Science Translational Medicine最新文献

{"title":"Sustained neutrophil extracellular traps cause fracture nonunion","authors":"Weixin Xie,&nbsp;Lilly-Charlotte Albertsen,&nbsp;Gesine Eis-Janzyk,&nbsp;Charlotte Kühlwein,&nbsp;Shan Jiang,&nbsp;Carsten Schlickewei,&nbsp;Holger Kleinertz,&nbsp;Ruben Augustin,&nbsp;Jan Sevecke,&nbsp;Saskia Schröder,&nbsp;Mayla Rickert,&nbsp;Samira Weisselberg,&nbsp;Antonia Donat,&nbsp;Haoyan Pan,&nbsp;Paul Knapstein,&nbsp;Verena Fischer,&nbsp;Melanie Haffner-Luntzer,&nbsp;Annika Bay,&nbsp;Michael Amling,&nbsp;Tim Rolvien,&nbsp;Matthias Krause,&nbsp;Thomas Renné,&nbsp;Karl-Heinz Frosch,&nbsp;Anke Baranowsky,&nbsp;Johannes Keller","doi":"10.1126/scitranslmed.adx9869","DOIUrl":"10.1126/scitranslmed.adx9869","url":null,"abstract":"<div >Fracture healing is an evolutionarily conserved process that depends on the complex interplay of osteogenic, angiogenic, and inflammatory responses. Impaired bone healing is observed in up to 10 to 15% of patients with fractures and can lead to nonunion, which is the absence of bone healing. Here, we explore a role of neutrophil extracellular traps (NETs) in fracture healing and their association with nonunion. In both mice and humans, skeletal injury triggers rapid but transient NET formation at the fracture site. The combined genetic deletion of enzymes essential for NET clearance, <i>DNase1</i> and <i>DNase1-like-3</i>, initially favors callus mineralization in the early healing phase. However, sustained NET elevation subsequently leads to impaired bone regeneration and fracture nonunion over the course of healing. Conversely, additional deletion of the NET-generating enzyme <i>Pad4</i> improves bone regeneration and lowers nonunion rates. Mechanistically, NETs up-regulate cGas-Sting signaling, thereby collapsing the formation of type-H vessels, which couple osteogenesis to angiogenesis in the fracture callus. Pharmacological inhibition of cGas-Sting restored type-H vessels, enhanced bone healing, and prevented nonunion in <i>DNase</i>-deficient but not <i>Pad4</i>-deficient mice. In patients, serum NET markers declined during normal healing but were elevated in nonunion, correlating with excessive NET and STING accumulation in the callus. Therapeutically, the inhibition of NET formation with the Pad4 inhibitor GSK484 or the promotion of NET clearance with dornase alfa (recombinant DNase1) accelerated bone repair and prevented nonunion in preclinical models. These findings identify sustained NETs as a disruptor of fracture healing and a potential target for enhancing bone regeneration.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue origins and immune correlates of viral rebound in SIV-infected rhesus macaques after ART discontinuation","authors":"Irena V. King,&nbsp;Malika Aid,&nbsp;Emek Kose,&nbsp;Taina T. Immonen,&nbsp;Charles A. Goodman,&nbsp;Christine M. Fennessey,&nbsp;Alessandro Colarusso,&nbsp;Victoria E. K. Walker-Sperling,&nbsp;Erica N. Borducchi,&nbsp;Romas Geleziunas,&nbsp;William J. Rinaldi,&nbsp;Melissa J. Ferguson,&nbsp;Louis J. Picker,&nbsp;Jeffrey D. Lifson,&nbsp;Brandon F. Keele,&nbsp;Dan H. Barouch","doi":"10.1126/scitranslmed.aeg7776","DOIUrl":"10.1126/scitranslmed.aeg7776","url":null,"abstract":"<div >Most persons living with HIV-1 who discontinue antiretroviral therapy (ART) demonstrate viral rebound, but the tissue-level events that lead to rebound viremia remain poorly understood. Here, we report the origin, dynamics, and correlates of viral rebound in 16 rhesus macaques (RMs) infected with molecularly barcoded SIVmac239M, treated with ART for 70 weeks, and necropsied on day 12 after ART