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Matrix bound nanovesicles: A great promise for TERM in less than a decade of research 基质结合纳米囊泡:在不到十年的研究中,对TERM有很大的希望
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-10-03 DOI: 10.1016/j.matbio.2025.10.001
Dalila Di Francesco , Diego Mantovani , George Hussey , Francesca Boccafoschi
Decellularized extracellular matrix materials have been widely studied for tissue engineering and regenerative medicine (TERM) applications, largely because of their intrinsic bioactivity and immunomodulatory potentials. These properties confer decellularized extracellular matrix biomaterials a biological advantage over other biomaterials, especially synthetic ones, leading to several successful applications in TERM. While the complex composition of decellularized materials is well known and thought to play a role in providing the regenerative advantage, the fine mechanisms laying behind their bioactivity and immunomodulation were not fully understood yet. In the last decade, researchers have discovered a novel component in decellularized extracellular matrix materials: the matrix bound nanovesicle (MBV). This newly described type of extracellular vesicle is characterized by a tight relation to the extracellular matrix, differently from other liquid phase vesicles, and presents a unique tissue specific cargo, thought to be secreted by cells for specific cell signalling purposes. Although other extracellular vesicles subtypes have been extensively studied in past years, MBVs are different in many ways, making this research field noticeably young. Major bioactivity and immune modulating ability are key features of MBVs that were evident right from the first research works. However, to understand how MBVs can recapitulate and confer decellularized biomaterials with their signature biological performance, they are being characterized in depth. In particular, their rich and varied cargo is being explored, which has shown to play a fundamental role in MBVs’ biological potential. This discovery not only revolutionized the look on decellularized extracellular matrix materials, but it also opened the way for research on a novel type of biomaterial, with plenty potential in therapeutical and regenerative applications. This review presents in detail what has been discovered up to now on MBVs, their properties, biological roles, and potential in TERM.
脱细胞细胞外基质材料由于其固有的生物活性和免疫调节潜能,在组织工程和再生医学领域得到了广泛的研究。这些特性使脱细胞细胞外基质生物材料比其他生物材料,特别是合成生物材料具有生物学优势,导致在TERM中的一些成功应用。虽然脱细胞材料的复杂组成是众所周知的,并且被认为在提供再生优势中发挥作用,但其生物活性和免疫调节背后的精细机制尚未完全了解。在过去的十年中,研究人员在脱细胞细胞外基质材料中发现了一种新的成分:基质结合纳米囊泡(MBV)。这种新描述的细胞外囊泡类型的特点是与细胞外基质紧密相关,不同于其他液相囊泡,并且呈现出独特的组织特异性货物,被认为是由细胞分泌的特定细胞信号目的。尽管其他细胞外囊泡亚型在过去几年已经被广泛研究,但mbv在许多方面都是不同的,这使得这一研究领域明显年轻。主要的生物活性和免疫调节能力是mbv的关键特征,从最初的研究工作中就很明显。然而,为了理解mbv如何概括和赋予脱细胞生物材料其标志性的生物学性能,我们正在对它们进行深入的表征。特别是,它们丰富多样的货物正在被探索,这已被证明在mbv的生物学潜力中起着重要作用。这一发现不仅彻底改变了人们对脱细胞细胞外基质材料的看法,而且为研究一种新型生物材料开辟了道路,这种材料在治疗和再生应用方面具有很大的潜力。本文详细介绍了迄今为止关于mbv的研究进展、性质、生物学作用和长期应用潜力。
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引用次数: 0
Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance 磷酸化的udp -葡萄糖脱氢酶增加糖胺聚糖的生物合成和促进肿瘤细胞的运动,球形生长和治疗抗性。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-10-17 DOI: 10.1016/j.matbio.2025.10.004
