Pub Date : 2025-01-03DOI: 10.1016/j.devcel.2024.12.019
Laura R. Lee, Bruno Guillotin, Ramin Rahni, Chanel Hutchison, Bénédicte Desvoyes, Crisanto Gutierrez, Kenneth D. Birnbaum
The plasticity of plant cells underlies their wide capacity to regenerate, with increasing evidence in plants and animals implicating cell-cycle dynamics in cellular reprogramming. To investigate the cell cycle during cellular reprogramming, we developed a comprehensive set of cell-cycle-phase markers in the Arabidopsis root. Using single-cell RNA sequencing profiles and live imaging during regeneration, we found that a subset of cells near an ablation injury dramatically increases division rate by truncating G1 phase. Cells in G1 undergo a transient nuclear peak of glutathione (GSH) prior to coordinated entry into S phase, followed by rapid divisions and cellular reprogramming. A symplastic block of the ground tissue impairs regeneration, which is rescued by exogenous GSH. We propose a model in which GSH from the outer tissues is released upon injury, licensing an exit from G1 near the wound to induce rapid cell division and reprogramming.
{"title":"Glutathione accelerates the cell cycle and cellular reprogramming in plant regeneration","authors":"Laura R. Lee, Bruno Guillotin, Ramin Rahni, Chanel Hutchison, Bénédicte Desvoyes, Crisanto Gutierrez, Kenneth D. Birnbaum","doi":"10.1016/j.devcel.2024.12.019","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.019","url":null,"abstract":"The plasticity of plant cells underlies their wide capacity to regenerate, with increasing evidence in plants and animals implicating cell-cycle dynamics in cellular reprogramming. To investigate the cell cycle during cellular reprogramming, we developed a comprehensive set of cell-cycle-phase markers in the Arabidopsis root. Using single-cell RNA sequencing profiles and live imaging during regeneration, we found that a subset of cells near an ablation injury dramatically increases division rate by truncating G1 phase. Cells in G1 undergo a transient nuclear peak of glutathione (GSH) prior to coordinated entry into S phase, followed by rapid divisions and cellular reprogramming. A symplastic block of the ground tissue impairs regeneration, which is rescued by exogenous GSH. We propose a model in which GSH from the outer tissues is released upon injury, licensing an exit from G1 near the wound to induce rapid cell division and reprogramming.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"34 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The exchange of molecular information across kingdoms is crucial for the survival of both plants and their pathogens. Recent research has identified that plants transfer their small RNAs and microRNAs into fungal pathogens to suppress infection. However, whether and how plants send defense proteins into pathogens remains unknown. Here, we report that rice (Oryza sativa) plants package defense proteins into extracellular vesicles (EVs) and deliver them to the fungal pathogen Rhizoctonia solani. These EVs, enriched with host defense proteins, are internalized by the fungal cells. Reducing the transfer of host defense proteins via EVs results in increased disease susceptibility. Furthermore, the overexpression of host defense proteins in either rice plants or the fungal cells reduced the infection. Therefore, plants use EVs to send defense proteins into fungal pathogens, thereby combating infection. This mechanism represents a form of protein exchange between plants and pathogens, which contributes to reducing crop diseases.
{"title":"Rice extracellular vesicles send defense proteins into fungus Rhizoctonia solani to reduce disease","authors":"Yifan Huang, Wei Li, Tiangu Liu, Xiaoli Lin, Yanhui Xia, Wenjing Zhu, Hailing Jin, Qiang Cai","doi":"10.1016/j.devcel.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.020","url":null,"abstract":"The exchange of molecular information across kingdoms is crucial for the survival of both plants and their pathogens. Recent research has identified that plants transfer their small RNAs and microRNAs into fungal pathogens to suppress infection. However, whether and how plants send defense proteins into pathogens remains unknown. Here, we report that rice (<em>Oryza sativa</em>) plants package defense proteins into extracellular vesicles (EVs) and deliver them to the fungal pathogen <em>Rhizoctonia solani</em>. These EVs, enriched with host defense proteins, are internalized by the fungal cells. Reducing the transfer of host defense proteins via EVs results in increased disease susceptibility. Furthermore, the overexpression of host defense proteins in either rice plants or the fungal cells reduced the infection. Therefore, plants use EVs to send defense proteins into fungal pathogens, thereby combating infection. This mechanism represents a form of protein exchange between plants and pathogens, which contributes to reducing crop diseases.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"18 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1016/j.devcel.2024.12.014
Jackie L. Norrie, Marybeth S. Lupo, Danielle R. Little, Abbas Shirinifard, Akhilesh Mishra, Qiong Zhang, Natalie Geiger, Daniel Putnam, Nadhir Djekidel, Cody Ramirez, Beisi Xu, Jacob M. Dundee, Jiang Yu, Xiang Chen, Michael A. Dyer
Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development correlate with changes in gene expression. However, those studies lack cellular resolution. Here, we integrate single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) with bulk data to identify cell-type-specific changes in chromatin structure during human and murine development. Although promoter activity is correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in Müller glial cells, which function to maintain retinal homeostasis and respond to stress, injury, or disease. We refer to these as “pliancy genes” because they allow the Müller glia to rapidly change their gene expression and cellular state in response to retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are important for regulating inflammation in the murine retina in vivo.