discontinuation. Barcode analysis of plasma during daily post-ART sampling identified 1 to 38 rebounding viral lineages per animal, with a mean of 2.4 lineages contributing to initial rebound viremia. Analysis of barcode viral RNA expression in tissues revealed presumptive anatomic origin sites for 56 of 175 rebounding viral lineages, with enrichment in the gastrointestinal (GI) tract and GI-associated lymph nodes by mixed-effects logistic regression. Daily transcriptomic and proteomic profiling in peripheral blood after ART discontinuation showed up-regulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism before detectable rebound viremia. These data show that viral rebound is initiated by oligofocal tissue expansion of a limited number of clonal lineages, followed by systemic dissemination and serial emergence of additional lineages from multiple tissues. Longer time to viral rebound was associated with metabolic, epigenetic, and immunologic signatures that suppress proviral reactivation. These findings advance our understanding of the tissue origins and host correlates of viral rebound and provide a framework for future studies examining GI-associated reservoir compartments, peripheral blood biomarker development, and host-directed strategies to prolong ART-free viral remission.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reallocation in spinal cord oligodendrocytes drives chronic pain in mice through neuronal Aβ42 production","authors":"Yannick Fotio,&nbsp;Saeed Al Masri,&nbsp;Zechuan Shi,&nbsp;Johnny Le,&nbsp;Sudeshna Das,&nbsp;Varvara I. Rubtsova,&nbsp;Alex Mabou Tagne,&nbsp;Cholsoon Jang,&nbsp;Vivek Swarup,&nbsp;Daniele Piomelli","doi":"10.1126/scitranslmed.aea8738","DOIUrl":"10.1126/scitranslmed.aea8738","url":null,"abstract":"<div >Recent evidence implicates a metabolic switch in afferent spinal circuits as a key driver of the transition from acute pain– to chronic pain–related behaviors in mice after tissue injury, yet the cellular substrates and functional consequences remain incompletely defined. Using a combination of pharmacological and genetic approaches, we investigated whether metabolic reprogramming in spinal cord cell populations constitutes a causal mechanism linking peripheral injury to the progression to pain chronicity. After peripheral injury induced by a hindpaw formalin injection in mice, single-nucleus RNA sequencing (snRNA-seq) revealed that spinal oligodendrocytes down-regulated transcripts for myelin protein synthesis and up-regulated transcripts important for lipid biosynthesis. Comparative lipidomics showed that this resource reallocation after peripheral injury was associated with disrupted spinal myelin composition. Moreover, axonal integrity was compromised, causing neuronal accumulation of amyloid precursor protein, enhanced β-site amyloid precursor protein–cleaving enzyme 1 (BACE1) expression, and increased insoluble amyloid-β₄₂ (Aβ₄₂) during a critical temporal window for the transition to pain chronicity. Blocking Aβ₄₂ production by BACE1 inhibition or clearing Aβ₄₂ by intrathecal 4G8 monoclonal antibody injection prevented the emergence of persistent pain after hindpaw formalin injection. Oligodendrocyte-specific deletion of <i>N</i>-acylethanolamine acid amidase, a key regulator of cell metabolism and pain, prevented Aβ₄₂ release and chronic pain development induced by formalin injection or sciatic nerve ligation. These findings uncover an unexpected mechanistic link between chronic pain and amyloid pathology and identify the NAAA→Aβ₄₂ pathway as a target for disease-modifying intervention.