首页 > 最新文献

International Journal of Oral Science最新文献

英文 中文
METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs METTL7A 介导的 corin m6A 修饰可逆转双膦酸盐对口面部 BMSC 骨细胞成骨分化的影响
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-23 DOI: 10.1038/s41368-024-00303-1
Yizhou Jin, Xiao Han, Yuejun Wang, Zhipeng Fan

Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

双膦酸盐相关性颌骨坏死(BRONJ)的特征是口面部骨髓基质细胞(BMSCs)的成骨分化受损。Corin 最近被证明是骨发育和骨科疾病的关键调节因子。然而,corin在与BRONJ相关的骨髓基质细胞功能障碍中的作用仍未明确。我们小组的一项 m6A 表转录组芯片研究表明,在口面部 BMSCs 成骨分化过程中,CORIN 基因显著上调,且 m6A 高甲基化。corin基因敲除抑制BMSCs成骨分化,而corin基因过表达或可溶性corin(sCorin)则具有促进作用。此外,corin 的表达受双磷酸盐(BPs)的负调控。Corin过表达或sCorin能逆转双膦酸盐对BMSCs分化能力的损害。从机理上讲,我们发现在 corin 敲除/过表达 BMSCs 和受 sCorin 刺激的 BMSCs 中,phos-ERK 的表达发生了改变。PD98059(一种选择性 ERK 抑制剂)阻断了 corin 介导的促进作用。考虑到成骨分化过程中 corin 的甲基化水平较高,我们使用了非选择性 m6A 甲基化酶抑制剂 Cycloleucine,它也能阻断 corin 介导的促进效应。此外,我们还证明了 METTL7A 可调节 corin m6A 修饰并逆转 BPs 受损的 BMSCs 功能,这表明 METTL7A 可调控 corin 的表达,从而促进口面部 BMSCs 的分化能力。总之,我们的研究揭示了 corin 逆转 BPs 诱导的 BMSCs 功能障碍,而 METTL7A 介导的 corin m6A 修饰是 corin 通过 ERK 通路促进成骨分化的基础。我们希望这能为 BRONJ 未来的临床治疗带来新的启示。
{"title":"METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs","authors":"Yizhou Jin, Xiao Han, Yuejun Wang, Zhipeng Fan","doi":"10.1038/s41368-024-00303-1","DOIUrl":"https://doi.org/10.1038/s41368-024-00303-1","url":null,"abstract":"<p>Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the <i>CORIN</i> gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure 多组学分析显示,VDR 是间充质干细胞衰老的核心调节因子,已知与高脂饮食暴露后的骨质疏松症有关
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-22 DOI: 10.1038/s41368-024-00309-9
Jiayao Chen, Shuhong Kuang, Jietao Cen, Yong Zhang, Zongshan Shen, Wei Qin, Qiting Huang, Zifeng Wang, Xianling Gao, Fang Huang, Zhengmei Lin

The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

高脂饮食(HFD)与骨质疏松症和脆性骨折风险增加有关。然而,高脂饮食诱发骨质疏松症的具体机制尚未完全明了。我们的研究表明,暴露于HFD会诱导骨髓间充质干细胞(BMSCs)过早衰老,降低其增殖和成骨能力,从而导致骨质疏松症。转录组和染色质可及性分析表明,维生素 D 受体(VDR)结合序列的染色质可及性降低,高密度脂蛋白胆固醇喂养小鼠骨髓间充质干细胞中的 VDR 信号转导减少,这表明 VDR 是骨髓间充质干细胞衰老的关键调节因子。值得注意的是,给高密度脂蛋白胆固醇喂养的小鼠注射 VDR 激活剂能挽救 BMSC 的衰老,并显著改善成骨、骨量和其他骨参数。从机理上讲,VDR 激活通过降低细胞内活性氧(ROS)水平和保护线粒体功能来减少 BMSC 的衰老。我们的研究结果不仅阐明了高氟酸膳食诱导 BMSC 衰老和相关骨质疏松症的机制,还为通过靶向 VDR-superoxide dismutase 2 (SOD2)-ROS 轴治疗高氟酸膳食诱导的骨质疏松症提供了新的见解。
{"title":"Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure","authors":"Jiayao Chen, Shuhong Kuang, Jietao Cen, Yong Zhang, Zongshan Shen, Wei Qin, Qiting Huang, Zifeng Wang, Xianling Gao, Fang Huang, Zhengmei Lin","doi":"10.1038/s41368-024-00309-9","DOIUrl":"https://doi.org/10.1038/s41368-024-00309-9","url":null,"abstract":"<p>The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease 人牙髓干细胞通过 AKT-GSK3β-Nrf2 通路减轻阿尔茨海默病的神经病理变化和认知能力下降
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-13 DOI: 10.1038/s41368-024-00300-4
Wei Xiong, Ye Liu, Heng Zhou, Junyi Li, Shuili Jing, Cailei Jiang, Mei Li, Yan He, Qingsong Ye