{"title":"Latent epigenetic programs in Müller glia contribute to stress and disease response in the retina","authors":"Jackie L. Norrie, Marybeth S. Lupo, Danielle R. Little, Abbas Shirinifard, Akhilesh Mishra, Qiong Zhang, Natalie Geiger, Daniel Putnam, Nadhir Djekidel, Cody Ramirez, Beisi Xu, Jacob M. Dundee, Jiang Yu, Xiang Chen, Michael A. Dyer","doi":"10.1016/j.devcel.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.014","url":null,"abstract":"Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development correlate with changes in gene expression. However, those studies lack cellular resolution. Here, we integrate single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) with bulk data to identify cell-type-specific changes in chromatin structure during human and murine development. Although promoter activity is correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in Müller glial cells, which function to maintain retinal homeostasis and respond to stress, injury, or disease. We refer to these as “pliancy genes” because they allow the Müller glia to rapidly change their gene expression and cellular state in response to retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are important for regulating inflammation in the murine retina <em>in vivo</em>.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"32 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Germ granules, or nuage, are RNA-rich condensates that are often docked on the cytoplasmic surface of germline nuclei. C. elegans perinuclear germ granules are composed of multiple subcompartments, including P granules, Mutator foci, Z granules, SIMR foci, P -bodies, and E granules. Although many perinuclear proteins have been identified, their precise localization within the subcompartments of the germ granule is still unclear. Here, we systematically labeled perinuclear proteins with fluorescent tags via CRISPR-Cas9 technology. Using this nematode strain library, we identified a series of proteins localized in Z or E granules and extended the characterization of the D granule. Finally, we found that the LOTUS domain protein MIP-1/EGGD-1 regulated the multiphase organization of the germ granule. Overall, our work identified the germ-granule architecture and redefined the compartmental localization of perinuclear proteins. Additionally, the library of genetically modified nematode strains will facilitate research on C. elegans germ granules.
{"title":"Compartmentalized localization of perinuclear proteins within germ granules in C. elegans","authors":"Xiaona Huang, Xuezhu Feng, Yong-Hong Yan, Demin Xu, Ke Wang, Chengming Zhu, Meng-Qiu Dong, Xinya Huang, Shouhong Guang, Xiangyang Chen","doi":"10.1016/j.devcel.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.016","url":null,"abstract":"Germ granules, or nuage, are RNA-rich condensates that are often docked on the cytoplasmic surface of germline nuclei. <em>C. elegans</em> perinuclear germ granules are composed of multiple subcompartments, including P granules, <em>M</em><em>utator</em> foci, Z granules, SIMR foci, P -bodies, and E granules. Although many perinuclear proteins have been identified, their precise localization within the subcompartments of the germ granule is still unclear. Here, we systematically labeled perinuclear proteins with fluorescent tags via CRISPR-Cas9 technology. Using this nematode strain library, we identified a series of proteins localized in Z or E granules and extended the characterization of the D granule. Finally, we found that the LOTUS domain protein MIP-1/EGGD-1 regulated the multiphase organization of the germ granule. Overall, our work identified the germ-granule architecture and redefined the compartmental localization of perinuclear proteins. Additionally, the library of genetically modified nematode strains will facilitate research on <em>C. elegans</em> germ granules.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"5 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1016/j.devcel.2024.12.012
Daxiao Sun, Xueping Zhao, Tina Wiegand, Cecilie Martin-Lemaitre, Tom Borianne, Lennart Kleinschmidt, Stephan W. Grill, Anthony A. Hyman, Christoph Weber, Alf Honigmann
Tight junctions play an essential role in sealing tissues, by forming belts of adhesion strands around cellular perimeters. Recent work has shown that the condensation of ZO1 scaffold proteins is required for tight junction assembly. However, the mechanisms by which junctional condensates initiate at cell-cell contacts and elongate around cell perimeters remain unknown. Combining biochemical reconstitutions and live-cell imaging of MDCKII tissue, we found that tight junction belt formation is driven by adhesion receptor-mediated ZO1 surface condensation coupled to local actin polymerization. Adhesion receptor oligomerization provides the signal for surface binding and local condensation of ZO1 at the cell membrane. Condensation produces a molecular scaffold that selectively enriches junctional proteins. Finally, ZO1 condensates directly facilitate local actin polymerization and filament bundling, driving the elongation into a continuous tight junction belt. More broadly, our work identifies how cells couple surface condensation with cytoskeleton organization to assemble and structure adhesion complexes.