Asher R. Utz , Linlin Ma , Dalton Hilovsky , Brenna M. Zimmer , Emily Allego , Jade Fluharty , Pooja Narasimhan , Jeffrey R. Enders , George Grady , Monica Milici , Pengda Liu , Xiaojing Liu , Joseph J. Barycki , Melanie A. Simpson
UDP-glucose 6-dehydrogenase (UGDH) is an essential enzyme that catalyzes the oxidation of UDP-glucose to UDP-glucuronate. UGDH is elevated in multiple cancers, including prostate cancer, and is functionally implicated in castration resistant recurrence. UGDH is composed of three dimeric units that associate stably as a hexamer in cellular conditions. The dynamic reorganization of noncovalent interactions at the dimer contact interfaces is essential for UGDH activity. In this study, we examined the functional relevance of a putative AGC kinase motif located at the dimer-dimer interface. We demonstrated that UGDH is phosphorylated in LNCaP cells, specifically at serine 316, by RSK2, p70S6K, and SGK1. To determine the functional implications of UGDH S316 phosphorylation, we generated and characterized phosphomimetic (S316D) and phosphodeficient (S316A) point mutations. Intrinsic properties of the purified recombinant proteins were only modestly affected by the substitutions. The stable overexpression of UGDH S316D in LNCaP cells significantly increased the rate of N- and O-glycan synthesis, as well as the production of hyaluronan and sulfated glycosaminoglycans, while reducing DHT glucuronidation, resulting in significant increases in growth of tumor spheroids, cell proliferation and motility, and resistance to enzalutamide. In contrast, UGDH S316A expression reduced the production of glycans and glycosaminoglycans, restored DHT glucuronidation, and impaired growth and motility. Overall, our results support UGDH phosphorylation as a point of control for intracellular and cell surface glycan production, thereby regulating cell proliferation, anchorage dependence, motility, and tumor cell therapeutic resistance.
udp -葡萄糖6-脱氢酶(UGDH)是催化udp -葡萄糖氧化为udp -葡萄糖酸盐的必需酶。UGDH在包括前列腺癌在内的多种癌症中升高,并在功能上与去势抵抗性复发有关。UGDH由三个二聚体组成,在细胞条件下稳定地结合为六聚体。二聚体接触界面上非共价相互作用的动态重组对UGDH活性至关重要。在这项研究中,我们研究了位于二聚体-二聚体界面的一个假定的AGC激酶基序的功能相关性。我们证明了UGDH在LNCaP细胞中被RSK2、p70S6K和SGK1磷酸化,特别是在丝氨酸316位点。为了确定UGDH S316磷酸化的功能意义,我们产生并表征了拟磷(S316D)和缺磷(S316A)点突变。所纯化的重组蛋白的内在特性仅受到取代的轻微影响。在LNCaP细胞中,UGDH S316D的稳定过表达显著提高了N-和o -聚糖的合成速度,以及透明质酸和硫代糖胺聚糖的产生,同时降低DHT糖醛酸化,导致肿瘤球体生长、细胞增殖和活力显著增加,对恩杂鲁胺的抗性显著增加。相比之下,UGDH S316A的表达减少了多糖和糖胺聚糖的产生,恢复了DHT糖醛酸化,损害了生长和运动能力。总之,我们的研究结果支持UGDH磷酸化作为细胞内和细胞表面聚糖产生的控制点,从而调节细胞增殖、锚定依赖性、运动性和肿瘤细胞的治疗抗性。
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引用次数: 0
Retraction Notice to “RETRACTED: The angiostatic molecule Multimerin 2 is processed by MMP-9 to allow sprouting angiogenesis” “撤回:血管抑制分子Multimerin 2被MMP-9处理以允许发芽血管生成”的撤回通知。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-10-17 DOI: 10.1016/j.matbio.2025.10.002
Eva Andreuzzi , Roberta Colladel , Rosanna Pellicani , Giulia Tarticchio , Renato Cannizzaro , Paola Spessotto , Benedetta Bussolati , Alessia Brossa , Paolo De Paoli , Vincenzo Canzonieri , Renato V. Iozzo , Alfonso Colombatti , Maurizio Mongiat
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引用次数: 0
Extracellular matrix architecture promotes immunosuppressive microenvironments in pancreatic cancer 细胞外基质结构促进胰腺癌的免疫抑制微环境。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-09-18 DOI: 10.1016/j.matbio.2025.09.004
Mackenzie K. Callaway , Brock J. Noonan , Kathryn L. Schwertfeger , Paolo P. Provenzano
Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with poor clinical outcomes, due in part to altered fibrotic environments and striking immune dysfunction. Physical properties within tumors, such as aligned extracellular matrix (ECM) fiber architectures, are fundamental to cancer progression and outcome. However, the influence of ECM alignment on immune cell localization and function within tumors, particularly PDA, remains largely unexplored. Here, analysis of mouse and human PDA reveal an inextricable link between collagen architecture and the distribution of immunosuppressive macrophages in both early preinvasive disease and invasive carcinomas. In vitro characterization of primary macrophages demonstrates alignment alone is sufficient to induce elongation, polarization, and immunosuppressive activity, including suppression of CD8+ T cell proliferation and motility. Analysis reveals differential focal adhesion kinase (FAK) activity in aligned macrophages, while FAK inhibition (FAKi) disrupts the immunosuppressive phenotype that emerges from encountering ECM alignment. Furthermore, FAKi in vivo significantly reduces the correlation between elongated immunosuppressive macrophages and aligned collagen, further highlighting the opportunity for FAKi to target stromal immunity. Importantly, the correlation between aligned collagen and immunosuppressive macrophages is also observed in human chronic pancreatitis, a known PDA risk factor that has recently been shown to prime stromal ECM alignments for early dissemination, suggesting that precursor disease is also likely to create stromal memory conducive to early immunosuppression. Taken together, these results support a model in which collagen architecture supports early establishment and maintenance of an immunosuppressive microenvironments and defines a role for targeting stromal matrices to “reprogram” patient immunity.
胰腺导管腺癌(PDA)是一种侵袭性癌症,临床预后较差,部分原因是纤维化环境改变和显著的免疫功能障碍。肿瘤内部的物理特性,如排列的细胞外基质(ECM)纤维结构,是癌症进展和结果的基础。然而,ECM排列对肿瘤内免疫细胞定位和功能的影响,特别是PDA,在很大程度上仍未被探索。本研究对小鼠和人PDA的分析显示,在早期侵袭前疾病和侵袭性癌中,胶原结构和免疫抑制巨噬细胞分布之间存在着不可分割的联系。原代巨噬细胞的体外表征表明,单靠排列就足以诱导伸长、极化和免疫抑制活性,包括抑制CD8+ T细胞的增殖和运动。分析显示,在排列的巨噬细胞中,局灶黏附激酶(FAK)活性存在差异,而FAK抑制(FAKi)破坏了遇到ECM排列时出现的免疫抑制表型。此外,在体内,FAKi显著降低了细长的免疫抑制巨噬细胞和排列的胶原之间的相关性,进一步强调了FAKi靶向基质免疫的机会。重要的是,排列的胶原蛋白和免疫抑制巨噬细胞之间的相关性也在人类慢性胰腺炎中被观察到,这是一个已知的PDA危险因素,最近被证明是基质ECM排列早期传播的主要因素,这表明前体疾病也可能产生有利于早期免疫抑制的基质记忆。综上所述,这些结果支持了一个模型,其中胶原结构支持免疫抑制微环境的早期建立和维持,并定义了靶向基质基质“重编程”患者免疫的作用。
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引用次数: 0
Biomechanical and compositional basement membrane defects due to a Col4a1 mutation affect cardiac morphology and function 由Col4a1突变引起的生物力学和成分基膜缺陷影响心脏形态和功能。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-09-12 DOI: 10.1016/j.matbio.2025.09.003
Erin Boland , Anna Hoyle , Olivia Robertson-Gray , William Fuller , Joe Swift , Marco Cantini , Matthew Walker , Eline Huethorst , Eilidh MacDonald , Christoper Loughrey , Manuel Salmeron-Sanchez , Godfrey L. Smith , Fabio Quondamatteo , Tom Van Agtmael
