。为此，我们使用部分颈动脉结扎模型，对纤维蛋白-5敲除（Fbln5-/-）小鼠颈动脉施加干扰血流。生物力学测试表明，Fbln5-/-动脉在血流干扰下的刚度比接近人类病变动脉，这些Fbln5-/-动脉中的内皮细胞通过内皮细胞到间充质细胞的转化（EndMT）进行了快速重编程。在动脉粥样硬化条件下，血流紊乱的Fbln5-/-动脉比野生型（WT）小鼠动脉更容易形成斑块。结缔组织生长因子/细胞通信网络因子2 （Ctgf/Ccn2）在ec体内随着年龄的增长而上调，Fbln5-/-动脉硬化，在硬化条件下因血流紊乱而再次升高，支持Ctgf作为血流和硬化的关键生物标志物。免疫组织化学证实了这一点，在患者颈动脉内膜切除术和外周动脉病变（PAD）标本中，CTGF沉积在血流紊乱区域增加。最后，为了测试CTGF在调节和结合这些过程中的作用，我们创建了ec特异性CTGF敲除（Ctgfecko）。我们发现，在血流紊乱和动脉粥样硬化条件下，雄性Ctgfecko小鼠的颈动脉斑块面积比WT对照组小鼠减少，而雌性小鼠则没有。然后，我们测试了Ctgf在WT和Fbln5-/-小鼠颈动脉内皮中受干扰或稳定血流影响的表达。我们发现，在水流干扰下，雄性小鼠的Ctgf表达高于雌性小鼠。这项工作表明，硬化 + 紊乱的血流条件驱动EC重编程，CTGF在这些条件下增加，并且这种增加在男性颈动脉中更为突出。未来探索这些纤维化途径的性别差异是有必要的，以开发有针对性的治疗方法，以限制病理性硬化 + 紊乱血流环境下的病理性动脉重塑。

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引用次数: 0

The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix 戊烷素-3的结构组织及其与α-抑制剂重链的相互作用调节透明质酸基质的交联。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-01-13 DOI: 10.1016/j.matbio.2025.01.002

Anokhi Shah , Xiaoli Zhang , Matthew Snee , Michael P. Lockhart-Cairns , Colin W. Levy , Thomas A. Jowitt , Holly L. Birchenough , Louisa Dean , Richard Collins , Rebecca J. Dodd , Abigail R.E. Roberts , Jan J. Enghild , Alberto Mantovani , Juan Fontana , Clair Baldock , Antonio Inforzato , Ralf P. Richter , Anthony J. Day

Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone et al., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric ‘Half-PTX3’ and a construct missing the 24 N-terminal residues (Δ1–24_PTX3). SAXS determined a length of ∼520 Å for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC•HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC•HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC•HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.

pentaxin -3 （PTX3）是一种八聚体蛋白，由八种相同的原体组成，在生殖生物学、先天免疫和癌症中具有多种功能。PTX3与大多糖透明质酸（HA）相互作用，而α-抑制剂（i -α-i）蛋白聚糖家族的重链（HC）共价附着于大多糖透明质酸（HA）上，在HC•HA复合物的（非共价）交联中起关键作用。这些相互作用稳定了积云基质，对哺乳动物的排卵和受精至关重要，并且在病毒性肺部感染的背景下也涉及致病性基质的形成。为了更好地理解PTX3的生理和病理作用，我们分析了PTX3的四级结构如何通过与hc的相互作用支持HA交联。x射线晶体学、低温电子显微镜（cryo-EM）和AlphaFold预测模型的结合显示，PTX3八聚体的c端戊烷素结构域排列在一个中心立方体中，两侧有两个长延伸，每个延伸由四个原聚体组装成四聚体卷曲线圈区域形成，基本上与(Noone等人，2022；doi: 10.1073 / pnas.2208144119)。从晶体学和低温电镜数据中，我们发现了一个促进八聚体组装的原聚体间盐桥网络。小角度x射线散射（SAXS）验证了我们的八聚体蛋白模型，包括对两种PTX3结构的分析：四聚体“半PTX3”和缺失24个n端残基的结构（Δ1-24-PTX3）。SAXS确定PTX3的长度为~ 520 Å，并结合cryo-EM数据的3D变异性分析，定义了n端扩展的灵活性。生物物理分析显示，在pH值7.4时，原型重链HC1不与PTX3相互作用，这与我们之前的研究结果一致，在该pH下，PTX3仅与HC•HA复合物结合，如果它们在其存在下形成。然而，PTX3在酸性pH下与HC1结合，并且在这些条件下也可以并入预形成的HC•HA配合物中。这为ptx3介导的HA交联调控提供了一种新的机制（例如，在炎症期间），可能是由HC1中ph依赖性构象变化介导的。PTX3八聚体被发现同时与多达8个HC1分子结合，因此，有可能在HC•HA基质中形成一个主要的交联节点，即，由此产生的基质的物理和生化特性可以通过HC/PTX3组成来调节。

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引用次数: 0

Neurocan regulates axon initial segment organization and neuronal activity Neurocan调节轴突初始段组织和神经元活动。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-01-07 DOI: 10.1016/j.matbio.2025.01.001

David Baidoe-Ansah , Hadi Mirzapourdelavar , Stepan Aleshin , Björn Hendrik Schott , Constanze Seidenbecher , Rahul Kaushik , Alexander Dityatev

The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also around synapses and in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, perisynaptically, and at the nodes of Ranvier and the AIS, highlighting its potential role in regulating axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, Western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AISs and regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulation of aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of ankyrin-G in the AIS, particularly in excitatory neurons, and with the elevated expression of Na_v1.6 channels. Our results suggest that Ncan regulates the expression of key proteins in PNNs and AISs and provide new insights into its role in fine-tuning neuronal functions.

