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A review of current status of cell-based therapies for aortic aneurysms. 细胞治疗主动脉瘤的现状综述。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-08-07 DOI: 10.1186/s41232-023-00280-8
Aika Yamawaki-Ogata, Masato Mutsuga, Yuji Narita

An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.

主动脉瘤(AA)被定义为局灶性主动脉扩张,主要发生在老年人和与动脉粥样硬化相关的慢性炎症。动脉瘤壁是一个复杂的炎症环境,其特征是内皮功能障碍、巨噬细胞活化、血管平滑肌细胞(VSMC)凋亡,以及浸润的炎症细胞如巨噬细胞、T细胞和B细胞、树突状细胞、中性粒细胞、肥大细胞和自然杀伤细胞分泌促炎分子和基质金属蛋白酶(MMPs)。迄今为止,对干细胞的研究已经开展了相当多的研究,越来越多的证据表明,炎症和组织修复可以通过干细胞/祖细胞的功能来控制。本文综述了目前基于细胞的治疗AA的方法,包括间充质干细胞、VSMCs、多系分化应激耐受细胞和抗炎M2巨噬细胞。这些细胞通过调节炎症环境,包括降低促炎分子和MMPs的活性,增加抗炎分子,调节VSMC表型和保留弹性蛋白,在AA治疗中产生有益的结果。本文还详细介绍了其病理生理机制的研究和目前的临床试验进展。
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引用次数: 1
Autoimmune-mediated astrocytopathy. 谷蛋白astrocytopathy。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-18 DOI: 10.1186/s41232-023-00291-5
Makoto Kinoshita, Tatsusada Okuno

Recently accumulating evidence identified the disease entity where astrocytes residing within the central nervous system (CNS) are the target of autoantibody-mediated autoimmunity. Aquaporin4 (AQP4) is the most common antigen to serve as astrocyte-targeted autoimmune responses. Here, in this review, the clinical and pathological aspects of AQP4-mediated astrocyte disease are discussed together with the pathogenic role of anti-AQP4 antibody. More recently, the mechanism of immune dysregulation resulting in the production of astrocyte-targeted autoantibody is also revealed, and the postulated hypothesis is discussed.

最近越来越多的证据表明,中枢神经系统内的星形胶质细胞是自身抗体介导的自身免疫的目标。水通道蛋白4 (AQP4)是星形胶质细胞靶向自身免疫反应中最常见的抗原。本文就aqp4介导的星形细胞病的临床和病理方面以及抗aqp4抗体的致病作用进行综述。最近,免疫失调导致星形胶质细胞靶向自身抗体产生的机制也被揭示,并讨论了假设的假设。
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引用次数: 0
Lipid in microglial biology - from material to mediator. 小胶质细胞生物学中的脂质——从物质到介质。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-17 DOI: 10.1186/s41232-023-00289-z
Shota Yamamoto, Takahiro Masuda

Microglia are resident macrophages in the central nervous system (CNS) that play various roles during brain development and in the pathogenesis of CNS diseases. Recently, reprogramming of cellular energetic metabolism in microglia has drawn attention as a crucial mechanism for diversification of microglial functionality. Lipids are highly diverse materials and crucial components of cell membranes in every cell. Accumulating evidence has shown that lipid and its metabolism are tightly involved in microglial biology. In this review, we summarize the current knowledge about microglial lipid metabolism in health and disease.

小胶质细胞是中枢神经系统(CNS)中的巨噬细胞,在大脑发育和中枢神经系统疾病的发病过程中发挥着多种作用。近年来,小胶质细胞能量代谢的重编程被认为是小胶质细胞功能多样化的重要机制。脂质是高度多样化的物质,是每个细胞中细胞膜的重要组成部分。越来越多的证据表明,脂质及其代谢与小胶质细胞生物学密切相关。本文就小胶质细胞脂质代谢在健康和疾病中的作用作一综述。
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引用次数: 0
ALKBH5-mediated m6A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability. alkbh5介导的m6A去甲基化通过增强PELI2 mRNA的稳定性来促进皮肤伤口的再上皮化。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-14 DOI: 10.1186/s41232-023-00288-0
Xin Huang, Yixuan Zhao, Daiming Liu, Shuchen Gu, Yunhan Liu, Yimin Khoong, Shenying Luo, Zewei Zhang, Wenzheng Xia, Meng Wang, Hsin Liang, Minxiong Li, Qingfeng Li, Tao Zan