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

人们日益认识到,氧化应激是阿尔茨海默病(AD)病理生理学的一个主要因素,尤其是在疾病的早期阶段。干细胞移植的多重优势使其成为许多神经退行性疾病的迷人治疗策略。我们在此证明,在体外AD模型中,人牙髓干细胞(hDPSCs)介导了氧化应激的改善和神经恢复效应,在调节高反应性小胶质细胞的极化和受损神经元的恢复中发挥了关键作用。重要的是,这些治疗效果在10个月大的3xTg-AD小鼠单次移植hDPSCs后得到了体现,接受治疗的小鼠在认知功能和神经病理学特征方面都有显著改善。从机理上讲,hDPSCs的抗氧化和神经保护作用以及认知能力的提高至少部分是由Nrf2核积累和下游抗氧化酶的表达通过激活AKT-GSK3β-Nrf2信号通路介导的。总之,我们的研究结果证实了hDPSCs在体外和体内AD模型中重塑神经病理微环境的神经保护能力,这可能是阿尔茨海默病的一个巨大的潜在治疗候选方案。
{"title":"Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease","authors":"Wei Xiong, Ye Liu, Heng Zhou, Junyi Li, Shuili Jing, Cailei Jiang, Mei Li, Yan He, Qingsong Ye","doi":"10.1038/s41368-024-00300-4","DOIUrl":"https://doi.org/10.1038/s41368-024-00300-4","url":null,"abstract":"<p>Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140914955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unveiling the oral-gut connection: chronic apical periodontitis accelerates atherosclerosis via gut microbiota dysbiosis and altered metabolites in apoE−/− Mice on a high-fat diet 揭开口腔与肠道的联系:慢性根尖牙周炎通过肠道微生物群失调和代谢物改变加速高脂饮食载脂蛋白E-/-小鼠的动脉粥样硬化
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-13 DOI: 10.1038/s41368-024-00301-3
Guowu Gan, Shihan Lin, Yufang Luo, Yu Zeng, Beibei Lu, Ren Zhang, Shuai Chen, Huaxiang Lei, Zhiyu Cai, Xiaojing Huang

The aim of this study was to explore the impact of chronic apical periodontitis (CAP) on atherosclerosis in apoE−/− mice fed high-fat diet (HFD). This investigation focused on the gut microbiota, metabolites, and intestinal barrier function to uncover potential links between oral health and cardiovascular disease (CVD). In this study, CAP was shown to exacerbate atherosclerosis in HFD-fed apoE−/− mice, as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining. 16S rRNA sequencing revealed significant alterations in the gut microbiota, with harmful bacterial species thriving while beneficial species declining. Metabolomic profiling indicated disruptions in lipid metabolism and primary bile acid synthesis, leading to elevated levels of taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and tauroursodeoxycholic acid (TDCA). These metabolic shifts may contribute to atherosclerosis development. Furthermore, impaired intestinal barrier function, characterized by reduced mucin expression and disrupted tight junction proteins, was observed. The increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions, highlighting the importance of the intestinal barrier in cardiovascular health. In conclusion, this research underscores the intricate interplay among oral health, gut microbiota composition, metabolite profiles, and CVD incidence. These findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues, as well as the need for further investigations into the intricate mechanisms linking oral health, gut microbiota, and metabolic pathways in CVD development.