{"title":"Assembly of tight junction belts by ZO1 surface condensation and local actin polymerization","authors":"Daxiao Sun, Xueping Zhao, Tina Wiegand, Cecilie Martin-Lemaitre, Tom Borianne, Lennart Kleinschmidt, Stephan W. Grill, Anthony A. Hyman, Christoph Weber, Alf Honigmann","doi":"10.1016/j.devcel.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.012","url":null,"abstract":"Tight junctions play an essential role in sealing tissues, by forming belts of adhesion strands around cellular perimeters. Recent work has shown that the condensation of ZO1 scaffold proteins is required for tight junction assembly. However, the mechanisms by which junctional condensates initiate at cell-cell contacts and elongate around cell perimeters remain unknown. Combining biochemical reconstitutions and live-cell imaging of MDCKII tissue, we found that tight junction belt formation is driven by adhesion receptor-mediated ZO1 surface condensation coupled to local actin polymerization. Adhesion receptor oligomerization provides the signal for surface binding and local condensation of ZO1 at the cell membrane. Condensation produces a molecular scaffold that selectively enriches junctional proteins. Finally, ZO1 condensates directly facilitate local actin polymerization and filament bundling, driving the elongation into a continuous tight junction belt. More broadly, our work identifies how cells couple surface condensation with cytoskeleton organization to assemble and structure adhesion complexes.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"1 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1016/j.devcel.2024.12.015
Alexandra L. Nguyen, Eric M. Smith, Iain M. Cheeseman
The cohesin complex is critical for genome organization and regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a mediator of cohesin and genome integrity. We show that PRR12 interacts with NIPBL/MAU2 and the cohesin complex, and that the loss of PRR12 results in reduced cohesin localization and a substantial increase in DNA double-strand breaks in mouse NIH-3T3 cells. Additionally, PRR12 co-localizes with NIPBL to sites of DNA damage in a NIPBL and cohesin-dependent manner. We find that the requirement for PRR12 differs across cell lines, with human HeLa cells exhibiting reduced sensitivity to PRR12 loss compared with mouse NIH-3T3 cells, indicating context-specific roles. Together, our work identifies PRR12 as a regulator of cohesin and provides insight into how genome integrity is maintained across diverse cellular contexts.
{"title":"Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity","authors":"Alexandra L. Nguyen, Eric M. Smith, Iain M. Cheeseman","doi":"10.1016/j.devcel.2024.12.015","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.015","url":null,"abstract":"The cohesin complex is critical for genome organization and regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a mediator of cohesin and genome integrity. We show that PRR12 interacts with NIPBL/MAU2 and the cohesin complex, and that the loss of PRR12 results in reduced cohesin localization and a substantial increase in DNA double-strand breaks in mouse NIH-3T3 cells. Additionally, PRR12 co-localizes with NIPBL to sites of DNA damage in a NIPBL and cohesin-dependent manner. We find that the requirement for PRR12 differs across cell lines, with human HeLa cells exhibiting reduced sensitivity to PRR12 loss compared with mouse NIH-3T3 cells, indicating context-specific roles. Together, our work identifies PRR12 as a regulator of cohesin and provides insight into how genome integrity is maintained across diverse cellular contexts.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"48 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The neurotransmitter gamma-aminobutyric acid (GABA) has been thought to be involved in the development of some types of cancer. Yet, the de novo synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA, and that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and reveal a role for β-catenin in sensing GABA, which contributes to HCC metastasis.
