首页 > 最新文献

Inflammation and Regeneration最新文献

英文 中文
Morphology-based noninvasive early prediction of serial-passage potency enhances the selection of clone-derived high-potency cell bank from mesenchymal stem cells. 基于形态学的无创序列传代效能早期预测提高了间充质干细胞克隆衍生高效细胞库的选择。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-10-02 DOI: 10.1186/s41232-022-00214-w
Takashi Suyama, Yuto Takemoto, Hiromi Miyauchi, Yuko Kato, Yumi Matsuzaki, Ryuji Kato

Background: Rapidly expanding clones (RECs) are one of the single-cell-derived mesenchymal stem cell clones sorted from human bone marrow mononuclear cells (BMMCs), which possess advantageous features. The RECs exhibit long-lasting proliferation potency that allows more than 10 repeated serial passages in vitro, considerably benefiting the manufacturing process of allogenic MSC-based therapeutic products. Although RECs aid the preparation of large-variation clone libraries for a greedy selection of better-quality clones, such a selection is only possible by establishing multiple-candidate cell banks for quality comparisons. Thus, there is a high demand for a novel method that can predict "low-risk and high-potency clones" early and in a feasible manner given the excessive cost and effort required to maintain such an establishment.

Methods: LNGFR and Thy-1 co-positive cells from BMMCs were single-cell-sorted into 96-well plates, and only fast-growing clones that reached confluency in 2 weeks were picked up and passaged as RECs. Fifteen RECs were prepared as passage 3 (P3) cryostock as the primary cell bank. From this cryostock, RECs were passaged until their proliferation limitation; their serial-passage limitation numbers were labeled as serial-passage potencies. At the P1 stage, phase-contrast microscopic images were obtained over 6-90 h to identify time-course changes of 24 morphological descriptors describing cell population information. Machine learning models were constructed using the morphological descriptors for predicting serial-passage potencies. The time window and field-of-view-number effects were evaluated to identify the most efficient image data usage condition for realizing high-performance serial-passage potency models.

Results: Serial-passage test results indicated variations of 7-13-repeated serial-passage potencies within RECs. Such potency values were predicted quantitatively with high performance (RMSE < 1.0) from P1 morphological profiles using a LASSO model. The earliest and minimum effort predictions require 6-30 h with 40 FOVs and 6-90 h with 15 FOVs, respectively.

Conclusion: We successfully developed a noninvasive morphology-based machine learning model to enhance the efficiency of establishing cell banks with single-cell-derived RECs for quantitatively predicting the future serial-passage potencies of clones. Conventional methods that can make noninvasive and quantitative predictions without wasting precious cells in the early stage are lacking; the proposed method will provide a more efficient and robust cell bank establishment process for allogenic therapeutic product manufacturing.

背景:快速扩增克隆(rec)是从人骨髓单核细胞(BMMCs)中分离出来的单细胞来源的间充质干细胞克隆之一,具有优势。RECs具有持久的增殖能力,可以在体外重复连续传代10次以上,极大地有利于同种异体msc治疗产品的制造过程。尽管RECs有助于制备大变异克隆文库,以贪婪地选择质量更好的克隆,但这种选择只有通过建立多个候选细胞库进行质量比较才能实现。因此,鉴于维持这种机构所需的过高成本和努力,迫切需要一种新颖的方法,能够以可行的方式及早预测“低风险和高效力的克隆”。方法:将BMMCs中lnfr和Thy-1共阳性细胞单细胞分选至96孔板中,取2周内达到融合的快速生长克隆作为RECs传代。制备15个RECs作为传代3 (P3)冷冻库作为原代细胞库。从冷冻液中传代RECs至其增殖极限;它们的连续传代限制数被标记为连续传代效价。在P1阶段,在6-90 h内获得相衬显微镜图像,以确定描述细胞群体信息的24个形态学描述符的时间变化。使用形态学描述符构建机器学习模型来预测序列传递的效力。评估了时间窗口和视场数效应,以确定实现高性能串行通道效能模型的最有效的图像数据使用条件。结果:序列传代试验结果显示,rec内7-13次重复序列传代效力存在差异。结论:我们成功开发了一种无创的基于形态学的机器学习模型,以提高建立单细胞来源的rec细胞库的效率,用于定量预测未来克隆的序列传代效力。在早期不浪费宝贵细胞的情况下进行非侵入性定量预测的传统方法是缺乏的;所提出的方法将为同种异体治疗产品的生产提供更有效和稳健的细胞库建立过程。
{"title":"Morphology-based noninvasive early prediction of serial-passage potency enhances the selection of clone-derived high-potency cell bank from mesenchymal stem cells.","authors":"Takashi Suyama,&nbsp;Yuto Takemoto,&nbsp;Hiromi Miyauchi,&nbsp;Yuko Kato,&nbsp;Yumi Matsuzaki,&nbsp;Ryuji Kato","doi":"10.1186/s41232-022-00214-w","DOIUrl":"https://doi.org/10.1186/s41232-022-00214-w","url":null,"abstract":"<p><strong>Background: </strong>Rapidly expanding clones (RECs) are one of the single-cell-derived mesenchymal stem cell clones sorted from human bone marrow mononuclear cells (BMMCs), which possess advantageous features. The RECs exhibit long-lasting proliferation potency that allows more than 10 repeated serial passages in vitro, considerably benefiting the manufacturing process of allogenic MSC-based therapeutic products. Although RECs aid the preparation of large-variation clone libraries for a greedy selection of better-quality clones, such a selection is only possible by establishing multiple-candidate cell banks for quality comparisons. Thus, there is a high demand for a novel method that can predict \"low-risk and high-potency clones\" early and in a feasible manner given the excessive cost and effort required to maintain such an establishment.</p><p><strong>Methods: </strong>LNGFR and Thy-1 co-positive cells from BMMCs were single-cell-sorted into 96-well plates, and only fast-growing clones that reached confluency in 2 weeks were picked up and passaged as RECs. Fifteen RECs were prepared as passage 3 (P3) cryostock as the primary cell bank. From this cryostock, RECs were passaged until their proliferation limitation; their serial-passage limitation numbers were labeled as serial-passage potencies. At the P1 stage, phase-contrast microscopic images were obtained over 6-90 h to identify time-course changes of 24 morphological descriptors describing cell population information. Machine learning models were constructed using the morphological descriptors for predicting serial-passage potencies. The time window and field-of-view-number effects were evaluated to identify the most efficient image data usage condition for realizing high-performance serial-passage potency models.</p><p><strong>Results: </strong>Serial-passage test results indicated variations of 7-13-repeated serial-passage potencies within RECs. Such potency values were predicted quantitatively with high performance (RMSE < 1.0) from P1 morphological profiles using a LASSO model. The earliest and minimum effort predictions require 6-30 h with 40 FOVs and 6-90 h with 15 FOVs, respectively.</p><p><strong>Conclusion: </strong>We successfully developed a noninvasive morphology-based machine learning model to enhance the efficiency of establishing cell banks with single-cell-derived RECs for quantitatively predicting the future serial-passage potencies of clones. Conventional methods that can make noninvasive and quantitative predictions without wasting precious cells in the early stage are lacking; the proposed method will provide a more efficient and robust cell bank establishment process for allogenic therapeutic product manufacturing.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40388208","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: 3
Identification of molecular subtypes based on inflammatory response in lower-grade glioma. 基于低级别胶质瘤炎症反应的分子亚型鉴定。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-10-01 DOI: 10.1186/s41232-022-00215-9
Wanzun Lin, Jing Gao, Haojiong Zhang, Li Chen, Xianxin Qiu, Qingting Huang, Jiyi Hu, Lin Kong, Jiade J Lu