Background: Impaired wound re-epithelialization contributes to cutaneous barrier reconstruction dysfunction. Recently, N6-methyladenosine (m6A) RNA modification has been shown to participate in the determination of RNA fate, and its aberration triggers the pathogenesis of numerous diseases. Howbeit, the function of m6A in wound re-epithelialization remains enigmatic.

Methods: Alkbh5‒/‒ mouse was constructed to study the rate of wound re-epithelialization after ALKBH5 ablation. Integrated high-throughput analysis combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq was used to identify the downstream target of ALKBH5. In vitro and in vivo rescue experiments were conducted to verify the role of the downstream target on the functional phenotype of ALKBH5-deficient cells or animals. Furthermore, the interacting reader protein and regulatory mechanisms were determined through RIP-qPCR, RNA pull-down, and RNA stability assays.

Results: ALKBH5 was specifically upregulated in the wound edge epidermis. Ablation of ALKBH5 suppressed keratinocyte migration and resulted in delayed wound re-epithelialization in Alkbh5‒/‒ mouse. Integrated high-throughput analysis revealed that PELI2, an E3 ubiquitin protein ligase, serves as the downstream target of ALKBH5. Concordantly, exogenous PELI2 supplementation partially rescued keratinocyte migration and accelerated re-epithelialization in ALKBH5-deficient cells, both in vitro and in vivo. In terms of its mechanism, ALKBH5 promoted PELI2 expression by removing the m6A modification from PELI2 mRNA and enhancing its stability in a YTHDF2-dependent manner.

Conclusions: This study identifies ALKBH5 as an endogenous accelerator of wound re-epithelialization, thereby benefiting the development of a reprogrammed m6A targeted therapy for refractory wounds.

背景:伤口再上皮化受损导致皮肤屏障重建功能障碍。近年来,n6 -甲基腺苷(m6A) RNA修饰已被证明参与RNA命运的决定,其畸变触发许多疾病的发病机制。然而,m6A在伤口再上皮化中的作用仍然是一个谜。方法:构建Alkbh5 - / -小鼠,研究Alkbh5消融后创面再上皮化率。采用甲基化RNA免疫沉淀测序(MeRIP-seq)和RNA-seq相结合的综合高通量分析方法鉴定ALKBH5的下游靶点。通过体外和体内救援实验验证下游靶点对alkbh5缺陷细胞或动物功能表型的作用。此外,通过RIP-qPCR、RNA下拉和RNA稳定性分析确定了相互作用的读取器蛋白和调控机制。结果:ALKBH5在创面边缘表皮特异性上调。在ALKBH5 - / -小鼠中,消融ALKBH5抑制角化细胞迁移并导致伤口再上皮化延迟。综合高通量分析发现,E3泛素蛋白连接酶PELI2是ALKBH5的下游靶点。与此同时,在体外和体内,外源性PELI2补充部分地挽救了角化细胞的迁移,加速了alkbh5缺陷细胞的再上皮化。就其机制而言,ALKBH5通过去除PELI2 mRNA上的m6A修饰,增强PELI2的稳定性,从而促进PELI2的表达,其机制依赖于ythdf2。结论:本研究确定了ALKBH5是伤口再上皮化的内源性促进剂,从而有利于开发一种重编程m6A靶向治疗难治性伤口的方法。
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引用次数: 0
Atypical cholangiocytes derived from hepatocyte-cholangiocyte transdifferentiation mediated by COX-2: a kind of misguided liver regeneration. COX-2介导肝细胞-胆管细胞转分化产生的非典型胆管细胞:一种误入歧途的肝再生。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-14 DOI: 10.1186/s41232-023-00284-4
Tian Lan, Yang Tai, Chong Zhao, Yang Xiao, Zhu Yang, Linhao Zhang, Can Gan, Wenting Dai, Huan Tong, Chengwei Tang, Zhiyin Huang, Jinhang Gao

Background: Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism.