Collagen IV is a major constituent of basement membranes and mutations in the genes COL4A1 and COL4A2 present clinically as a variable, multi-system disorder called COL4A1 (Gould) syndrome. Evidence from case reports supports a cardiac component to this disease, but the phenotypic and functional implications affecting the heart, their progression and underlying mechanisms all remain poorly characterised. Indeed, the role of the basement membrane (BM) in adult cardiac disease remains underexplored. We set out to address these knowledge gaps by combining in-depth phenotypic and molecular analyses of a Col4a1 mutation on cardiac biology in a murine model (Col4a1+/svc) of Gould Syndrome. This revealed morphological cardiac defects including cardiomyocyte hypertrophy with myocardial and vascular fibrotic remodelling that impaired cardiac function. The Col4a1 mutation causes systolic and diastolic dysfunction with reduced left ventricular developed pressure. Mechanistically, we show these defects are due to secretion of mutant protein and BM defects rather than collagen misfolding and proteotoxic stress. The BM defects lead to a pro-fibrotic state with increased fibrillar collagen deposition, cardiac stiffness, and ECM compositional defects. These are accompanied by altered regulation of pathways involved in sarcomere formation, sarcolemma stability and cardiomyocyte metabolism, establishing a molecular signature of COL4A1-related cardiac disease. Intriguingly, aspects of this molecular signature including cardiac metabolic pathways, regulation of cardiac muscle contraction and BM component expression, are shared with common cardiomyopathies such as coronary micro-embolism, and dilated, ischemic and hypertrophic obstructive cardiomyopathies. By defining the molecular and phenotypic cardiac components of Gould syndrome these data show that the BM is essential for maintaining systolic and diastolic function and that alterations to the BM leads to a fibrotic response. These data increase insight into the role of the basement membrane and collagen IV in cardiac biology, and highlights mechanisms shared between Gould syndrome and common adult cardiac disease.
IV型胶原是基底膜的主要成分,COL4A1和COL4A2基因的突变在临床上表现为一种可变的多系统疾病,称为COL4A1(古尔德)综合征。来自病例报告的证据支持该疾病的心脏成分,但影响心脏的表型和功能影响,其进展和潜在机制都仍然缺乏特征。事实上,基底膜(BM)在成人心脏病中的作用仍未得到充分探讨。我们着手解决这些知识空白,结合深入的表型和分子分析Col4a1突变对心脏生物学的小鼠模型(Col4a1+/svc)古尔德综合征。这揭示了形态学上的心脏缺陷,包括心肌细胞肥大,心肌和血管纤维化重构,心功能受损。Col4a1突变导致收缩和舒张功能障碍,并伴有左心室发达压降低。从机制上讲,我们发现这些缺陷是由于突变蛋白的分泌和BM缺陷,而不是胶原蛋白错误折叠和蛋白质毒性应激。基底膜缺陷导致前纤维化状态,纤维性胶原沉积增加,心脏僵硬,ECM成分缺陷。这些都伴随着涉及肌瘤形成、肌膜稳定性和心肌细胞代谢的通路调节的改变,建立了col4a1相关心脏病的分子特征。有趣的是,这一分子特征的各个方面,包括心脏代谢途径、心肌收缩调节和BM成分表达,与常见的心肌病如冠状动脉微栓塞、扩张型、缺血性和肥厚性梗阻性心肌病有共同之处。通过定义Gould综合征的分子和表型心脏成分,这些数据表明,基底膜对维持收缩和舒张功能至关重要,基底膜的改变导致纤维化反应。这些数据增加了对基底膜和IV型胶原蛋白在心脏生物学中的作用的认识,并突出了Gould综合征和常见成人心脏病之间的共同机制。
{"title":"Biomechanical and compositional basement membrane defects due to a Col4a1 mutation affect cardiac morphology and function","authors":"Erin Boland ,&nbsp;Anna Hoyle ,&nbsp;Olivia Robertson-Gray ,&nbsp;William Fuller ,&nbsp;Joe Swift ,&nbsp;Marco Cantini ,&nbsp;Matthew Walker ,&nbsp;Eline Huethorst ,&nbsp;Eilidh MacDonald ,&nbsp;Christoper Loughrey ,&nbsp;Manuel Salmeron-Sanchez ,&nbsp;Godfrey L. Smith ,&nbsp;Fabio Quondamatteo ,&nbsp;Tom Van Agtmael","doi":"10.1016/j.matbio.2025.09.003","DOIUrl":"10.1016/j.matbio.2025.09.003","url":null,"abstract":"<div><div>Collagen IV is a major constituent of basement membranes and mutations in the genes <em>COL4A1</em> and <em>COL4A2</em> present clinically as a variable, multi-system disorder called COL4A1 (Gould) syndrome. Evidence from case reports supports a cardiac component to this disease, but the phenotypic and functional implications