Background: Inflammatory response is an important characteristic affecting prognosis and therapeutic response in lower-grade glioma (LGG). However, the molecular subtypes based on inflammatory response are still under exploitation.

Methods: The RNA sequencing, somatic mutation, and corresponding clinical data from 1205 LGG patients were obtained from the TCGA, CGGA, and Rembrandt cohorts. Consensus clustering was performed to identify molecular subtypes associated with inflammation. Prognosis, clinicopathologic features, immune cell infiltration, and somatic mutation profile were compared among these inflammation-associated subtypes.

Results: Our results demonstrate that LGG could be categorized into inflammation-, low, -mid, and -high subtypes with distinct clinicopathologic features, prognostic and tumor microenvironment. We established that this categorization was reproducible, as well as predictable. In general, inflammation-high subtype presents a dismal prognosis with the immunosuppressive microenvironment and high frequency of oncogene mutation. Inversely, inflammation-low subtype was associated with the most favorable clinical outcomes with the immunoreactive microenvironment among three subtypes. Moreover, we develop and validate an inflammation-related prognostic model, which shows strong power for prognosis assessment.

Conclusion: In conclusion, we established a novel glioma classification based on the inflammation subtype. This classification had significant outcomes for estimating the prognosis, as well as the tumor microenvironment.

背景:炎症反应是影响低级别胶质瘤(LGG)预后和治疗反应的重要特征。然而,基于炎症反应的分子亚型仍在开发中。方法:从TCGA、CGGA和Rembrandt队列中获取1205例LGG患者的RNA测序、体细胞突变和相应的临床资料。进行一致聚类以确定与炎症相关的分子亚型。比较了这些炎症相关亚型的预后、临床病理特征、免疫细胞浸润和体细胞突变谱。结果:我们的研究结果表明,LGG可分为炎症型、低型、中型和高型,具有不同的临床病理特征、预后和肿瘤微环境。我们确定这种分类是可重复的,也是可预测的。一般情况下,炎症高亚型预后差,微环境免疫抑制,癌基因突变频率高。相反,在三种亚型中,低炎症亚型与免疫反应性微环境最有利的临床结果相关。此外,我们开发并验证了炎症相关的预后模型,该模型显示了预后评估的强大功能。结论:我们建立了一种新的基于炎症亚型的胶质瘤分类方法。这种分类在估计预后和肿瘤微环境方面有显著的结果。
{"title":"Identification of molecular subtypes based on inflammatory response in lower-grade glioma.","authors":"Wanzun Lin,&nbsp;Jing Gao,&nbsp;Haojiong Zhang,&nbsp;Li Chen,&nbsp;Xianxin Qiu,&nbsp;Qingting Huang,&nbsp;Jiyi Hu,&nbsp;Lin Kong,&nbsp;Jiade J Lu","doi":"10.1186/s41232-022-00215-9","DOIUrl":"https://doi.org/10.1186/s41232-022-00215-9","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory response is an important characteristic affecting prognosis and therapeutic response in lower-grade glioma (LGG). However, the molecular subtypes based on inflammatory response are still under exploitation.</p><p><strong>Methods: </strong>The RNA sequencing, somatic mutation, and corresponding clinical data from 1205 LGG patients were obtained from the TCGA, CGGA, and Rembrandt cohorts. Consensus clustering was performed to identify molecular subtypes associated with inflammation. Prognosis, clinicopathologic features, immune cell infiltration, and somatic mutation profile were compared among these inflammation-associated subtypes.</p><p><strong>Results: </strong>Our results demonstrate that LGG could be categorized into inflammation-, low, -mid, and -high subtypes with distinct clinicopathologic features, prognostic and tumor microenvironment. We established that this categorization was reproducible, as well as predictable. In general, inflammation-high subtype presents a dismal prognosis with the immunosuppressive microenvironment and high frequency of oncogene mutation. Inversely, inflammation-low subtype was associated with the most favorable clinical outcomes with the immunoreactive microenvironment among three subtypes. Moreover, we develop and validate an inflammation-related prognostic model, which shows strong power for prognosis assessment.</p><p><strong>Conclusion: </strong>In conclusion, we established a novel glioma classification based on the inflammation subtype. This classification had significant outcomes for estimating the prognosis, as well as the tumor microenvironment.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40384481","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: 2
Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury. 伊马替尼通过阻断脊髓损伤PDGF-BB/PDGFRβ通路抑制周细胞-成纤维细胞转化和炎症,促进轴突再生。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-26 DOI: 10.1186/s41232-022-00223-9
Fei Yao, Yang Luo, Yan-Chang Liu, Yi-Hao Chen, Yi-Teng Li, Xu-Yang Hu, Xing-Yu You, Shui-Sheng Yu, Zi-Yu Li, Lei Chen, Da-Sheng Tian, Mei-Ge Zheng, Li Cheng, Jue-Hua Jing

