Cell reportsPub Date : 2024-11-18DOI: 10.1016/j.celrep.2024.114994
Jessie M Barra, Rob A Robino, Roberto Castro-Gutierrez, James Proia, Holger A Russ, Leonardo M R Ferreira
{"title":"Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells.","authors":"Jessie M Barra, Rob A Robino, Roberto Castro-Gutierrez, James Proia, Holger A Russ, Leonardo M R Ferreira","doi":"10.1016/j.celrep.2024.114994","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114994","url":null,"abstract":"<p><p>Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114994"},"PeriodicalIF":7.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674706","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}
Cell reportsPub Date : 2024-11-18DOI: 10.1016/j.celrep.2024.114976
Courtney Matheny-Rabun, Sneha S Mokashi, Silvia Radenkovic, Kali Wiggins, Lynn Dukes-Rimsky, Peggi Angel, Bart Ghesquiere, Tamas Kozicz, Richard Steet, Eva Morava, Heather Flanagan-Steet
{"title":"O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder.","authors":"Courtney Matheny-Rabun, Sneha S Mokashi, Silvia Radenkovic, Kali Wiggins, Lynn Dukes-Rimsky, Peggi Angel, Bart Ghesquiere, Tamas Kozicz, Richard Steet, Eva Morava, Heather Flanagan-Steet","doi":"10.1016/j.celrep.2024.114976","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114976","url":null,"abstract":"<p><p>Core components of the N-glycosylation pathway are known, but the metabolic and post-translational mechanisms regulating this pathway in normal and disease states remain elusive. Using a multi-omic approach in zebrafish, we discovered a mechanism whereby O-GlcNAcylation directly impacts the expression and abundance of two rate-limiting proteins in the N-linked glycosylation pathway. We show in a model of an inherited glycosylation disorder PMM2-CDG, congenital disorders of glycosylation that phosphomannomutase deficiency is associated with increased levels of UDP-GlcNAc and protein O-GlcNAcylation. O-GlcNAc modification increases the transcript and protein abundance of both NgBR and Dpagt1 in pmm2<sup>m/m</sup> mutants. Modulating O-GlcNAc levels, NgBR abundance, or Dpagt1 activity exacerbated the cartilage phenotypes in pmm2 mutants, suggesting that O-GlcNAc-mediated increases in the N-glycosylation machinery are protective. These findings highlight nucleotide-sugar donors as metabolic sensors that regulate two spatially separated glycosylation pathways, demonstrating how their coordination is relevant to disease severity in the most common congenital disorder of glycosylation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114976"},"PeriodicalIF":7.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674792","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}
Cell reportsPub Date : 2024-11-14DOI: 10.1016/j.celrep.2024.114927
Yuting Lu, Jana Travnickova, Mihaly Badonyi, Florian Rambow, Andrea Coates, Zaid Khan, Jair Marques, Laura C Murphy, Pablo Garcia-Martinez, Richard Marais, Pakavarin Louphrasitthiphol, Alex H Y Chan, Christopher J Schofield, Alex von Kriegsheim, Joseph A Marsh, Valeria Pavet, Owen J Sansom, Robert S Illingworth, E Elizabeth Patton
{"title":"ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.","authors":"Yuting Lu, Jana Travnickova, Mihaly Badonyi, Florian Rambow, Andrea Coates, Zaid Khan, Jair Marques, Laura C Murphy, Pablo Garcia-Martinez, Richard Marais, Pakavarin Louphrasitthiphol, Alex H Y Chan, Christopher J Schofield, Alex von Kriegsheim, Joseph A Marsh, Valeria Pavet, Owen J Sansom, Robert S Illingworth, E Elizabeth Patton","doi":"10.1016/j.celrep.2024.114927","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114927","url":null,"abstract":"","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114927"},"PeriodicalIF":7.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638493","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}
{"title":"Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.","authors":"Eriko Deguchi, Shuhao Lin, Daiki Hirayama, Kimiya Matsuda, Akira Tanave, Kenta Sumiyama, Shinya Tsukiji, Tetsuhisa Otani, Mikio Furuse, Alexander Sorkin, Michiyuki Matsuda, Kenta Terai","doi":"10.1016/j.celrep.2024.114986","DOIUrl":"10.1016/j.celrep.2024.114986","url":null,"abstract":"<p><p>Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114986"},"PeriodicalIF":7.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638495","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}