affecting the heart, their progression and underlying mechanisms all remain poorly characterised. Indeed, the role of the basement membrane (BM) in adult cardiac disease remains underexplored. We set out to address these knowledge gaps by combining in-depth phenotypic and molecular analyses of a <em>Col4a1</em> mutation on cardiac biology in a murine model (<em>Col4a1<sup>+/svc</sup></em>) of Gould Syndrome. This revealed morphological cardiac defects including cardiomyocyte hypertrophy with myocardial and vascular fibrotic remodelling that impaired cardiac function. The <em>Col4a1</em> mutation causes systolic and diastolic dysfunction with reduced left ventricular developed pressure. Mechanistically, we show these defects are due to secretion of mutant protein and BM defects rather than collagen misfolding and proteotoxic stress. The BM defects lead to a pro-fibrotic state with increased fibrillar collagen deposition, cardiac stiffness, and ECM compositional defects. These are accompanied by altered regulation of pathways involved in sarcomere formation, sarcolemma stability and cardiomyocyte metabolism, establishing a molecular signature of COL4A1-related cardiac disease. Intriguingly, aspects of this molecular signature including cardiac metabolic pathways, regulation of cardiac muscle contraction and BM component expression, are shared with common cardiomyopathies such as coronary micro-embolism, and dilated, ischemic and hypertrophic obstructive cardiomyopathies. By defining the molecular and phenotypic cardiac components of Gould syndrome these data show that the BM is essential for maintaining systolic and diastolic function and that alterations to the BM leads to a fibrotic response. These data increase insight into the role of the basement membrane and collagen IV in cardiac biology, and highlights mechanisms shared between Gould syndrome and common adult cardiac disease.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"141 ","pages":"Pages 82-100"},"PeriodicalIF":4.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion 硫酸乙酰肝素n -去乙酰化酶/ n -硫转移酶-1调控胶质母细胞瘤细胞的迁移和侵袭。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-08-10 DOI: 10.1016/j.matbio.2025.08.003
Argyris Spyrou , Ananya Roy , Anqi Xiong , Soumi Kundu , Xi Lu , Ylva Jansson , Anna Falk , Christoph Riethmüller , Burkhard Greve , Martin Götte , Xinqi Chen , Lena Kjellén , Karin Forsberg-Nilsson
The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell migration, reduce cell adhesion, induce EMT markers and increase invasion. Conversely, when NDST1 levels were reduced by shRNA in GBM cells, that had higher baseline expression, we find that invasion is reduced, and instead, self-renewal capacity increases alongside elevated stem cell marker expression. Moreover, overexpression of NDST1 changes chromatin accessibility of gene regulatory regions with the capacity to affect transcription factor expression, and pathways that favors cell motility and invasion. Furthermore, NDST1 overexpression results in increased activation of several receptor tyrosine kinases. This study shows that low NDST1 levels support GBM cell stemness, whereas high NDST1 levels endow tumor cells with a motile cell phenotype. We therefore propose that NDST1 is important for regulation of the balance between proliferation and invasive properties in GBM cells.