Background: Fibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive.

Methods: Fibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ+ cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence.

Results: PDGFRβ+ pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ+ cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment.

Conclusions: We reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI.

背景:纤维化瘢痕形成和炎症是脊髓损伤核心的特征性病理,被广泛认为是轴突再生的主要障碍,导致永久性功能恢复失败。周细胞是形成纤维化瘢痕的成纤维细胞的主要来源。然而,脊髓损伤后周细胞向成纤维细胞转变的机制尚不清楚。方法:建立挤压性脊髓损伤模型后,采用免疫荧光染色法观察纤维化瘢痕和微血管的形成情况。为了研究周细胞向成纤维细胞转化的过程,我们采用免疫荧光法分析了周细胞标记物和成纤维细胞标记物的表达。免疫荧光法检测血小板衍生生长因子(PDGF)-BB的分布及细胞来源。PDGF-BB敲低并阻断PDGF-BB/PDGFRβ信号传导后,采用免疫组织化学和Western blot检测周细胞向成纤维细胞的转化。鞘内注射伊马替尼选择性抑制PDGF-BB/PDGFRβ信号传导。采用Basso小鼠量表评分和足迹分析来评估功能恢复。随后,用免疫荧光技术评估轴突再生、纤维化瘢痕、成纤维细胞数量、PDGFRβ+细胞增殖和凋亡、微血管渗漏和炎症反应。结果:脊髓损伤后PDGFRβ+周细胞脱离血管壁,向成纤维细胞转化形成纤维化瘢痕。PDGF-BB主要分布在损伤核心周围,微血管内皮细胞是急性期PDGF-BB的来源之一。微血管内皮细胞通过体外PDGF-BB/PDGFRβ信号通路诱导周细胞向成纤维细胞转变。药理学阻断PDGF-BB/PDGFRβ通路可促进运动功能恢复和轴突再生,抑制纤维化瘢痕形成。在纤维化瘢痕形成后,阻断PDGFRβ受体可抑制PDGFRβ+细胞的增殖,促进PDGFRβ+细胞的凋亡。伊马替尼没有改变微血管上的周细胞覆盖,而伊马替尼治疗后微血管渗漏和炎症明显减少。结论:我们发现微血管内皮细胞和周细胞之间的串扰通过PDGF-BB/PDGFRβ信号通路促进周细胞向成纤维细胞转变。我们的发现表明,用伊马替尼阻断PDGF-BB/PDGFRβ信号通路有助于脊髓损伤后的功能恢复、纤维化瘢痕形成和炎症减弱,并为脊髓损伤治疗提供了一个潜在的靶点。
{"title":"Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury.","authors":"Fei Yao,&nbsp;Yang Luo,&nbsp;Yan-Chang Liu,&nbsp;Yi-Hao Chen,&nbsp;Yi-Teng Li,&nbsp;Xu-Yang Hu,&nbsp;Xing-Yu You,&nbsp;Shui-Sheng Yu,&nbsp;Zi-Yu Li,&nbsp;Lei Chen,&nbsp;Da-Sheng Tian,&nbsp;Mei-Ge Zheng,&nbsp;Li Cheng,&nbsp;Jue-Hua Jing","doi":"10.1186/s41232-022-00223-9","DOIUrl":"https://doi.org/10.1186/s41232-022-00223-9","url":null,"abstract":"<p><strong>Background: </strong>Fibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive.</p><p><strong>Methods: </strong>Fibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ<sup>+</sup> cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence.</p><p><strong>Results: </strong>PDGFRβ<sup>+</sup> pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ<sup>+</sup> cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment.</p><p><strong>Conclusions: </strong>We reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9511779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40375068","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: 4
Enhancer RNA commits osteogenesis via microRNA-3129 expression in human bone marrow-derived mesenchymal stem cells. 增强子RNA在人骨髓间充质干细胞中通过microRNA-3129的表达实现成骨。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-16 DOI: 10.1186/s41232-022-00228-4
Anh Phuong Nguyen, Kaoru Yamagata, Shigeru Iwata, Gulzhan Trimova, Tong Zhang, Yu Shan, Mai-Phuong Nguyen, Koshiro Sonomoto, Shingo Nakayamada, Shigeaki Kato, Yoshiya Tanaka

Background: Highly regulated gene expression program underlies osteogenesis of mesenchymal stem cells (MSCs), but the regulators in the program are not entirely identified. As enhancer RNAs (eRNAs) have recently emerged as a key regulator in gene expression, we assume a commitment of an eRNA in osteogenesis.