Methods: A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro.

Results: Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro.

Conclusions: Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function.

背景:肝细胞-胆管细胞转分化(HCT)是慢性损伤后肝再生中胆管细胞增殖的潜在来源。本研究旨在确定慢性肝损伤后的HCT,验证HCT对肝脏修复的影响,通过了解其机制避免有害再生。方法:建立野生型(WT-TAA组)和COX-2全敲除组(KO-TAA组)小鼠肝损伤模型。在体内和离体小鼠肝细胞中,通过肝细胞和胆管细胞标记物的染色鉴定HCT。胆道注射墨水,全肝光学清视。测定血清和肝脏胆汁酸(BA)浓度。在体外给予COX-2选择性抑制剂或β-catenin途径抑制剂。结果:慢性肝损伤时肝内小管反应与COX-2上调有关。免疫荧光和RNA测序表明,非典型胆管细胞具有介于肝细胞和胆管细胞之间的中间遗传表型,可能来源于肝细胞。HCT导致胆道系统结构受损,BA代谢失调,这是由TGF-β/β-catenin信号通路介导的。基因缺失或药物抑制COX-2可显著降低体内HCT。COX-2选择性抑制剂依托妥昔布体外通过TGF-β-TGFBR1-β-catenin途径抑制HCT。结论:非典型胆管细胞可来源于慢性肝损伤时胆汁引流系统发育不良和BA稳态失衡的HCT。抑制COX-2可通过COX-2- tgf -β-TGFBR1-β-catenin通路改善HCT,改善肝功能。
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引用次数: 1
Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling. 衰老通过TGF-β-Smad3信号通路改变细胞周期阻滞对结肠上皮类器官形成和生长的影响
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-13 DOI: 10.1186/s41232-023-00282-6
Min Kyoung Jo, Chang Mo Moon, Hyeon-Jeong Jeon, Yerim Han, Eun Sook Lee, Ji-Hee Kwon, Kyung-Min Yang, Young-Ho Ahn, Seong-Eun Kim, Sung-Ae Jung, Tae Il Kim

Background: This study aimed to investigate how aging alters the homeostasis of the colonic intestinal epithelium and regeneration after tissue injury using organoid models and to identify its underlying molecular mechanism.

Methods: To investigate aging-related changes in the colonic intestinal epithelium, we conducted organoid cultures from old (older than 80 weeks) and young (6-10 weeks) mice and compared the number and size of organoids at day 5 of passage 0 and the growth rate of organoids between the two groups.

Results: The number and size of organoids from old mice was significantly lower than that from young mice (p < 0.0001) at day 5 of passage 0. The growth rate of old-mouse organoids from day 4 to 5 of passage 0 was significantly slower than that of young-mouse organoids (2.21 times vs. 1.16 times, p < 0.001). RNA sequencing showed that TGF-β- and cell cycle-associated genes were associated with the aging effect. With regard to mRNA and protein levels, Smad3 and p-Smad3 in the old-mouse organoids were markedly increased compared with those in the young-mouse organoids. Decreased expression of ID1, increased expression of p16INK4a, and increased cell cycle arrest were observed in the old mouse-organoids. Treatment with SB431542, a type I TGF-β receptor inhibitor, significantly increased the formation and growth of old-mouse organoids, and TGF-β1 treatment markedly suppressed the formation of young-mouse organoids. In the acute dextran sulfate sodium-colitis model and its organoid experiments, the colonic epithelial regeneration after tissue injury in old mice was significantly decreased compared with young mice.

Conclusions: Aging reduced the formation ability and growth rate of colonic epithelial organoids by increasing cell cycle arrest through TGF-β-Smad3-p16INK4a signaling.