胶质母细胞瘤(GBM)微环境经历适应以支持肿瘤进展,包括细胞外基质失调,硫酸肝素(HS)蛋白聚糖改变。我们研究了n -去乙酰化酶/ n -硫转移酶-1 (NDST1),因为NDST1是HS生物合成的初始修饰酶,在设计HS磺化模式中起关键作用。这反过来又控制着与生长因子和其他生物分子的相互作用。我们报道了NDST1在GBM中的表达低于正常大脑,并且在神经干细胞培养条件下生长的患者来源的GBM细胞的HS水平低于正常星形胶质细胞。NDST1在固有NDST1水平较低的GBM细胞中过表达,可刺激细胞迁移,降低细胞粘附,诱导EMT标志物,增加侵袭。相反,当具有较高基线表达的GBM细胞中的NDST1水平被shRNA降低时,我们发现侵袭减少,相反,自我更新能力随着干细胞标记物表达的升高而增加。此外,NDST1的过表达改变了基因调控区域的染色质可及性,从而影响转录因子的表达,以及有利于细胞运动和侵袭的途径。此外,NDST1过表达导致几种受体酪氨酸激酶的激活增加。该研究表明,低NDST1水平支持GBM细胞的干性,而高NDST1水平赋予肿瘤细胞运动细胞表型。因此,我们认为NDST1在GBM细胞增殖和侵袭特性之间的平衡调节中很重要。
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引用次数: 0
Corrigendum to “Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis” [Matrix Biology Volume 95 (2021)1-14] “Decorin缺乏促进上皮-间质转化和结肠癌转移”的勘误[基质生物学卷95(2021)1-14]。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-08-16 DOI: 10.1016/j.matbio.2025.08.002
Liping Mao , Jinxue Yang , Jiaxin Yue , Yang Chen , Hongrui Zhou , Dongdong Fan , Qiuhua Zhang , Simone Buraschi , Renato V. Iozzo , Xiuli Bi
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引用次数: 0
Evidence for the major role of PH4⍺EFB in the prolyl 4-hydroxylation of Drosophila collagen IV PH4 - EFB在果蝇胶原脯氨酰4-羟基化中主要作用的证据。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-09-12 DOI: 10.1016/j.matbio.2025.09.002
Yoshihiro Ishikawa , Melissa A. Toups , Marwan Elkrewi , Allison L. Zajac , Sally Horne-Badovinac , Yutaka Matsubayashi
Collagens are fundamental components of extracellular matrices, requiring precise intracellular post-translational modifications for proper function. Among the modifications, prolyl 4-hydroxylation is critical to stabilise the collagen triple helix. In humans, this reaction is mediated by collagen prolyl 4-hydroxylases (P4Hs). While humans possess three genes encoding these enzymes (P4H⍺s), Drosophila melanogaster harbour at least 26 candidates for collagen P4H⍺s despite its simple genome, and it is poorly understood which of them are actually working on collagen in the fly. In this study, we addressed this question by carrying out thorough bioinformatic and biochemical analyses. We demonstrate that among the 26 potential collagen P4H⍺s, PH4⍺EFB shares the highest homology with vertebrate collagen P4H⍺s. Furthermore, while collagen P4Hs and their substrates must exist in the same cells, our transcriptomic analyses at the tissue and single cell levels showed a global co-expression of PH4⍺EFB but not the other P4H⍺-related genes with the collagen IV genes. Moreover, expression of PH4⍺EFB during embryogenesis was found to precede that of collagen IV, presumably enabling efficient collagen modification by PH4⍺EFB. Finally, biochemical assays confirm that PH4⍺EFB binds collagen, supporting its direct role in collagen IV modification. Collectively, we identify PH4⍺EFB as the primary and potentially constitutive prolyl 4-hydroxylase responsible for collagen IV biosynthesis in Drosophila. Our findings highlight the remarkably simple nature of Drosophila collagen IV biosynthesis, which may serve as a blueprint for defining the minimal requirements for collagen engineering.