本研究旨在探讨慢性根尖周炎(CAP)对以高脂饮食(HFD)喂养的载脂蛋白E-/-小鼠动脉粥样硬化的影响。这项调查的重点是肠道微生物群、代谢物和肠道屏障功能,以揭示口腔健康与心血管疾病(CVD)之间的潜在联系。在这项研究中,通过油红 O 染色观察到的主动脉壁斑块大小和体积的增加证明了 CAP 会加剧高密度脂蛋白饮食载脂蛋白 E-/- 小鼠的动脉粥样硬化。16S rRNA 测序显示肠道微生物群发生了显著变化,有害细菌种类增多,而有益细菌种类减少。代谢组学分析表明,脂质代谢和初级胆汁酸合成紊乱,导致牛磺鹅去氧胆酸(TCDCA)、牛磺酸(TCA)和牛磺酸去氧胆酸(TDCA)水平升高。这些代谢变化可能会导致动脉粥样硬化的发生。此外,还观察到肠道屏障功能受损,表现为粘蛋白表达减少和紧密连接蛋白紊乱。观察到的肠道渗透性增加与动脉粥样硬化病变的严重程度呈正相关,这突出了肠道屏障在心血管健康中的重要性。总之,这项研究强调了口腔健康、肠道微生物群组成、代谢物谱和心血管疾病发病率之间错综复杂的相互作用。这些发现强调了保持良好的口腔卫生作为潜在的心血管问题预防措施的重要性,以及进一步研究口腔健康、肠道微生物群和代谢途径在心血管疾病发展中的复杂联系机制的必要性。
{"title":"Unveiling the oral-gut connection: chronic apical periodontitis accelerates atherosclerosis via gut microbiota dysbiosis and altered metabolites in apoE−/− Mice on a high-fat diet","authors":"Guowu Gan, Shihan Lin, Yufang Luo, Yu Zeng, Beibei Lu, Ren Zhang, Shuai Chen, Huaxiang Lei, Zhiyu Cai, Xiaojing Huang","doi":"10.1038/s41368-024-00301-3","DOIUrl":"https://doi.org/10.1038/s41368-024-00301-3","url":null,"abstract":"<p>The aim of this study was to explore the impact of chronic apical periodontitis (CAP) on atherosclerosis in apoE<sup>−/−</sup> mice fed high-fat diet (HFD). This investigation focused on the gut microbiota, metabolites, and intestinal barrier function to uncover potential links between oral health and cardiovascular disease (CVD). In this study, CAP was shown to exacerbate atherosclerosis in HFD-fed apoE<sup>−/−</sup> mice, as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining. 16S rRNA sequencing revealed significant alterations in the gut microbiota, with harmful bacterial species thriving while beneficial species declining. Metabolomic profiling indicated disruptions in lipid metabolism and primary bile acid synthesis, leading to elevated levels of taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and tauroursodeoxycholic acid (TDCA). These metabolic shifts may contribute to atherosclerosis development. Furthermore, impaired intestinal barrier function, characterized by reduced mucin expression and disrupted tight junction proteins, was observed. The increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions, highlighting the importance of the intestinal barrier in cardiovascular health. In conclusion, this research underscores the intricate interplay among oral health, gut microbiota composition, metabolite profiles, and CVD incidence. These findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues, as well as the need for further investigations into the intricate mechanisms linking oral health, gut microbiota, and metabolic pathways in CVD development.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140914976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sinensetin protects against periodontitis through binding to Bach1 enhancing its ubiquitination degradation and improving oxidative stress Sinensetin 通过与 Bach1 结合,增强其泛素化降解并改善氧化应激,从而预防牙周炎
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-11 DOI: 10.1038/s41368-024-00305-z
Zhiyao Yuan, Junjie Li, Fuyu Xiao, Yu Wu, Zhiting Zhang, Jiahong Shi, Jun Qian, Xudong Wu, Fuhua Yan

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm. The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress. Sinensetin (Sin) is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities. Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms. We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells (PDLCs) under inflammatory conditions. Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo. By molecular docking, we identified Bach1 as a strong binding target of Sin, and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays. Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter, subsequently upregulating the expression of the key antioxidant factor HO-1. Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects. Additionally, we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1, thereby inducing HO-1 expression and inhibiting oxidative stress. Overall, Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