背景:本研究旨在通过类器官模型研究衰老如何改变组织损伤后结肠肠上皮的稳态和再生,并确定其潜在的分子机制。方法:为研究老年(80周龄以上)小鼠和幼龄(6-10周龄)小鼠结肠上皮的衰老相关变化,分别进行类器官培养,比较两组小鼠第0代第5天类器官的数量、大小和生长速度。结果:老年小鼠类器官的数量和大小明显低于年轻小鼠(p INK4a),老年小鼠类器官的细胞周期阻滞增加。1型TGF-β受体抑制剂SB431542可显著促进老年小鼠类器官的形成和生长,TGF-β1可显著抑制年轻小鼠类器官的形成。在急性葡聚糖硫酸钠结肠炎模型及其类器官实验中,老龄小鼠组织损伤后的结肠上皮再生明显低于年轻小鼠。结论:衰老通过TGF-β-Smad3-p16INK4a信号通路增加细胞周期阻滞,从而降低结肠上皮类器官的形成能力和生长速度。
{"title":"Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling.","authors":"Min Kyoung Jo,&nbsp;Chang Mo Moon,&nbsp;Hyeon-Jeong Jeon,&nbsp;Yerim Han,&nbsp;Eun Sook Lee,&nbsp;Ji-Hee Kwon,&nbsp;Kyung-Min Yang,&nbsp;Young-Ho Ahn,&nbsp;Seong-Eun Kim,&nbsp;Sung-Ae Jung,&nbsp;Tae Il Kim","doi":"10.1186/s41232-023-00282-6","DOIUrl":"https://doi.org/10.1186/s41232-023-00282-6","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to investigate how aging alters the homeostasis of the colonic intestinal epithelium and regeneration after tissue injury using organoid models and to identify its underlying molecular mechanism.</p><p><strong>Methods: </strong>To investigate aging-related changes in the colonic intestinal epithelium, we conducted organoid cultures from old (older than 80 weeks) and young (6-10 weeks) mice and compared the number and size of organoids at day 5 of passage 0 and the growth rate of organoids between the two groups.</p><p><strong>Results: </strong>The number and size of organoids from old mice was significantly lower than that from young mice (p < 0.0001) at day 5 of passage 0. The growth rate of old-mouse organoids from day 4 to 5 of passage 0 was significantly slower than that of young-mouse organoids (2.21 times vs. 1.16 times, p < 0.001). RNA sequencing showed that TGF-β- and cell cycle-associated genes were associated with the aging effect. With regard to mRNA and protein levels, Smad3 and p-Smad3 in the old-mouse organoids were markedly increased compared with those in the young-mouse organoids. Decreased expression of ID1, increased expression of p16<sup>INK4a</sup>, and increased cell cycle arrest were observed in the old mouse-organoids. Treatment with SB431542, a type I TGF-β receptor inhibitor, significantly increased the formation and growth of old-mouse organoids, and TGF-β1 treatment markedly suppressed the formation of young-mouse organoids. In the acute dextran sulfate sodium-colitis model and its organoid experiments, the colonic epithelial regeneration after tissue injury in old mice was significantly decreased compared with young mice.</p><p><strong>Conclusions: </strong>Aging reduced the formation ability and growth rate of colonic epithelial organoids by increasing cell cycle arrest through TGF-β-Smad3-p16<sup>INK4a</sup> signaling.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9871423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cartilage evaluation by ultrasonography in patients with rheumatoid arthritis: a scoping review. 类风湿性关节炎患者的软骨超声评估:范围审查。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-07-04 DOI: 10.1186/s41232-023-00286-2
Takehisa Ogura, Takaharu Katagiri, Hideto Kameda

Background: This study aimed to provide an overview of ultrasonographic cartilage evaluation in patients with rheumatoid arthritis (RA) and identify research gaps in the utilization of cartilage evaluation.

Methods: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. A systematic literature search of the PubMed, Embase, and Cochrane Library databases was conducted for articles published up to July 2022 using the search term variations of "cartilage," "ultrasonography," and "rheumatoid arthritis." Studies that included patients with RA who underwent cartilage evaluation by ultrasonography were selected. Articles published in languages other than English and about juvenile idiopathic arthritis were excluded.