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.aea8738","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-224 orchestrates BMP and TGFβ signaling and is a therapeutic target in preclinical pulmonary arterial hypertension","authors":"Olympia Bikou,&nbsp;Aymen Halouani,&nbsp;Yifei Sun,&nbsp;Malik Bisserier,&nbsp;Clemens Eisenacher,&nbsp;Samar A. Antar,&nbsp;Petros Avramopoulos,&nbsp;Carlos G. Santos-Gallego,&nbsp;Catherine Swarts,&nbsp;Erik Kohlbrenner,&nbsp;Kiyotake Ishikawa,&nbsp;Marc Humbert,&nbsp;Roger J. Hajjar,&nbsp;Antonio Lax,&nbsp;Stefan Engelhardt,&nbsp;Martin J. Walsh,&nbsp;Sebastien Bonnet,&nbsp;Lahouaria Hadri,&nbsp;Yassine Sassi","doi":"10.1126/scitranslmed.aef6676","DOIUrl":"10.1126/scitranslmed.aef6676","url":null,"abstract":"<div >Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that leads to right heart failure and ultimately death. Therapeutic options targeting the underlying mechanisms of the disease are urgently needed. MicroRNAs (miRs) have emerged as critical regulators of cardiovascular homeostasis and disease. Here, we identified microRNA-224-5p (miR-224) as a regulator of pulmonary vascular remodeling and delineate its mechanism of action in PAH. miR-224 expression was increased in the lungs of patients with PAH and across multiple experimental models of pulmonary hypertension, including mouse, rat, and pig models, as well as in pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with PAH. In vitro, miR-224 overexpression was sufficient to induce PASMC proliferation. In vivo, adeno-associated virus 1 (AAV1)–mediated overexpression of miR-224 exacerbated PAH in mice, whereas intratracheal delivery of aerosolized AAV1–ToughDecoy–miR-224 or a chemically modified antisense oligonucleotide targeting miR-224 (LNA-224) attenuated disease severity in Sugen/Hypoxia (Su/Hx) and monocrotaline models in both mice and rats. Moreover, SMC-specific inhibition of miR-224 via an AAV1 vector expressing ToughDecoy–miR-224 reversed pulmonary vascular remodeling and improved right ventricular function in the Su/Hx mouse model. Mechanistically, miR-224 targeted multiple components of the bone morphogenetic protein (BMP)/transforming growth factor–β (TGFβ) signaling pathway, leading to suppressed BMP/SMAD signaling and enhanced TGFβ-associated responses. Inhibition of miR-224 restored the balance between growth-inhibitory BMP signaling and growth-promoting TGFβ signaling in PASMCs. Collectively, these findings identify miR-224 as a regulator of pulmonary vascular remodeling and highlight miR-224 inhibition as a promising therapeutic strategy for PAH.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional antibody responses from a primate Shigella outbreak inform vaccine design","authors":"Robert M. Gallant,&nbsp;Paul Savarino,&nbsp;Sophia Pulido,&nbsp;Morgan S. A. Gilman,&nbsp;Ti Lu,&nbsp;Jennifer Hayes,&nbsp;Nicholas L. Xerri,&nbsp;Torrey Williams,&nbsp;Mark A. Ochoa,&nbsp;Zackary Dietz,&nbsp;Eric Peterson,&nbsp;Timothy Scott,&nbsp;Faye Hartmann,&nbsp;Stephen G. Baker,&nbsp;Robert W. Kaminski,&nbsp;Devin Sok,&nbsp;Andrew C. Kruse,&nbsp;Wendy Picking,&nbsp;Saverio V. Capuano,&nbsp;Hayden R. Schmidt","doi":"10.1126/scitranslmed.aef7084","DOIUrl":"10.1126/scitranslmed.aef7084","url":null,"abstract":"<div >There is currently no approved vaccine for <i>Shigella</i> spp., a leading cause of diarrhea with increasing rates of antimicrobial resistance. <i>Shigella</i> vaccine development is complicated in part by an incomplete understanding of the structural and molecular determinants of immunity. To address this, we isolated monoclonal antibodies against candidate <i>Shigella</i> vaccine antigens