胶原是细胞外基质的基本组成部分,需要精确的细胞内翻译后修饰才能发挥正常功能。在这些修饰中,脯氨酰4-羟基化对稳定胶原蛋白三螺旋结构至关重要。在人类中,这种反应是由胶原脯氨酸4-羟化酶(P4Hs)介导的。虽然人类拥有三个编码这些酶的基因(P4H s),但黑胃果蝇尽管基因组简单,但至少有26个候选蛋白P4H s,而且人们对其中哪些基因实际上对果蝇的胶原蛋白起作用知之甚少。在这项研究中,我们通过进行彻底的生物信息学和生化分析来解决这个问题。我们发现在26种潜在的胶原蛋白P4H中,PH4与脊椎动物胶原蛋白P4H具有最高的同源性。此外,虽然胶原P4Hs及其底物必须存在于相同的细胞中,但我们在组织和单细胞水平上的转录组学分析显示,PH4 EFB与胶原IV基因共表达,而其他P4H相关基因则不表达。此外,在胚胎发生过程中发现PH4 EFB的表达先于胶原IV,推测PH4 EFB可以有效地修饰胶原。最后,生化分析证实PH4能与胶原结合,支持其在IV型胶原修饰中的直接作用。总的来说,我们确定PH4是果蝇中负责胶原IV生物合成的主要和潜在组成的脯氨酸4-羟化酶。我们的研究结果强调了果蝇胶原IV生物合成的非常简单的性质,这可能作为确定胶原工程最低要求的蓝图。
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引用次数: 0
Exploring basement membrane dynamics through cross-scale imaging, manipulation, and molecular mapping 通过跨尺度成像、操作和分子作图探索基底膜动力学。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-09-02 DOI: 10.1016/j.matbio.2025.09.001
Kohei Omachi, Hironobu Fujiwara
The basement membrane (BM), a specialized extracellular matrix (ECM), provides structural support for epithelial, endothelial, and other parenchymal cells. Once considered a static scaffold, the BM is now recognized as a dynamic and complex nanostructure composed of a diversity of molecules that actively regulate cell behavior and tissue organization. Its molecular composition, assembly, and remodeling are precisely controlled in a tissue- and stage-specific manner, contributing to the regulation of local and global mechanical properties and biochemical signaling. Understanding BM structure and function requires integrated approaches across biological scales—from nanoscale molecular interactions to tissue-level architecture. In this review, we highlight advances in three methodological areas: (1) imaging techniques that reveal BM nanostructure and dynamics, (2) manipulation strategies that uncover causal roles of BM components, and (3) omics-based approaches that map BM composition and cellular sources. Integrating these strategies enables the bridging of molecular events and organ-level functions, offering new insights into how the BM is involved in development, homeostasis, and disease progression. The aim of this review is to provide researchers with a comprehensive perspective on evolving tools for dissecting BM structure, dynamics, and function.