Results: Twenty-nine articles were identified. Most were cross-sectional studies (86%), mainly involving the metacarpophalangeal (55%) and knee (34%) joints. Assessments were performed using quantitative, binary, and semi-quantitative methods in 15, 10, and 15 studies, respectively. Reliability assessments were conducted in 10 studies, which showed feasible reliability but were limited to the finger joints. The validity assessment was validated in one study each that compared cartilage thickness measurements with cadaveric specimens and histological and semi-quantitative methods with surgical specimens, respectively. Comparisons with conventional radiography were also performed in six studies, which showed significant correlations. However, there was heterogeneity in the examination and assessment methods, and no adequate longitudinal evaluation was conducted.

Conclusion: This review highlights the need for further research and validation of ultrasonographic cartilage assessment in patients with RA.

背景:本研究旨在综述超声软骨评估在类风湿关节炎(RA)患者中的应用,并找出软骨评估应用方面的研究空白。方法:本研究按照系统评价的首选报告项目和范围评价的元分析扩展指南进行。对PubMed、Embase和Cochrane图书馆数据库进行了系统的文献检索,检索截止到2022年7月发表的文章,检索词包括“软骨”、“超声”和“类风湿关节炎”。研究对象包括接受超声软骨评估的RA患者。用英语以外的语言发表的关于青少年特发性关节炎的文章被排除在外。结果:共鉴定29篇。大多数是横断面研究(86%),主要涉及掌指关节(55%)和膝关节(34%)。分别在15项、10项和15项研究中采用定量、二元和半定量方法进行评估。在10项研究中进行了可靠性评估,显示出可行的可靠性,但仅限于手指关节。有效性评估在一项研究中得到验证,该研究分别将软骨厚度测量与尸体标本和组织学和半定量方法与手术标本进行比较。在六项研究中,与常规x线摄影进行了比较,显示出显著的相关性。但考核评价方法存在异质性,且未进行充分的纵向评价。结论:本综述强调超声软骨评估在RA患者中的应用需要进一步的研究和验证。
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引用次数: 0
Stem cell-based drug delivery strategy for skin regeneration and wound healing: potential clinical applications. 基于干细胞的皮肤再生和伤口愈合药物递送策略:潜在的临床应用。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-06-30 DOI: 10.1186/s41232-023-00287-1
Weiyue Zhang, Xin Huang

Stem cell-based therapy is widely accepted to be a promising strategy in tissue regenerative medicine. Nevertheless, there are several obstacles to applying stem cells in skin regeneration and wound healing, which includes determining the optimum source, the processing and administration methods of stem cells, and the survival and functions of stem cells in wound sites. Owing to the limitations of applying stem cells directly, this review aims to discuss several stem cell-based drug delivery strategies in skin regeneration and wound healing and their potential clinical applications. We introduced diverse types of stem cells and their roles in wound repair. Moreover, the stem cell-based drug delivery systems including stem cell membrane-coated nanoparticles, stem cell-derived extracellular vesicles, stem cell as drug carriers, scaffold-free stem cell sheets, and stem cell-laden scaffolds were further investigated in the field of skin regeneration and wound healing. More importantly, stem cell membrane-coating nanotechnology confers great advantages compared to other drug delivery systems in a broad field of biomedical contexts. Taken together, the stem cell-based drug delivery strategy holds great promise for treating skin regeneration and wound healing.

干细胞为基础的治疗被广泛认为是一种有前途的组织再生医学策略。然而,将干细胞应用于皮肤再生和伤口愈合还存在一些障碍,包括确定最佳来源、干细胞的处理和给药方法以及干细胞在伤口部位的存活和功能。由于直接应用干细胞的局限性,本文旨在讨论几种基于干细胞的皮肤再生和伤口愈合药物递送策略及其潜在的临床应用。我们介绍了不同类型的干细胞及其在伤口修复中的作用。此外,基于干细胞的药物传递系统,包括干细胞膜包被纳米颗粒、干细胞来源的细胞外囊泡、干细胞作为药物载体、无支架干细胞片和装载干细胞的支架,在皮肤再生和伤口愈合领域得到了进一步的研究。更重要的是,干细胞膜涂层纳米技术在广泛的生物医学领域与其他药物传递系统相比具有很大的优势。综上所述,基于干细胞的药物递送策略在治疗皮肤再生和伤口愈合方面具有很大的前景。
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引用次数: 0
Promotion of axon regeneration and protection on injured retinal ganglion cells by rCXCL2. rCXCL2促进轴突再生及对损伤视网膜神经节细胞的保护作用。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-06-20 DOI: 10.1186/s41232-023-00283-5
Zi-Yuan Zhang, Zhao-Yang Zuo, Yang Liang, Si-Ming Zhang, Chun-Xia Zhang, Jing Chi, Bin Fan, Guang-Yu Li