{"title":"The de novo synthesis of GABA and its gene regulatory function control hepatocellular carcinoma metastasis","authors":"Li Li, Youli Kang, Running Cheng, Fangming Liu, Fujia Wu, Zizhao Liu, Junjie Kou, Zhenxi Zhang, Wei Li, Haitao Zhao, Xiaojing He, Wenjing Du","doi":"10.1016/j.devcel.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.007","url":null,"abstract":"The neurotransmitter gamma-aminobutyric acid (GABA) has been thought to be involved in the development of some types of cancer. Yet, the <em>de novo</em> synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA, and that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and reveal a role for β-catenin in sensing GABA, which contributes to HCC metastasis.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"21 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Strigolactone (SL) is a plant hormone required for plant development. DWARF53 (D53) functions as a transcription repressor in SL signaling. However, the role of D53 in cotton (Gossypium hirsutum, Gh) fiber development remains unclear. Here, we identify that GhD53 suppresses fiber elongation by repressing transcription of GhFAD3 genes, which control linolenic acid (C18:3) biosynthesis. Mechanistically, GhD53 interacts with SL-related transcriptional activate factor (GhSLRF) to prevent its binding on Omega-3 fatty acid desaturase gene (GhFAD3) promoters, thereby inhibiting GhFAD3 transcription. Upon SL exposure, GhD53 is degraded and leads to GhSLRF activation. This activation further promotes GhFAD3 transcription, C18:3 biosynthesis, and fiber elongation. Our findings identify the molecular mechanism of how SL controls cell elongation via D53 and offer potential strategies to improve cotton quality through SL application.
{"title":"Strigolactone promotes cotton fiber cell elongation by de-repressing DWARF53 on linolenic acid biosynthesis","authors":"Huiqin Wang, Liping Zhu, Mengyuan Fan, Shuangshuang Weng, Xin Zhou, Hanxuan Zhao, Yongcui Shen, Jiaquan Chai, Liyong Hou, Miaomiao Hao, Rezwan Tanvir, Ling Li, Guanghui Xiao","doi":"10.1016/j.devcel.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.009","url":null,"abstract":"Strigolactone (SL) is a plant hormone required for plant development. DWARF53 (D53) functions as a transcription repressor in SL signaling. However, the role of D53 in cotton (<em>Gossypium hirsutum</em>, Gh) fiber development remains unclear. Here, we identify that GhD53 suppresses fiber elongation by repressing transcription of <em>GhFAD3</em> genes, which control linolenic acid (C18:3) biosynthesis. Mechanistically, GhD53 interacts with SL-related transcriptional activate factor (GhSLRF) to prevent its binding on Omega-3 fatty acid desaturase gene (<em>GhFAD3</em>) promoters, thereby inhibiting <em>GhFAD3</em> transcription. Upon SL exposure, GhD53 is degraded and leads to GhSLRF activation. This activation further promotes <em>GhFAD3</em> transcription, C18:3 biosynthesis, and fiber elongation. Our findings identify the molecular mechanism of how SL controls cell elongation via D53 and offer potential strategies to improve cotton quality through SL application.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"20 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2low) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.
{"title":"HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis","authors":"Xiang Peng, Bin Sun, Chaohui Tang, Chengyu Shi, Xianwei Xie, Xueyu Wang, Dingsheng Jiang, Shuo Li, Ying Jia, Yani Wang, Huifang Tang, Shan Zhong, Minghui Piao, Xiuru Cui, Shenghao Zhang, Fan Wang, Yan Wang, Ruisi Na, Renping Huang, Yanan Jiang, Jinwei Tian","doi":"10.1016/j.devcel.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.011","url":null,"abstract":"Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2<sup>low</sup>) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"33 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.devcel.2024.12.010
Pin-Ji Lei, Katarina J. Ruscic, Kangsan Roh, Johanna J. Rajotte, Meghan J. O’Melia, Echoe M. Bouta, Marla Marquez, Ethel R. Pereira, Ashwin S. Kumar, Mohammad S. Razavi, Hengbo Zhou, Lutz Menzel, Liqing Huang, Heena Kumra, Mark Duquette, Peigen Huang, James W. Baish, Lance L. Munn, Natasza A. Kurpios, Jessalyn M. Ubellacker, Timothy P. Padera
Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.
{"title":"Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice","authors":"Pin-Ji Lei, Katarina J. Ruscic, Kangsan Roh, Johanna J. Rajotte, Meghan J. O’Melia, Echoe M. Bouta, Marla Marquez, Ethel R. Pereira, Ashwin S. Kumar, Mohammad S. Razavi, Hengbo Zhou, Lutz Menzel, Liqing Huang, Heena Kumra, Mark Duquette, Peigen Huang, James W. Baish, Lance L. Munn, Natasza A. Kurpios, Jessalyn M. Ubellacker, Timothy P. Padera","doi":"10.1016/j.devcel.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.010","url":null,"abstract":"Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"313 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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