牙周炎是一种由龈下生物膜诱发的慢性炎症和免疫反应性疾病。由于过度的炎症反应和氧化应激,对易感患者的治疗效果往往不尽人意。西奈素(Sin)是一种具有抗炎和抗氧化活性的天然多甲氧基黄酮类化合物。我们的研究旨在探讨 Sin 对牙周炎的有益作用及其具体的分子机制。我们发现,在炎症条件下,Sin 可减轻氧化应激和牙周韧带细胞(PDLCs)的炎症水平。给结扎诱导的牙周炎模型大鼠服用 Sin 对体内牙周炎有保护作用。通过分子对接,我们发现Bach1是Sin的强结合靶点,并通过细胞热位移实验和免疫荧光实验进一步验证了这种结合。染色质免疫沉淀-定量聚合酶链反应结果也显示,Sin阻碍了Bach1与HMOX1启动子的结合,从而上调了关键抗氧化因子HO-1的表达。在敲除和过表达 Bach1 的进一步功能实验中,我们验证了 Bach1 是 Sin 发挥抗氧化作用的关键靶点。此外,我们还证明,Sin 通过增强 Bach1 的泛素化降解,促使 Bach1 的减少,从而诱导 HO-1 的表达,抑制氧化应激。总之,通过与 Bach1 的靶向结合,Sin 可以成为治疗牙周炎的一种有前途的候选药物。
{"title":"Sinensetin protects against periodontitis through binding to Bach1 enhancing its ubiquitination degradation and improving oxidative stress","authors":"Zhiyao Yuan, Junjie Li, Fuyu Xiao, Yu Wu, Zhiting Zhang, Jiahong Shi, Jun Qian, Xudong Wu, Fuhua Yan","doi":"10.1038/s41368-024-00305-z","DOIUrl":"https://doi.org/10.1038/s41368-024-00305-z","url":null,"abstract":"<p>Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm. The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress. Sinensetin (Sin) is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities. Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms. We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells (PDLCs) under inflammatory conditions. Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo. By molecular docking, we identified Bach1 as a strong binding target of Sin, and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays. Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter, subsequently upregulating the expression of the key antioxidant factor HO-1. Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects. Additionally, we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1, thereby inducing HO-1 expression and inhibiting oxidative stress. Overall, Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A 3D In-vitro model of the human dentine interface shows long-range osteoinduction from the dentine surface 人体牙本质界面的三维体外模型显示了牙本质表面的长程骨诱导作用
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-11 DOI: 10.1038/s41368-024-00298-9
William Macalester, Asme Boussahel, Rafael O. Moreno-Tortolero, Mark R. Shannon, Nicola West, Darryl Hill, Adam Perriman

Emerging regenerative cell therapies for alveolar bone loss have begun to explore the use of cell laden hydrogels for minimally invasive surgery to treat small and spatially complex maxilla-oral defects. However, the oral cavity presents a unique and challenging environment for in vivo bone tissue engineering, exhibiting both hard and soft periodontal tissue as well as acting as key biocenosis for many distinct microbial communities that interact with both the external environment and internal body systems, which will impact on cell fate and subsequent treatment efficacy. Herein, we design and bioprint a facile 3D in vitro model of a human dentine interface to probe the effect of the dentine surface on human mesenchymal stem cells (hMSCs) encapsulated in a microporous hydrogel bioink. We demonstrate that the dentine substrate induces osteogenic differentiation of encapsulated hMSCs, and that both dentine and β-tricalcium phosphate substrates stimulate extracellular matrix production and maturation at the gel-media interface, which is distal to the gel-substrate interface. Our findings demonstrate the potential for long-range effects on stem cells by mineralized surfaces during bone tissue engineering and provide a framework for the rapid development of 3D dentine-bone interface models.