Background: In addition to rescuing injured retinal ganglion cells (RGCs) by stimulating the intrinsic growth ability of damaged RGCs in various retinal/optic neuropathies, increasing evidence has shown that the external microenvironmental factors also play a crucial role in restoring the survival of RGCs by promoting the regrowth of RGC axons, especially inflammatory factors. In this study, we aimed to screen out the underlying inflammatory factor involved in the signaling of staurosporine (STS)-induced axon regeneration and verify its role in the protection of RGCs and the promotion of axon regrowth.

Methods: We performed transcriptome RNA sequencing for STS induction models in vitro and analyzed the differentially expressed genes. After targeting the key gene, we verified the role of the candidate factor in RGC protection and promotion of axon regeneration in vivo with two RGC-injured animal models (optic nerve crush, ONC; retinal N-methyl-D-aspartate, NMDA damage) by using cholera toxin subunit B anterograde axon tracing and specific immunostaining of RGCs.

Results: We found that a series of inflammatory genes expressed upregulated in the signaling of STS-induced axon regrowth and we targeted the candidate CXCL2 gene since the level of the chemokine CXCL2 gene elevated significantly among the top upregulated genes. We further demonstrated that intravitreal injection of rCXCL2 robustly promoted axon regeneration and significantly improved RGC survival in ONC-injured mice in vivo. However, different from its role in ONC model, the intravitreal injection of rCXCL2 was able to simply protect RGCs against NMDA-induced excitotoxicity in mouse retina and maintain the long-distance projection of RGC axons, yet failed to promote significant axon regeneration.

Conclusions: We provide the first in vivo evidence that CXCL2, as an inflammatory factor, is a key regulator in the axon regeneration and neuroprotection of RGCs. Our comparative study may facilitate deciphering the exact molecular mechanisms of RGC axon regeneration and developing high-potency targeted drugs.

背景:在各种视网膜/视神经病变中,除了通过刺激受损视网膜神经节细胞(RGCs)的内在生长能力来挽救受损视网膜神经节细胞(RGCs)外,越来越多的证据表明,外部微环境因素,尤其是炎症因素,通过促进RGC轴突的再生,在恢复RGCs的存活中也起着至关重要的作用。在本研究中,我们旨在筛选staurosporine (STS)诱导的轴突再生信号通路中潜在的炎症因子,并验证其在保护rgc和促进轴突再生中的作用。方法:对体外STS诱导模型进行转录组RNA测序,分析差异表达基因。在靶向关键基因后,我们通过两种RGC损伤动物模型(视神经挤压,ONC;采用霍乱毒素亚基B顺行轴突示踪和RGCs特异性免疫染色法检测视网膜n -甲基- d -天冬氨酸(NMDA)损伤。结果:我们发现在sts诱导的轴突再生信号通路中,一系列炎症基因表达上调,由于趋化因子CXCL2基因在上调最高的基因中水平显著升高,我们将候选CXCL2基因作为目标。我们进一步证明,在onc损伤小鼠体内,玻璃体内注射rCXCL2可显著促进轴突再生,并显著提高RGC存活。然而,与其在ONC模型中的作用不同,rCXCL2玻璃体内注射仅能保护RGC免受nmda诱导的小鼠视网膜兴奋性毒性,维持RGC轴突的远距离投射,而不能显著促进轴突再生。结论:我们提供了第一个体内证据,证明CXCL2作为一种炎症因子,是RGCs轴突再生和神经保护的关键调节因子。我们的对比研究可能有助于破译RGC轴突再生的确切分子机制和开发高效靶向药物。
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引用次数: 0
Enhancement of bone regeneration by coadministration of angiogenic and osteogenic factors using messenger RNA. 利用信使RNA联合使用血管生成因子和成骨因子促进骨再生。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2023-06-20 DOI: 10.1186/s41232-023-00285-3
Maorui Zhang, Yuta Fukushima, Kosuke Nozaki, Hideyuki Nakanishi, Jia Deng, Noriyuki Wakabayashi, Keiji Itaka