using samples from a <i>Shigella flexneri</i> outbreak in a nonhuman primate (NHP) research facility. We found that antibodies targeting the <i>Shigella</i> O-antigen can undergo substantial affinity maturation (&gt;10%) to acquire broad cross-reactivity across <i>S. flexneri</i> serotypes. We also found that the virulence-associated type III secretion system (T3SS) proteins IpaD and IpaB elicit moderate T cell and robust antibody responses. T3SS antibodies could either inhibit or enhance bacterial virulence in vitro and differed in vivo depending on their epitope specificity. Collectively, these findings provide insights into protective and deleterious immune responses against <i>Shigella</i> that directly inform vaccine immunogen design.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated translocator protein in skull bone marrow is linked to human chronic pain","authors":"Mehrbod Mohammadian,&nbsp;Nikos Efthimiou,&nbsp;Katherin Gabriel,&nbsp;Ludovica Brusaferri,&nbsp;Joya Cooper-Hohn,&nbsp;Minhae Kim,&nbsp;Jennifer P. Murphy,&nbsp;Zeynab Alshelh,&nbsp;Grace Grmek,&nbsp;Jack H. Schnieders,&nbsp;Courtney A. Chane,&nbsp;Thomas G. Carmichael,&nbsp;Danika Yang,&nbsp;Julia J. Schubert,&nbsp;Federico E. Turkheimer,&nbsp;Rafael A. Cazuza,&nbsp;Peter M. Grace,&nbsp;Ciprian Catana,&nbsp;Steven M. Stufflebeam,&nbsp;Robert R. Edwards,&nbsp;Vitaly Napadow,&nbsp;Kimberly Sullivan,&nbsp;Matthias Nahrendorf,&nbsp;Theodore J. Price,&nbsp;Jodi M. Gilman,&nbsp;Marco L. Loggia","doi":"10.1126/scitranslmed.aed8729","DOIUrl":"10.1126/scitranslmed.aed8729","url":null,"abstract":"<div >The skull bone marrow (SBM) is emerging as a critical hub for neuroimmune signaling, yet its role in chronic pain is unknown. Using integrated positron emission tomography/magnetic resonance imaging, here, we show that the levels of 18-kilodalton translocator protein (TSPO), a putative marker of immune cell density, are elevated in the SBM of individuals with chronic pain [<i>n</i> = 125; chronic low back pain (cLBP), <i>n</i> = 88; knee osteoarthritis (KOA), <i>n</i> = 37] compared with healthy controls (<i>n</i> = 22). These elevations were widespread, generally more pronounced for KOA than cLBP, associated with pain and pain-comorbid symptoms in partially segregated spatial patterns, and supported by preliminary immunohistochemical evidence in human SBM samples from a donor with a history of chronic pain (compared with a healthy donor). Because TSPO is highly expressed in myeloid cells, these results link SBM immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function of ALDH3B2 transdifferentiates human pancreatic duct cells into β-like cells","authors":"Jian Li,&nbsp;Kevin Bode,&nbsp;Yu-chi Lee,&nbsp;Noelle Morrow,&nbsp;Andy Ma,&nbsp;Mulin He,&nbsp;Siying Wei,&nbsp;Jessica da Silva Pereira,&nbsp;Taylor Stewart,&nbsp;Alexander Lee-Papastavros,&nbsp;Jennifer Hollister-Lock,&nbsp;Brooke A. Sullivan,&nbsp;Hui Pan,&nbsp;Jonathan M. Dreyfuss,&nbsp;Susan Bonner-Weir,&nbsp;Peng Yi","doi":"10.1126/scitranslmed.ady2234","DOIUrl":"10.1126/scitranslmed.ady2234","url":null,"abstract":"<div >Replenishment of pancreatic β cells is key to a cure for diabetes. β cell regeneration is achieved predominantly by self-replication, especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into β cells. How pancreatic duct cells are transdifferentiated and whether we can manipulate transdifferentiation to replenish β cell mass are not well understood. Using a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, we found that the loss of function of aldehyde dehydrogenase family 3 member B2 (<i>ALDH3B2</i>) was sufficient