Methods: We performed in silico analysis to identify potential osteogenic microRNA (miRNA) gene predicted to be regulated by super-enhancers (SEs). SE inhibitor treatment and eRNA knocking-down were used to confirm the regulational mechanism of eRNA. miRNA function in osteogenesis was elucidated by miR mimic and inhibitor transfection experiments.

Results: miR-3129 was found to be located adjacent in a SE (osteoblast-specific SE_46171) specifically activated in osteoblasts by in silico analysis. A RT-quantitative PCR analysis of human bone marrow-derived MSC (hBMSC) cells showed that eRNA_2S was transcribed from the SE with the expression of miR-3129. Knockdown of eRNA_2S by locked nucleic acid as well as treatment of SE inhibitors JQ1 or THZ1 resulted in low miR-3129 levels. Overexpression of miR-3129 promoted hBMSC osteogenesis, while knockdown of miR-3129 inhibited hBMSC osteogenesis. Solute carrier family 7 member 11 (SLC7A11), encoding a bone formation suppressor, was upregulated following miR-3129-5p inhibition and identified as a target gene for miR-3129 during differentiation of hBMSCs into osteoblasts.

Conclusions: miR-3129 expression is regulated by SEs via eRNA_2S and this miRNA promotes hBMSC differentiation into osteoblasts through downregulating the target gene SLC7A11. Thus, the present study uncovers a commitment of an eRNA via a miR-3129/SLC7A11 regulatory pathway during osteogenesis of hBMSCs.

背景:高度调控的基因表达程序是间充质干细胞(MSCs)成骨的基础,但该程序中的调控因子尚未完全确定。随着增强rna (eRNA)最近成为基因表达的关键调节因子,我们假设eRNA在成骨过程中起着重要作用。方法:采用计算机分析方法,鉴定可能受超级增强子(superenhancer, SEs)调控的潜在成骨microRNA (miRNA)基因。通过SE抑制剂处理和eRNA敲低来证实eRNA的调控机制。miRNA在成骨过程中的功能通过miR模拟物和miR抑制剂转染实验得以阐明。结果:通过计算机分析发现miR-3129位于成骨细胞特异性激活的SE(成骨细胞特异性SE_46171)的邻近区域。人骨髓源性MSC (hBMSC)细胞的rt -定量PCR分析显示,eRNA_2S从SE转录,miR-3129表达。通过锁定的核酸敲低eRNA_2S以及SE抑制剂JQ1或THZ1的处理导致miR-3129水平降低。过表达miR-3129促进hBMSC成骨,而敲低miR-3129抑制hBMSC成骨。编码骨形成抑制因子的溶质载体家族7成员11 (SLC7A11)在miR-3129-5p抑制后上调,并在hBMSCs向成骨细胞分化过程中被鉴定为miR-3129的靶基因。结论:miR-3129的表达受SEs通过eRNA_2S调控,该miRNA通过下调靶基因SLC7A11促进hBMSC向成骨细胞分化。因此,本研究揭示了在hBMSCs成骨过程中,eRNA通过miR-3129/SLC7A11调控途径参与。
{"title":"Enhancer RNA commits osteogenesis via microRNA-3129 expression in human bone marrow-derived mesenchymal stem cells.","authors":"Anh Phuong Nguyen,&nbsp;Kaoru Yamagata,&nbsp;Shigeru Iwata,&nbsp;Gulzhan Trimova,&nbsp;Tong Zhang,&nbsp;Yu Shan,&nbsp;Mai-Phuong Nguyen,&nbsp;Koshiro Sonomoto,&nbsp;Shingo Nakayamada,&nbsp;Shigeaki Kato,&nbsp;Yoshiya Tanaka","doi":"10.1186/s41232-022-00228-4","DOIUrl":"https://doi.org/10.1186/s41232-022-00228-4","url":null,"abstract":"<p><strong>Background: </strong>Highly regulated gene expression program underlies osteogenesis of mesenchymal stem cells (MSCs), but the regulators in the program are not entirely identified. As enhancer RNAs (eRNAs) have recently emerged as a key regulator in gene expression, we assume a commitment of an eRNA in osteogenesis.</p><p><strong>Methods: </strong>We performed in silico analysis to identify potential osteogenic microRNA (miRNA) gene predicted to be regulated by super-enhancers (SEs). SE inhibitor treatment and eRNA knocking-down were used to confirm the regulational mechanism of eRNA. miRNA function in osteogenesis was elucidated by miR mimic and inhibitor transfection experiments.</p><p><strong>Results: </strong>miR-3129 was found to be located adjacent in a SE (osteoblast-specific SE_46171) specifically activated in osteoblasts by in silico analysis. A RT-quantitative PCR analysis of human bone marrow-derived MSC (hBMSC) cells showed that eRNA_2S was transcribed from the SE with the expression of miR-3129. Knockdown of eRNA_2S by locked nucleic acid as well as treatment of SE inhibitors JQ1 or THZ1 resulted in low miR-3129 levels. Overexpression of miR-3129 promoted hBMSC osteogenesis, while knockdown of miR-3129 inhibited hBMSC osteogenesis. Solute carrier family 7 member 11 (SLC7A11), encoding a bone formation suppressor, was upregulated following miR-3129-5p inhibition and identified as a target gene for miR-3129 during differentiation of hBMSCs into osteoblasts.</p><p><strong>Conclusions: </strong>miR-3129 expression is regulated by SEs via eRNA_2S and this miRNA promotes hBMSC differentiation into osteoblasts through downregulating the target gene SLC7A11. Thus, the present study uncovers a commitment of an eRNA via a miR-3129/SLC7A11 regulatory pathway during osteogenesis of hBMSCs.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9479228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40363985","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
Entering the era of precision medicine through multiomics approach. 通过多组学方法进入精准医疗时代。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-09 DOI: 10.1186/s41232-022-00229-3
Keishi Fujio
{"title":"Entering the era of precision medicine through multiomics approach.","authors":"Keishi Fujio","doi":"10.1186/s41232-022-00229-3","DOIUrl":"https://doi.org/10.1186/s41232-022-00229-3","url":null,"abstract":"","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9461182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33456081","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
Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer's disease. 胃幽门螺杆菌感染诱发神经炎症:细菌外膜囊泡在阿尔茨海默病动物模型中的潜在作用。
IF 5 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-09-05 DOI: 10.1186/s41232-022-00224-8
Ah-Mee Park, Ikuo Tsunoda

Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer's disease (AD) and Parkinson's disease (PD). Since HP does not invade the central nervous system (CNS), it has been considered that systemic immunological changes induced by HP infection may play pathogenic roles in AD and PD. Here, we investigated the effects of HP infection on the CNS in vivo and in vitro. In the CNS, chronically HP-infected mice had microglial activation without HP colonization, although systemic immunological changes were not observed. This led us to explore the possibility that HP-derived outer membrane vesicles (HP-OMVs) could cause neuroinflammation. OMVs are small, spherical bilayer vesicles (20-500 nm) released into the extracellular space from the outer membrane of Gram-negative bacteria; OMVs contain lipopolysaccharide, proteins, peptidoglycan, DNA, and RNA. OMVs have also been shown to activate both innate and acquired immune cells in vitro, and to disrupt the tight junctions of the gastric epithelium ("leaky gut") as well as cross the blood-brain barrier in vivo. Thus, in theory, OMVs can activate immune responses in the remote organs, including the lymphoid organs and CNS, if only OMVs enter the systemic circulation. From the exosome fraction of sera from HP-infected mice, we detected HP-specific DNA, suggesting the presence of HP-OMVs. We also found that microglia incubated with HP-OMVs in vitro increased the cell proliferation, inflammatory cytokine production, and migration. On the other hand, HP-OMVs suppressed the cell proliferation of neuroblastoma in vitro. Lastly, we found that AD model mice infected with HP had amyloid plaques adjacent to activated microglia and astrocytes in vivo. Based on the literature review and our experimental data, we propose our working hypothesis that OMVs produced in chronic HP infection in the gut induce neuroinflammation in the CNS, explaining the higher prevalence of AD in HP-infected people.