Background: Bone defects remain a challenge today. In addition to osteogenic activation, the crucial role of angiogenesis has also gained attention. In particular, vascular endothelial growth factor (VEGF) is likely to play a significant role in bone regeneration, not only to restore blood supply but also to be directly involved in the osteogenic differentiation of mesenchymal stem cells. In this study, to produce additive angiogenic-osteogenic effects in the process of bone regeneration, VEGF and Runt-related transcription factor 2 (Runx2), an essential transcription factor for osteogenic differentiation, were coadministered with messenger RNAs (mRNAs) to bone defects in the rat mandible.

Methods: The mRNAs encoding VEGF or Runx2 were prepared via in vitro transcription (IVT). Osteogenic differentiation after mRNA transfection was evaluated using primary osteoblast-like cells, followed by an evaluation of the gene expression levels of osteogenic markers. The mRNAs were then administered to a bone defect prepared in the rat mandible using our original cationic polymer-based carrier, the polyplex nanomicelle. The bone regeneration was evaluated by micro-computerized tomography (μCT) imaging, and histologic analyses.

Results: Osteogenic markers such as osteocalcin (Ocn) and osteopontin (Opn) were significantly upregulated after mRNA transfection. VEGF mRNA was revealed to have a distinct osteoblastic function similar to that of Runx2 mRNA, and the combined use of the two mRNAs resulted in further upregulation of the markers. After in vivo administration into the bone defect, the two mRNAs induced significant enhancement of bone regeneration with increased bone mineralization. Histological analyses using antibodies against the Cluster of Differentiation 31 protein (CD31), alkaline phosphatase (ALP), or OCN revealed that the mRNAs induced the upregulation of osteogenic markers in the defect, together with increased vessel formation, leading to rapid bone formation.

Conclusions: These results demonstrate the feasibility of using mRNA medicines to introduce various therapeutic factors, including transcription factors, into target sites. This study provides valuable information for the development of mRNA therapeutics for tissue engineering.

背景:骨缺损在今天仍然是一个挑战。除了成骨激活外,血管生成的关键作用也引起了人们的关注。特别是血管内皮生长因子(VEGF)可能在骨再生中发挥重要作用,不仅恢复血液供应,而且直接参与间充质干细胞的成骨分化。在本研究中,为了在骨再生过程中产生加性的血管生成-成骨作用,我们将VEGF和成骨分化必需的转录因子runt相关转录因子2 (Runx2)与信使rna (mrna)共同给予大鼠下颌骨骨缺损。方法:采用体外转录(IVT)法制备编码VEGF或Runx2的mrna。利用原代成骨细胞样细胞评估mRNA转染后的成骨分化,随后评估成骨标志物的基因表达水平。然后使用我们的原始阳离子聚合物载体,复合纳米胶束,将mrna施用于大鼠下颌骨制备的骨缺损。采用显微计算机断层扫描(μCT)和组织学分析评估骨再生情况。结果:转染mRNA后,骨钙素(Ocn)、骨桥蛋白(Opn)等成骨标志物显著上调。VEGF mRNA被发现具有与Runx2 mRNA相似的独特成骨功能,两种mRNA联合使用导致标志物进一步上调。在体内给药到骨缺损后,这两种mrna诱导骨再生显著增强,骨矿化增加。使用抗分化簇31蛋白(CD31)、碱性磷酸酶(ALP)或OCN的抗体进行组织学分析显示,mrna诱导缺陷中成骨标志物上调,同时血管形成增加,导致骨快速形成。结论:这些结果证明了利用mRNA药物将包括转录因子在内的各种治疗因子引入靶点的可行性。本研究为组织工程mRNA疗法的发展提供了有价值的信息。
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引用次数: 1
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Inflammation and Regeneration
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