基底膜(BM)是一种特殊的细胞外基质(ECM),为上皮细胞、内皮细胞和其他实质细胞提供结构支持。BM曾经被认为是一个静态支架,现在被认为是一个动态和复杂的纳米结构,由多种分子组成,积极调节细胞行为和组织组织。它的分子组成、组装和重塑以组织和阶段特异性的方式精确控制,有助于调节局部和全局的机械特性和生化信号。了解BM的结构和功能需要跨生物尺度的综合方法-从纳米级分子相互作用到组织级结构。在这篇综述中,我们强调了三个方法学领域的进展:(1)揭示BM纳米结构和动力学的成像技术,(2)揭示BM成分因果作用的操作策略,以及(3)基于组学的方法,绘制BM成分和细胞来源。整合这些策略可以将分子事件和器官水平功能连接起来,为脑转移如何参与发育、体内平衡和疾病进展提供新的见解。这篇综述的目的是为研究人员提供一个全面的视角,以了解不断发展的工具来解剖脑基底膜的结构、动力学和功能。
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引用次数: 0
Laminin γ1 chain is essential for the cardiorespiratory and muscular systems 层粘连蛋白γ - 1链对心肺和肌肉系统至关重要
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-01 Epub Date: 2025-08-23 DOI: 10.1016/j.matbio.2025.08.006
Kinga I. Gawlik , Deniz A. Bölükbas , Fatima Daoud , Niccolò Peruzzi , Ellinor Welinder , Trevor S. Wendt , Marycarmen Arévalo Martinez , Sinem Tas , Johan Holmberg , Nika Gvazava , Saema Ansar , Sebastian Albinsson , Darcy Wagner , Karl Swärd , Karin Tran-Lundmark , Madeleine Durbeej
Laminins are basement membrane components that regulate a plethora of biological processes. Despite decades of research, the exact roles of laminins in different tissues and in organogenesis remain to be elucidated. Here, we investigated the function of laminin γ1 chain in heart, lung and other tissues by generating a mouse that lacks laminin γ1 in cells expressing SM22α (Tagln) (LMγ1 flox/SM22α Cre mouse, referred to as LMγ1KO). Laminin γ1 deletion led to basement membrane disruption around cardiomyocytes, smooth muscle cells, alveolar cells and skeletal muscle. This, in turn, led to perinatal death of conditional LMγ1KO mice. Synchrotron-based imaging revealed developmental heart abnormalities: ventricular and atrioventricular septal defects. Lung tissue from embryos and newborns showed impaired alveolization and this defect was not reversed ex vivo. We also created adult inducible laminin γ1 knockout mice (iLMγ1KO) with targeted knockdown in all tissues, and they exhibited decreased contractility of smooth muscle in colonic and arterial tissue. Finally, both LMγ1KO neonates and iLMγ1KO adults displayed severe dystrophic features in skeletal muscle.
In summary, our study reveals novel roles for laminin γ1 chain and basement membranes in heart, lung, skeletal and smooth muscle. Compromising basement membranes around various cell types expressing SM22α during embryonic development did not impair early organogenesis of lung, heart and skeletal muscle, but rather disturbed late developmental events in these tissues. Our results could help to understand clinical implications for patients with laminin α2 chain mutations (muscular dystrophy) and laminin α4 mutations (cardiomyopathy), but also for patients with congenital heart disease and lung diseases.
层粘连蛋白是调节大量生物过程的基膜成分。尽管经过几十年的研究,层粘连蛋白在不同组织和器官发生中的确切作用仍有待阐明。在此,我们通过在表达SM22α (Tagln)的细胞中产生缺乏层粘连蛋白γ1的小鼠(LMγ1 flox/SM22α Cre小鼠,简称LMγ1KO)来研究层粘连蛋白γ1链在心脏、肺和其他组织中的功能。层粘连蛋白γ - 1缺失导致心肌细胞、平滑肌细胞、肺泡细胞和骨骼肌周围的基底膜破坏。这进而导致条件性LMγ1KO小鼠的围产期死亡。基于同步加速器的成像显示发育性心脏异常:心室和房室间隔缺损。胚胎和新生儿的肺组织显示肺泡化受损,这种缺陷在体外不能逆转。我们还建立了成年诱导型层粘连蛋白γ1敲除小鼠(iLMγ1KO),在所有组织中都有靶向敲除,它们在结肠和动脉组织中表现出平滑肌收缩性降低。最后,iLMγ1KO新生儿和iLMγ1KO成人都表现出严重的骨骼肌营养不良特征。
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Matrix Biology
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