针对牙槽骨缺失的新兴再生细胞疗法已开始探索使用含细胞的水凝胶进行微创手术,以治疗小型和空间复杂的上颌骨-口腔缺损。然而,口腔为体内骨组织工程学提供了一个独特而具有挑战性的环境,它同时表现出牙周软硬组织,也是许多不同微生物群落的关键生物栖息地,这些微生物群落与外部环境和体内系统相互作用,这将影响细胞的命运和随后的治疗效果。在此,我们设计并生物打印了一个简便的人体牙本质界面三维体外模型,以探究牙本质表面对包裹在微孔水凝胶生物墨水中的人体间充质干细胞(hMSCs)的影响。我们证明,牙本质基底可诱导封装的 hMSCs 成骨分化,而且牙本质和β-磷酸三钙基底都能刺激凝胶-介质界面(即凝胶-基底界面的远端)上细胞外基质的生成和成熟。我们的研究结果表明,在骨组织工程过程中,矿化表面可能对干细胞产生长程影响,并为快速开发三维牙-骨界面模型提供了一个框架。
{"title":"A 3D In-vitro model of the human dentine interface shows long-range osteoinduction from the dentine surface","authors":"William Macalester, Asme Boussahel, Rafael O. Moreno-Tortolero, Mark R. Shannon, Nicola West, Darryl Hill, Adam Perriman","doi":"10.1038/s41368-024-00298-9","DOIUrl":"https://doi.org/10.1038/s41368-024-00298-9","url":null,"abstract":"<p>Emerging regenerative cell therapies for alveolar bone loss have begun to explore the use of cell laden hydrogels for minimally invasive surgery to treat small and spatially complex maxilla-oral defects. However, the oral cavity presents a unique and challenging environment for in vivo bone tissue engineering, exhibiting both hard and soft periodontal tissue as well as acting as key biocenosis for many distinct microbial communities that interact with both the external environment and internal body systems, which will impact on cell fate and subsequent treatment efficacy. Herein, we design and bioprint a facile 3D in vitro model of a human dentine interface to probe the effect of the dentine surface on human mesenchymal stem cells (hMSCs) encapsulated in a microporous hydrogel bioink. We demonstrate that the dentine substrate induces osteogenic differentiation of encapsulated hMSCs, and that both dentine and β-tricalcium phosphate substrates stimulate extracellular matrix production and maturation at the gel-media interface, which is distal to the gel-substrate interface. Our findings demonstrate the potential for long-range effects on stem cells by mineralized surfaces during bone tissue engineering and provide a framework for the rapid development of 3D dentine-bone interface models.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling 抑制 m1A 可通过下调 MYC/PD-L1 信号促进溶瘤病毒诱导的抗肿瘤免疫力
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-10 DOI: 10.1038/s41368-024-00304-0
Shujin Li, Tian Feng, Yuantong Liu, Qichao Yang, An Song, Shuo Wang, Jun Xie, Junjie Zhang, Bifeng Yuan, Zhijun Sun

N1-methyladenosine (m1A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels. Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.

N1-甲基腺苷(m1A)RNA甲基化是调节mRNA翻译的关键;然而,它在头颈部鳞状细胞癌(HNSCC)的发生、发展和免疫疗法反应中的作用在很大程度上仍然未知。我们利用 Tgfbr1 和 Pten 条件性基因敲除(2cKO)小鼠发现,口腔黏膜的肿瘤性转化伴随着 m1A 修饰水平的增加。对m1A相关基因的分析发现,TRMT61A是与癌症进展和不良预后相关的关键m1A基因。从机理上讲,TRMT61A介导的tRNA-m1A修饰促进了MYC蛋白的合成,上调了程序性死亡配体1(PD-L1)的表达。此外,用溶瘤性单纯疱疹病毒(oHSV)治疗的肿瘤中,m1A修饰水平也会升高,从而导致PD-L1的反应性上调。治疗性 m1A 抑制可维持 oHSV 诱导的抗肿瘤免疫力并减少肿瘤生长,是一种很有前景的缓解抗药性策略。这些研究结果表明,m1A抑制剂可以通过减少PD-L1的表达来防止oHSV治疗后的免疫逃逸,提供了一种相互促进的联合免疫疗法方法。
{"title":"m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling","authors":"Shujin Li, Tian Feng, Yuantong Liu, Qichao Yang, An Song, Shuo Wang, Jun Xie, Junjie Zhang, Bifeng Yuan, Zhijun Sun","doi":"10.1038/s41368-024-00304-0","DOIUrl":"https://doi.org/10.1038/s41368-024-00304-0","url":null,"abstract":"<p><i>N</i><sup>1</sup>-methyladenosine (m<sup>1</sup>A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using <i>Tgfbr1</i> and <i>Pten</i> conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m<sup>1</sup>A modification levels. Analysis of m<sup>1</sup>A-associated genes identified TRMT61A as a key m<sup>1</sup>A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m<sup>1</sup>A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m<sup>1</sup>A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m<sup>1</sup>A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m<sup>1</sup>A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fully automatic AI segmentation of oral surgery-related tissues based on cone beam computed tomography images 基于锥形束计算机断层扫描图像的口腔手术相关组织全自动人工智能分割
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-08 DOI: 10.1038/s41368-024-00294-z
Yu Liu, Rui Xie, Lifeng Wang, Hongpeng Liu, Chen Liu, Yimin Zhao, Shizhu Bai, Wenyong Liu