幽门螺杆菌(HP)是一种革兰氏阴性菌,长期定植于人类胃部。幽门螺杆菌在胃粘膜上的定植不仅会引起胃肠道疾病,而且还与胃肠道以外的疾病有关,如特发性血小板减少性紫癜和神经系统疾病。在神经系统疾病中,流行病学研究表明,HP 感染会增加阿尔茨海默病(AD)和帕金森病(PD)的发病率。由于 HP 不会侵入中枢神经系统(CNS),因此有人认为 HP 感染诱发的全身免疫学变化可能在 AD 和 PD 中起到致病作用。在此,我们研究了体内和体外 HP 感染对中枢神经系统的影响。在中枢神经系统中,长期感染HP的小鼠在没有HP定植的情况下会出现微胶质细胞活化,但并未观察到系统性免疫学变化。这促使我们探索 HP 衍生的外膜囊泡 (HP-OMVs) 可能导致神经炎症的可能性。外膜囊泡是革兰氏阴性细菌外膜释放到细胞外空间的小球形双层囊泡(20-500 nm);外膜囊泡含有脂多糖、蛋白质、肽聚糖、DNA 和 RNA。研究还表明,OMV 在体外可激活先天性免疫细胞和获得性免疫细胞,在体内可破坏胃上皮细胞的紧密连接("肠漏")并穿过血脑屏障。因此,从理论上讲,只要有 OMV 进入全身循环,OMV 就能激活远端器官(包括淋巴器官和中枢神经系统)的免疫反应。我们从HP感染小鼠血清的外泌体部分检测到了HP特异性DNA,这表明HP-OMVs的存在。我们还发现,在体外与 HP-OMV 培育的小胶质细胞会增加细胞增殖、炎症细胞因子的产生和迁移。另一方面,HP-OMVs 在体外抑制了神经母细胞瘤的细胞增殖。最后,我们发现感染 HP 的 AD 模型小鼠体内的淀粉样蛋白斑块与活化的小胶质细胞和星形胶质细胞相邻。根据文献综述和我们的实验数据,我们提出了我们的工作假设,即肠道慢性HP感染产生的OMV会诱发中枢神经系统的神经炎症,从而解释了HP感染者中AD发病率较高的原因。
{"title":"Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer's disease.","authors":"Ah-Mee Park, Ikuo Tsunoda","doi":"10.1186/s41232-022-00224-8","DOIUrl":"10.1186/s41232-022-00224-8","url":null,"abstract":"<p><p>Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer's disease (AD) and Parkinson's disease (PD). Since HP does not invade the central nervous system (CNS), it has been considered that systemic immunological changes induced by HP infection may play pathogenic roles in AD and PD. Here, we investigated the effects of HP infection on the CNS in vivo and in vitro. In the CNS, chronically HP-infected mice had microglial activation without HP colonization, although systemic immunological changes were not observed. This led us to explore the possibility that HP-derived outer membrane vesicles (HP-OMVs) could cause neuroinflammation. OMVs are small, spherical bilayer vesicles (20-500 nm) released into the extracellular space from the outer membrane of Gram-negative bacteria; OMVs contain lipopolysaccharide, proteins, peptidoglycan, DNA, and RNA. OMVs have also been shown to activate both innate and acquired immune cells in vitro, and to disrupt the tight junctions of the gastric epithelium (\"leaky gut\") as well as cross the blood-brain barrier in vivo. Thus, in theory, OMVs can activate immune responses in the remote organs, including the lymphoid organs and CNS, if only OMVs enter the systemic circulation. From the exosome fraction of sera from HP-infected mice, we detected HP-specific DNA, suggesting the presence of HP-OMVs. We also found that microglia incubated with HP-OMVs in vitro increased the cell proliferation, inflammatory cytokine production, and migration. On the other hand, HP-OMVs suppressed the cell proliferation of neuroblastoma in vitro. Lastly, we found that AD model mice infected with HP had amyloid plaques adjacent to activated microglia and astrocytes in vivo. Based on the literature review and our experimental data, we propose our working hypothesis that OMVs produced in chronic HP infection in the gut induce neuroinflammation in the CNS, explaining the higher prevalence of AD in HP-infected people.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2022-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9442937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40348103","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
Transforming growth factor-β-induced secretion of extracellular vesicles from oral cancer cells evokes endothelial barrier instability via endothelial-mesenchymal transition. 转化生长因子-β诱导的口腔癌细胞外囊泡分泌通过内皮-间质转化引起内皮屏障不稳定。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-04 DOI: 10.1186/s41232-022-00225-7
Miho Kobayashi, Kashio Fujiwara, Kazuki Takahashi, Yusuke Yoshioka, Takahiro Ochiya, Katarzyna A Podyma-Inoue, Tetsuro Watabe

Background: During metastasis, cancer cells undergo epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β), which is abundant in the tumor microenvironment, and acquire invasive and metastatic potentials. Metastasis to distant organs requires intravascular invasion and extravasation of cancer cells, which is accompanied by the disruption of the adhesion between vascular endothelial cells. Cancer cell-derived extracellular vesicles (EVs) have been suggested to induce the destabilization of normal blood vessels at the metastatic sites. However, the roles of EVs secreted from cancer cells that have undergone EMT in the destabilization of blood vessels remain to be elucidated. In the present study, we characterized EVs secreted by oral cancer cells undergoing TGF-β-induced EMT and elucidated their effects on the characteristics of vascular endothelial cells.

Methods: Induction of EMT by TGF-β in human oral cancer cells was assessed using quantitative RT-PCR (qRT-PCR) and immunocytochemistry. Oral cancer cell-derived EVs were isolated from the conditioned media of oral cancer cells that were treated with or without TGF-β using ultracentrifugation, and characterized using nanoparticle tracking analysis and immunoblotting. The effects of EVs on human umbilical artery endothelial cells were examined by qRT-PCR, cellular staining, and permeability assay. The significant differences between means were determined using a t-test or one-way analysis of variance with Tukey's multiple comparisons test.

Results: Oral cancer cells underwent EMT in response to TGF-β as revealed by changes in the expression of epithelial and mesenchymal cell markers at both the RNA and protein levels. Oral cancer cells treated with TGF-β showed increased EV production and altered EV composition when compared with untreated cells. The EVs that originated from cells that underwent EMT by TGF-β induced endothelial-mesenchymal transition, which was characterized by the decreased and increased expression of endothelial and mesenchymal cell markers, respectively. EVs derived from oral cancer cells also induced intercellular gap formation which led to the loss of endothelial cell barrier stability.

Conclusions: EVs released from oral cancer cells that underwent TGF-β-induced EMT target endothelial cells to induce vascular destabilization. Detailed characterization of oral cancer-derived EVs and factors responsible for EV-mediated vascular instability will lead to the development of agents targeting metastasis.