{"title":"Engineered IscB-ωRNA system with improved base editing efficiency for disease correction via single AAV delivery in mice.","authors":"Ruochen Guo, Xiaozhi Sun, Feizuo Wang, Dingyi Han, Qiaoxia Yang, Hua Gao, Zhifang Li, Zhuang Shao, Jinqi Shi, Rongrong Yang, Xiaona Huo, Junda Yan, Guoling Li, Qingquan Xiao, Yuanhua Liu, Senfeng Zhang, Xinyu Liu, Yingsi Zhou, Leyun Wang, Chunyi Hu, Chunlong Xu","doi":"10.1016/j.celrep.2024.114973","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114973","url":null,"abstract":"<p><p>IscBs, as hypercompact ancestry proteins of Cas9 nuclease, are suitable for in vivo gene editing via single adeno-associated virus (AAV) delivery. Due to the low activity of natural IscBs in eukaryotic cells, recent studies have been focusing on improving OgeuIscB's gene editing efficiency via protein engineering. However, in vivo gene editing efficacy of IscBs for disease correction remained to be demonstrated. Here, we showed effective gene knockout and base editing in mouse embryos. To further improve IscB activity, we performed systematic engineering of IscB-associated ωRNA and identified a variant, ωRNA<sup>∗</sup>-v2, with enhanced gene editing efficiency. Furthermore, our study demonstrated the efficacy of an engineered IscB-ωRNA system for robust gene knockout and base editing in vivo. Single AAV delivery of IscB-derived cytosine and adenine base editors achieved disease correction in a mouse model of tyrosinemia. Therefore, our results indicated the great potential of miniature IscBs for developing single-AAV-based gene editing therapeutics.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114973"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615922","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}
Cell reportsPub Date : 2024-11-13DOI: 10.1016/j.celrep.2024.114979
Amy L Wilson, Laura R Moffitt, Brittany R Doran, Bashira Basri, Jennie Do, Thomas W Jobling, Magdalena Plebanski, Andrew N Stephens, Maree Bilandzic
{"title":"Leader cells promote immunosuppression to drive ovarian cancer progression in vivo.","authors":"Amy L Wilson, Laura R Moffitt, Brittany R Doran, Bashira Basri, Jennie Do, Thomas W Jobling, Magdalena Plebanski, Andrew N Stephens, Maree Bilandzic","doi":"10.1016/j.celrep.2024.114979","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114979","url":null,"abstract":"<p><p>Over 75% of patients with ovarian cancer present with late-stage disease, often accompanied by extensive metastasis. The metastatic cascade is driven by a sub-population of transcriptionally plastic cells known as \"leader cells\" (LCs), which play a critical role in collective invasion yet remain poorly understood. LCs are marked by the expression of keratin-14 (KRT14), which determines their migratory and invasive capacity in ovarian cancer. This study demonstrates that KRT14+ LCs promote tumor progression through immunosuppression and immune privilege in vivo. In the ID8 syngeneic epithelial ovarian cancer mouse model, tumor-specific loss of KRT14+ LCs impairs tumor progression and metastatic spread without affecting cellular proliferation. Immune profiling shows reduced immunosuppressive regulatory T cells (Tregs) and M2 macrophages and improved CD8<sup>+</sup> T cell/Treg ratios in LC knockout (LC<sup>KO</sup>) mice. Conversely, forced LC overexpression accelerates metastasis and increases the secretion of immunosuppressive chemokines, such as CCL22 and CCL5, highlighting the role of KRT14+ LCs in immune suppression and metastatic progression.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114979"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614408","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}
Cell reportsPub Date : 2024-11-13DOI: 10.1016/j.celrep.2024.114967
A S M Zisanur Rahman, Egor A Syroegin, Julieta Novomisky Nechcoff, Archit Devarajan, Yury S Polikanov, Silvia T Cardona
{"title":"Rationally designed pooled CRISPRi-seq uncovers an inhibitor of bacterial peptidyl-tRNA hydrolase.","authors":"A S M Zisanur Rahman, Egor A Syroegin, Julieta Novomisky Nechcoff, Archit Devarajan, Yury S Polikanov, Silvia T Cardona","doi":"10.1016/j.celrep.2024.114967","DOIUrl":"10.1016/j.celrep.2024.114967","url":null,"abstract":"<p><p>Bacterial mutant libraries with downregulated antibiotic targets are useful tools for elucidating the mechanisms of action of antibacterial compounds, a pivotal step in antibiotic discovery. However, achieving genomic coverage of antibacterial targets poses a challenge due to the uneven proliferation of knockdown mutants during pooled growth, leading to the unintended loss of important targets. To overcome this issue, we constructed an arrayed essential gene mutant library (EGML) in the antibiotic-resistant bacterium Burkholderia cenocepacia using CRISPR interference (CRISPRi). By modeling depletion levels and adjusting knockdown mutant inocula, we rationally designed and optimized a CRISPR interference-mediated pooled library of essential genes (CIMPLE) approaching coverage of the bacterial essential genome with mutant sensitization. We exposed CIMPLE to an uncharacterized bacterial growth inhibitor structurally different from antibiotics and discovered that it inhibits the essential peptidyl-tRNA hydrolase. Overall, CIMPLE leverages the advantages of arrayed and pooled CRISPRi libraries to uncover unexplored targets for antibiotic action.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114967"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615213","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}