Accurate segmentation of oral surgery-related tissues from cone beam computed tomography (CBCT) images can significantly accelerate treatment planning and improve surgical accuracy. In this paper, we propose a fully automated tissue segmentation system for dental implant surgery. Specifically, we propose an image preprocessing method based on data distribution histograms, which can adaptively process CBCT images with different parameters. Based on this, we use the bone segmentation network to obtain the segmentation results of alveolar bone, teeth, and maxillary sinus. We use the tooth and mandibular regions as the ROI regions of tooth segmentation and mandibular nerve tube segmentation to achieve the corresponding tasks. The tooth segmentation results can obtain the order information of the dentition. The corresponding experimental results show that our method can achieve higher segmentation accuracy and efficiency compared to existing methods. Its average Dice scores on the tooth, alveolar bone, maxillary sinus, and mandibular canal segmentation tasks were 96.5%, 95.4%, 93.6%, and 94.8%, respectively. These results demonstrate that it can accelerate the development of digital dentistry.

从锥束计算机断层扫描(CBCT)图像中对口腔手术相关组织进行精确分割,可大大加快治疗计划的制定并提高手术的准确性。在本文中,我们提出了一种用于牙科植入手术的全自动组织分割系统。具体来说,我们提出了一种基于数据分布直方图的图像预处理方法,它可以自适应地处理不同参数的 CBCT 图像。在此基础上,我们使用骨分割网络获得牙槽骨、牙齿和上颌窦的分割结果。我们将牙齿和下颌区域作为牙齿分割和下颌神经管分割的 ROI 区域,以实现相应的任务。牙齿分割结果可以获得牙列的顺序信息。相应的实验结果表明,与现有方法相比,我们的方法能达到更高的分割精度和效率。其在牙齿、牙槽骨、上颌窦和下颌管分割任务上的平均 Dice 分数分别为 96.5%、95.4%、93.6% 和 94.8%。这些结果表明,它可以加速数字牙科的发展。
{"title":"Fully automatic AI segmentation of oral surgery-related tissues based on cone beam computed tomography images","authors":"Yu Liu, Rui Xie, Lifeng Wang, Hongpeng Liu, Chen Liu, Yimin Zhao, Shizhu Bai, Wenyong Liu","doi":"10.1038/s41368-024-00294-z","DOIUrl":"https://doi.org/10.1038/s41368-024-00294-z","url":null,"abstract":"<p>Accurate segmentation of oral surgery-related tissues from cone beam computed tomography (CBCT) images can significantly accelerate treatment planning and improve surgical accuracy. In this paper, we propose a fully automated tissue segmentation system for dental implant surgery. Specifically, we propose an image preprocessing method based on data distribution histograms, which can adaptively process CBCT images with different parameters. Based on this, we use the bone segmentation network to obtain the segmentation results of alveolar bone, teeth, and maxillary sinus. We use the tooth and mandibular regions as the ROI regions of tooth segmentation and mandibular nerve tube segmentation to achieve the corresponding tasks. The tooth segmentation results can obtain the order information of the dentition. The corresponding experimental results show that our method can achieve higher segmentation accuracy and efficiency compared to existing methods. Its average Dice scores on the tooth, alveolar bone, maxillary sinus, and mandibular canal segmentation tasks were 96.5%, 95.4%, 93.6%, and 94.8%, respectively. These results demonstrate that it can accelerate the development of digital dentistry.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK 苯乙双胍通过 NIBAN1 和 DDIT4 激活 ER 应激,促进口腔鳞状细胞癌细胞自噬性死亡,而与 AMPK 无关
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-05-08 DOI: 10.1038/s41368-024-00297-w
Dexuan Zhuang, Shuangshuang Wang, Huiting Deng, Yuxin Shi, Chang Liu, Xue Leng, Qun Zhang, Fuxiang Bai, Bin Zheng, Jing Guo, Xunwei Wu