背景:在转移过程中,癌细胞在肿瘤微环境中丰富的转化生长因子-β (TGF-β)的作用下发生上皮-间质转化(epithelial-mesenchymal transition, EMT),并获得侵袭和转移潜能。转移到远处器官需要癌细胞在血管内的侵袭和外渗,这伴随着血管内皮细胞之间粘附的破坏。癌细胞来源的细胞外囊泡(EVs)被认为可以诱导正常血管在转移部位的不稳定。然而,从经历EMT的癌细胞分泌的ev在血管不稳定中的作用仍有待阐明。在本研究中,我们对口腔癌细胞在TGF-β诱导的EMT过程中分泌的EVs进行了表征,并阐明了其对血管内皮细胞特性的影响。方法:采用定量RT-PCR (qRT-PCR)和免疫细胞化学方法观察TGF-β对人口腔癌细胞EMT的诱导作用。从TGF-β处理或不处理口腔癌细胞的条件培养基中分离出口腔癌细胞源性ev,并采用纳米颗粒跟踪分析和免疫印迹法对其进行表征。采用qRT-PCR、细胞染色和通透性实验检测ev对人脐动脉内皮细胞的影响。均值之间的显著性差异采用t检验或单因素方差分析,采用Tukey多重比较检验。结果:上皮细胞和间充质细胞标志物在RNA和蛋白水平上的表达变化揭示了TGF-β对口腔癌细胞EMT的响应。与未处理的细胞相比,TGF-β处理的口腔癌细胞显示出EV产生增加和EV组成改变。来源于TGF-β诱导EMT细胞的内皮-间充质转化,其特征是内皮细胞和间充质细胞标志物的表达分别下降和增加。来源于口腔癌细胞的ev也诱导了细胞间隙的形成,导致内皮细胞屏障稳定性的丧失。结论:口腔癌细胞经TGF-β诱导EMT后释放的ev靶向内皮细胞,诱导血管不稳定。对口腔癌源性EVs和EVs介导的血管不稳定因素的详细描述将导致针对转移的药物的发展。
{"title":"Transforming growth factor-β-induced secretion of extracellular vesicles from oral cancer cells evokes endothelial barrier instability via endothelial-mesenchymal transition.","authors":"Miho Kobayashi,&nbsp;Kashio Fujiwara,&nbsp;Kazuki Takahashi,&nbsp;Yusuke Yoshioka,&nbsp;Takahiro Ochiya,&nbsp;Katarzyna A Podyma-Inoue,&nbsp;Tetsuro Watabe","doi":"10.1186/s41232-022-00225-7","DOIUrl":"https://doi.org/10.1186/s41232-022-00225-7","url":null,"abstract":"<p><strong>Background: </strong>During metastasis, cancer cells undergo epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β), which is abundant in the tumor microenvironment, and acquire invasive and metastatic potentials. Metastasis to distant organs requires intravascular invasion and extravasation of cancer cells, which is accompanied by the disruption of the adhesion between vascular endothelial cells. Cancer cell-derived extracellular vesicles (EVs) have been suggested to induce the destabilization of normal blood vessels at the metastatic sites. However, the roles of EVs secreted from cancer cells that have undergone EMT in the destabilization of blood vessels remain to be elucidated. In the present study, we characterized EVs secreted by oral cancer cells undergoing TGF-β-induced EMT and elucidated their effects on the characteristics of vascular endothelial cells.</p><p><strong>Methods: </strong>Induction of EMT by TGF-β in human oral cancer cells was assessed using quantitative RT-PCR (qRT-PCR) and immunocytochemistry. Oral cancer cell-derived EVs were isolated from the conditioned media of oral cancer cells that were treated with or without TGF-β using ultracentrifugation, and characterized using nanoparticle tracking analysis and immunoblotting. The effects of EVs on human umbilical artery endothelial cells were examined by qRT-PCR, cellular staining, and permeability assay. The significant differences between means were determined using a t-test or one-way analysis of variance with Tukey's multiple comparisons test.</p><p><strong>Results: </strong>Oral cancer cells underwent EMT in response to TGF-β as revealed by changes in the expression of epithelial and mesenchymal cell markers at both the RNA and protein levels. Oral cancer cells treated with TGF-β showed increased EV production and altered EV composition when compared with untreated cells. The EVs that originated from cells that underwent EMT by TGF-β induced endothelial-mesenchymal transition, which was characterized by the decreased and increased expression of endothelial and mesenchymal cell markers, respectively. EVs derived from oral cancer cells also induced intercellular gap formation which led to the loss of endothelial cell barrier stability.</p><p><strong>Conclusions: </strong>EVs released from oral cancer cells that underwent TGF-β-induced EMT target endothelial cells to induce vascular destabilization. Detailed characterization of oral cancer-derived EVs and factors responsible for EV-mediated vascular instability will lead to the development of agents targeting metastasis.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9441046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40345849","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: 4
Thymic self-antigen expression for immune tolerance and surveillance. 胸腺自身抗原表达对免疫耐受和监测的影响。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-03 DOI: 10.1186/s41232-022-00211-z
Rayene Benlaribi, Qiao Gou, Hiroyuki Takaba

T cells are a group of lymphocytes that play a central role in the immune system, notably, eliminating pathogens and attacking cancer while being tolerant of the self. Elucidating how immune tolerance is ensured has become a significant research issue for understanding the pathogenesis of autoimmune diseases as well as cancer immunity. T cell immune tolerance is established mainly in the thymic medulla by the removal of self-responsive T cells and the generation of regulatory T cells, this process depends mainly on the expression of a variety of tissue restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs). The expression of TRAs is known to be regulated by at least two independent factors, Fezf2 and Aire, which play non-redundant and complementary roles by different mechanisms. In this review, we introduce the molecular logic of thymic self-antigen expression that underlies T cell selection for the prevention of autoimmunity and the establishment of immune surveillance.