神经细胞外基质（ECM）以神经元周围网（PNNs）的形式积累，特别是在皮层和海马的快速峰值gaba能中间神经元周围，但也在突触周围以及与轴突初始段（AIS）和Ranvier节点相关。越来越多的证据强调了神经can （Ncan）在双相情感障碍和精神分裂症等神经精神疾病的病理生理学中的作用，神经can是ECM的一种脑特异性成分。Ncan定位于pnn，突触周围，Ranvier和AIS节点，突出了其在调节轴突兴奋性中的潜在作用。本研究采用敲除和敲除小鼠原代皮质神经元的方法，结合免疫细胞化学、western blotting和电生理技术来表征Ncan在pnn和ais的组织以及神经元活性上调中的作用。我们发现，Ncan水平的降低通过Aggrecan mRNA和蛋白水平的上调、活性依赖性c-Fos和FosB基因的表达增加以及自发突触活性的升高，导致神经元周围pnn的重塑。后者与AIS中锚定蛋白g水平升高，特别是兴奋性神经元中锚定蛋白g水平升高以及Nav1.6通道表达升高相关。我们的研究结果表明，Ncan调节pnn和ais中关键蛋白的表达，并为其在微调神经元功能中的作用提供了新的见解。

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引用次数: 0

FGF and TGF-β growth factor isoform modulation of human gingival and periodontal ligament fibroblast wound healing phenotype FGF和TGF-β生长因子亚型对人牙龈和牙周韧带成纤维细胞伤口愈合表型的调节。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-01-03 DOI: 10.1016/j.matbio.2024.12.011

Chengyu Guo , Amin S. Rizkalla , Douglas W. Hamilton

Release of growth factors in the tissue microenvironment is a critical process in the repair and regeneration of periodontal tissues, regulating fibroblast behavior and phenotype. As a result of the complex architecture of the periodontium, distinct fibroblast populations in the periodontal ligament and gingival connective tissue exist in close proximity. Growth factor therapies for periodontal regeneration have gained traction, but quantification of their effects on multiple different fibroblast populations that are required for repair has been poorly investigated. In this study, we examined the effects of TGF-β1, TGF-β3, FGF-2, and FGF-9 on human gingival fibroblasts (hGF) and human periodontal ligament cells (hPDL), as well as the combined effects of TGF-β3 and FGF-2. We show that FGF-2 enhances cell migration while TGF-β1 and TGF-β3 promotes matrix production, and TGF-β1 promotes fibroblast to myofibroblast transition. Interestingly, the combination of TGF-β3 and FGF-2, acting through both p-SMAD3 and p-ERK pathways, mitigates the inhibitory effects of TGF-β3 on migration in hPDL cells, suggesting synergistic and complimentary effects of FGF-2 and TGF-β3. Additionally, fibronectin production in hGF increased when treated with the combined TGF-β3+FGF-2 compared to FGF-2 alone, indicating that the effects of TGF-β3 in promoting extracellular matrix production are still active in the combined treatment condition. Finally, our study highlights that FGF-9 did not influence migration, α-SMA expression, or extracellular matrix production in either cell type, emphasizing the unique roles of specific growth factors in cellular responses. The synergistic effects observed with combined TGF-β3 and FGF-2 treatments present promising avenues for further research and clinical advancements in regenerative medicine.

组织微环境中生长因子的释放是牙周组织修复和再生、调节成纤维细胞行为和表型的关键过程。由于牙周组织结构复杂，在牙周韧带和牙龈结缔组织中存在着不同的成纤维细胞群。生长因子治疗牙周再生已经获得了广泛的关注，但是对其对修复所需的多种不同成纤维细胞群体的影响的量化研究却很少。本研究考察了TGF-β1、TGF-β3、FGF-2和FGF-9对人牙龈成纤维细胞（hGF）和人牙周韧带细胞（hPDL）的影响，以及TGF-β3和FGF-2的联合作用。我们发现FGF-2促进细胞迁移，TGF-β1和TGF-β3促进基质生成，TGF-β1促进成纤维细胞向肌成纤维细胞转变。有趣的是，TGF-β3和FGF-2联合作用，通过p-SMAD3和p-ERK途径，减轻了TGF-β3对hPDL细胞迁移的抑制作用，提示FGF-2和TGF-β3具有协同和互补作用。此外，TGF-β3+FGF-2联合治疗hGF比单独治疗FGF-2时，hGF中纤维连接蛋白的生成增加，表明TGF-β3促进细胞外基质生成的作用在联合治疗条件下仍然活跃。最后，我们的研究强调了FGF-9在两种细胞类型中都不影响迁移、α-SMA表达或细胞外基质的产生，强调了特定生长因子在细胞反应中的独特作用。TGF-β3和FGF-2联合治疗的协同效应为再生医学的进一步研究和临床进展提供了有希望的途径。

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