The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

口腔鳞状细胞癌(OSCC)的有效临床治疗仍然是一项挑战,需要开发有效的新药。与二甲双胍相比,苯乙双胍对不同肿瘤具有更强的抗肿瘤活性,但苯乙双胍对OSCC细胞的影响却鲜为人知。我们发现苯乙双胍可抑制OSCC细胞增殖,促进OSCC细胞自噬和凋亡,从而显著抑制OSCC细胞在体内和体外的生长。RNA-seq分析显示,自噬通路是苯福明的主要靶点,并发现了两个新靶点DDIT4(DNA损伤诱导转录本4)和NIBAN1(尼班凋亡调节因子1)。我们发现苯福明能明显诱导DDIT4和NIBAN1的表达,从而促进OSCC的自噬。此外,苯乙福明诱导的DDIT4和NIBAN1的表达增强并未被AMPK的敲除所阻断,但却被苯乙福明处理OSCC细胞时诱导的转录因子ATF4(活化转录因子4)的敲除所抑制。这些结果从机理上揭示了苯福明引发内质网(ER)应激激活PERK(蛋白激酶R样ER激酶),PERK使过渡初始因子eIF2磷酸化,eIF2磷酸化增加导致ATF4翻译增加。综上所述,我们发现苯乙双胍能诱导其新靶点DDIT4,尤其是NIBAN1,促进细胞自噬和凋亡,从而抑制OSCC细胞的生长。我们的研究为苯福明在未来治疗 OSCC 的潜在临床应用提供了支持。
{"title":"Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK","authors":"Dexuan Zhuang, Shuangshuang Wang, Huiting Deng, Yuxin Shi, Chang Liu, Xue Leng, Qun Zhang, Fuxiang Bai, Bin Zheng, Jing Guo, Xunwei Wu","doi":"10.1038/s41368-024-00297-w","DOIUrl":"https://doi.org/10.1038/s41368-024-00297-w","url":null,"abstract":"<p>The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration 支架诱导缝合间充质再生的转录组和细胞解码
IF 14.9 1区 医学 Q1 Dentistry Pub Date : 2024-04-23 DOI: 10.1038/s41368-024-00295-y
Jiayi Wu, Feifei Li, Peng Yu, Changhao Yu, Chuyi Han, Yitian Wang, Fanyuan Yu, Ling Ye

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.

精确协调细胞命运决定是基于支架的骨骼再生成功的基础。尽管对矿化实质组织重建进行了广泛研究,但再生和维持钙骨内未分化间充质仍极具挑战性,进展有限。现有知识证明,重建缝间充质干细胞龛对避免严重的脑损伤甚至系统性损伤是不可或缺的。但迄今为止,仍缺乏有前景的治疗生物材料/支架。究其原因,在于缺乏了解支架细胞命运调控的基础知识和方法证据。为了解决这些问题,在本研究中,我们系统地研究了不同类型的常用腓骨支架对细胞命运的决定作用和转录组机制。我们的数据阐明了无支架移植的自然过程,并展示了不同支架如何改变体内细胞反应。接下来,我们确定了一种可行的支架--聚乳酸电纺丝膜(PLA),它能精确控制间充质的生长和自我更新,在缺损中心重建非骨质生成的缝合线样组织,同时支持与缺损骨边缘的适当骨整合。特别是,该研究通过转录组分析,破译了 PLA 精心策划的细胞命运决定的细胞机制。这项研究首次从细胞角度解读了缝合骨复合体缺损愈合过程中支架的命运调控,为临床医生再生此类复杂损伤提供了可能的选择。
{"title":"Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration","authors":"Jiayi Wu, Feifei Li, Peng Yu, Changhao Yu, Chuyi Han, Yitian Wang, Fanyuan Yu, Ling Ye","doi":"10.1038/s41368-024-00295-y","DOIUrl":"https://doi.org/10.1038/s41368-024-00295-y","url":null,"abstract":"<p>Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.</p>","PeriodicalId":14191,"journal":{"name":"International Journal of Oral Science","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
International Journal of Oral Science
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