Cell reportsPub Date : 2024-11-13DOI: 10.1016/j.celrep.2024.114975
Neuza S Sousa, Marta Bica, Margarida F Brás, Ana C Sousa, Inês B Antunes, Isabel A Encarnação, Tiago M Costa, Inês B Martins, Nuno L Barbosa-Morais, Pedro Sousa-Victor, Joana Neves
{"title":"The immune landscape of murine skeletal muscle regeneration and aging.","authors":"Neuza S Sousa, Marta Bica, Margarida F Brás, Ana C Sousa, Inês B Antunes, Isabel A Encarnação, Tiago M Costa, Inês B Martins, Nuno L Barbosa-Morais, Pedro Sousa-Victor, Joana Neves","doi":"10.1016/j.celrep.2024.114975","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114975","url":null,"abstract":"<p><p>Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging; however, the contribution of immune aging to regenerative failure is just starting to be explored. Here, we apply a strategy combining single-cell RNA sequencing with flow cytometry, histological analysis, and functional assays to perform a complete analysis of the immune environment of the aged regenerating skeletal muscle on a time course following injury with single-cell resolution. Our results reveal an unanticipated complexity and functional heterogeneity in immune populations within the skeletal muscle that have been regarded as homogeneous. Furthermore, we uncover a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a set of potential targets to improve skeletal muscle health and regenerative capacity in aging.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114975"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615392","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}
Cell reportsPub Date : 2024-11-13DOI: 10.1016/j.celrep.2024.114977
Neža Cankar, Natalie Beschorner, Anastasia Tsopanidou, Filippa L Qvist, Ana R Colaço, Mie Andersen, Celia Kjaerby, Christine Delle, Marius Lambert, Filip Mundt, Pia Weikop, Mathias Jucker, Matthias Mann, Niels Henning Skotte, Maiken Nedergaard
{"title":"Sleep deprivation leads to non-adaptive alterations in sleep microarchitecture and amyloid-β accumulation in a murine Alzheimer model.","authors":"Neža Cankar, Natalie Beschorner, Anastasia Tsopanidou, Filippa L Qvist, Ana R Colaço, Mie Andersen, Celia Kjaerby, Christine Delle, Marius Lambert, Filip Mundt, Pia Weikop, Mathias Jucker, Matthias Mann, Niels Henning Skotte, Maiken Nedergaard","doi":"10.1016/j.celrep.2024.114977","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114977","url":null,"abstract":"<p><p>Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer's disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer's disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer's disease.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114977"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615372","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}
Cell reportsPub Date : 2024-11-13DOI: 10.1016/j.celrep.2024.114969
Gerben Marsman, Xuhui Zheng, Dora Čerina, Keenan A Lacey, Menghan Liu, Daniel Humme, Christian Goosmann, Volker Brinkmann, C J Harbort, Victor J Torres, Arturo Zychlinsky
{"title":"Histone H1 kills MRSA.","authors":"Gerben Marsman, Xuhui Zheng, Dora Čerina, Keenan A Lacey, Menghan Liu, Daniel Humme, Christian Goosmann, Volker Brinkmann, C J Harbort, Victor J Torres, Arturo Zychlinsky","doi":"10.1016/j.celrep.2024.114969","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114969","url":null,"abstract":"<p><p>The antimicrobial activity of histones was discovered in the 1940s, but their mechanism of action is not fully known. Here we show that methicillin-resistant Staphylococcus aureus (MRSA) is susceptible to histone H1 (H1), even in the presence of divalent cations and serum. Through selective evolution and a genome-wide screen of a transposon library, as well as physiological and pharmacological experiments, we elucidated how H1 kills MRSA. We show that H1 first binds to wall teichoic acids with high affinity. Once bound, H1 requires a potentiated membrane and a metabolically active bacterium to permeabilize the membrane and enter the cell. Upon entry, H1 accumulates intracellularly, in close association with the bacterial DNA. Of note, anti-H1 antibodies inhibit neutrophil extracellular trap killing of MRSA. Moreover, H1 colocalizes with bacterial DNA in abscess samples of MRSA-infected patients, suggesting a role for H1 in combating MRSA in vivo.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114969"},"PeriodicalIF":7.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638494","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