T细胞是一组淋巴细胞,在免疫系统中起着核心作用,特别是在消除病原体和攻击癌症的同时对自身具有容忍度。阐明如何确保免疫耐受已成为了解自身免疫性疾病发病机制和癌症免疫的重要研究课题。T细胞免疫耐受主要在胸腺髓质中通过清除自身反应性T细胞和产生调节性T细胞而建立,这一过程主要依赖于胸腺髓质上皮细胞(mTECs)表达多种组织限制性抗原(TRAs)。已知TRAs的表达受至少两个独立因子Fezf2和Aire的调控,它们通过不同的机制发挥非冗余和互补的作用。在这篇综述中,我们介绍了胸腺自身抗原表达的分子逻辑,这是T细胞选择预防自身免疫和建立免疫监视的基础。
{"title":"Thymic self-antigen expression for immune tolerance and surveillance.","authors":"Rayene Benlaribi,&nbsp;Qiao Gou,&nbsp;Hiroyuki Takaba","doi":"10.1186/s41232-022-00211-z","DOIUrl":"https://doi.org/10.1186/s41232-022-00211-z","url":null,"abstract":"<p><p>T cells are a group of lymphocytes that play a central role in the immune system, notably, eliminating pathogens and attacking cancer while being tolerant of the self. Elucidating how immune tolerance is ensured has become a significant research issue for understanding the pathogenesis of autoimmune diseases as well as cancer immunity. T cell immune tolerance is established mainly in the thymic medulla by the removal of self-responsive T cells and the generation of regulatory T cells, this process depends mainly on the expression of a variety of tissue restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs). The expression of TRAs is known to be regulated by at least two independent factors, Fezf2 and Aire, which play non-redundant and complementary roles by different mechanisms. In this review, we introduce the molecular logic of thymic self-antigen expression that underlies T cell selection for the prevention of autoimmunity and the establishment of immune surveillance.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40346512","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: 2
Osteoclast biology in the single-cell era. 单细胞时代的破骨细胞生物学。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-02 DOI: 10.1186/s41232-022-00213-x
Masayuki Tsukasaki, Hiroshi Takayanagi

Osteoclasts, the only cells that can resorb bone, play a central role in bone homeostasis as well as bone damage under pathological conditions such as osteoporosis, arthritis, periodontitis, and bone metastasis. Recent studies using single-cell technologies have uncovered the regulatory mechanisms underlying osteoclastogenesis at unprecedented resolution and shed light on the possibility that there is heterogeneity in the origin, function, and fate of osteoclast-lineage cells. Here, we discuss the current advances and emerging concepts in osteoclast biology.

破骨细胞是唯一能够吸收骨的细胞,在骨质疏松、关节炎、牙周炎和骨转移等病理条件下的骨稳态和骨损伤中起着核心作用。最近使用单细胞技术的研究以前所未有的分辨率揭示了破骨细胞发生的调节机制,并揭示了破骨细胞谱系细胞的起源、功能和命运存在异质性的可能性。在这里,我们讨论了破骨细胞生物学的最新进展和新概念。
{"title":"Osteoclast biology in the single-cell era.","authors":"Masayuki Tsukasaki,&nbsp;Hiroshi Takayanagi","doi":"10.1186/s41232-022-00213-x","DOIUrl":"https://doi.org/10.1186/s41232-022-00213-x","url":null,"abstract":"<p><p>Osteoclasts, the only cells that can resorb bone, play a central role in bone homeostasis as well as bone damage under pathological conditions such as osteoporosis, arthritis, periodontitis, and bone metastasis. Recent studies using single-cell technologies have uncovered the regulatory mechanisms underlying osteoclastogenesis at unprecedented resolution and shed light on the possibility that there is heterogeneity in the origin, function, and fate of osteoclast-lineage cells. Here, we discuss the current advances and emerging concepts in osteoclast biology.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40341592","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: 7
Controlling skin microbiome as a new bacteriotherapy for inflammatory skin diseases. 控制皮肤微生物群是治疗炎症性皮肤病的一种新的细菌疗法。
IF 8.1 3区 医学 Q1 Medicine Pub Date : 2022-09-01 DOI: 10.1186/s41232-022-00212-y
Yoshihiro Ito, Masayuki Amagai

The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.

皮肤是人体与环境之间的界面,与微生物群落相互作用。皮肤微生物群由细菌、真菌、螨虫和病毒等微生物组成,它们的波动取决于由解剖位置和生理功能定义的微环境。宿主和微生物群之间相互作用的平衡在皮肤稳态的协调中起着关键作用;然而,由于微生物群落的改变而引起的平衡紊乱,即生态失调,导致各种皮肤疾病。测序技术的最新发展为皮肤微生物群落的结构和功能提供了新的见解。基于高通量测序分析,越来越多的证据表明,使用活细菌的新治疗方法,称为细菌疗法,是由生态失调引起的皮肤病的可行治疗选择。特别是,特定细菌菌株的管理已被研究作为针对慢性皮肤病相关病原体的排他治疗策略,而使用分离活细菌的这种治疗方法的安全性,有效性和可持续性需要进一步探索。在这篇综述中,我们总结了我们目前对皮肤微生物群的了解,以及使用特征活菌菌株治疗皮肤炎症性疾病的治疗策略。宿主和皮肤微生物联合体之间相互作用形成的生态系统在很大程度上仍未被探索;然而,我们对皮肤微生物群在菌株水平上的功能的理解的进步将导致新的治疗方法的发展。
{"title":"Controlling skin microbiome as a new bacteriotherapy for inflammatory skin diseases.","authors":"Yoshihiro Ito,&nbsp;Masayuki Amagai","doi":"10.1186/s41232-022-00212-y","DOIUrl":"https://doi.org/10.1186/s41232-022-00212-y","url":null,"abstract":"<p><p>The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40335431","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: 12
期刊
Inflammation and Regeneration
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1