to transdifferentiate cell line–based and human pancreatic duct cells into functional β-like cells. The transdifferentiated cells had substantially increased the expression of β cell marker genes, secreted insulin in response to glucose, and lowered blood glucose to near normal for 6 weeks after transplantation into streptozotocin-induced diabetic mice under the kidney capsule. Our study identifies a gene that could potentially be targeted in human pancreatic duct cells to replenish β cell mass for diabetes therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 865","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LTBP4 deficiency induces MRC1+/CD44+ macrophages to drive cancer progression in preclinical colorectal cancer models","authors":"Songtao Ji,&nbsp;Shuya Du,&nbsp;Ge Miao,&nbsp;Xiaohua Yang,&nbsp;Haojia Wang,&nbsp;Xuemei Li,&nbsp;Wanqi Ma,&nbsp;Dan Wei,&nbsp;Tianyu Cao,&nbsp;Mingzhen Zhou,&nbsp;Jianing Yu,&nbsp;Xiangshu Cheng,&nbsp;Yuanci Zhang,&nbsp;Hua Han,&nbsp;Yongzhan Nie,&nbsp;Jipeng Li,&nbsp;Hongyan Qin,&nbsp;Liang Wang,&nbsp;Xin Wang,&nbsp;Yuanyuan Lu,&nbsp;Xiaodi Zhao","doi":"10.1126/scitranslmed.aeb2189","DOIUrl":"10.1126/scitranslmed.aeb2189","url":null,"abstract":"<div >The tumor microenvironment is crucial for cancer progression, but the mechanisms underlying the tumor-immune cell interactions in it remain poorly understood. Here, we identified latent transforming growth factor–β (TGFβ) binding protein 4 (LTBP4) deficiency in colorectal cancer (CRC) as a critical driver that reprogrammed tumor-associated macrophages (TAMs) and induced a distinct subset, which promoted tumor progression by coordinating immune evasion and extracellular matrix (ECM) remodeling. Clinically, LTBP4 deficiency correlated with CRC progression and poor patient survival. <i>Ltbp4</i> knockout markedly promoted tumor growth and metastasis in immunocompetent mice, an effect attenuated in immunodeficient hosts, establishing the essential role of host immunity in mediating the effects of LTBP4 deficiency. Single-cell RNA sequencing revealed that LTBP4 deficiency induced a mannose receptor C-type 1–positive (MRC1⁺)/CD44⁺ TAM subset and correlated with reduced CD8⁺ T cell infiltration. Mechanistically, LTBP4 deficiency increased active TGFβ1 levels, which acted in a paracrine manner to up-regulate MRC1 in TAMs, whereas autocrine signaling induced HAS2 (hyaluronan synthase 2) expression and hyaluronan production to increase CD44. CD44 signaling in TAMs up-regulated matrix metalloproteinases for collagen degradation, whereas MRC1 mediated collagen internalization, cooperatively remodeling the ECM to facilitate tumor invasion. The TGFβ1-driven MRC1⁺/CD44⁺ TAMs further suppressed CD8⁺ T cell function by diminishing the C-X-C motif chemokine ligand 16-C-X-C motif chemokine receptor 6 (CXCL16-CXCR6) axis. Therapeutically, targeted depleting MRC1⁺/CD44⁺ TAMs enhanced the efficacy of PD-1 (programmed cell death–1) blockade in LTBP4-deficient tumors. Our study positions LTBP4 as a key modulator of tumor progression and reveals a therapeutic strategy for LTBP4-deficient CRC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 864","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148815553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 3D human retina model reveals a non–cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder","authors":"Jimin Han,&nbsp;Nathaniel Foley,&nbsp;Sonal Dalvi,&nbsp;Janet A. H. Tang,&nbsp;Fesahat Emira Dogrul,&nbsp;Amit Chatterjee,&nbsp;Lal Krishan Kumar,&nbsp;Chad A. Galloway,&nbsp;Ajay Kumar Singh,&nbsp;Leah M. Stein,&nbsp;Yashoda Subedi,&nbsp;Kevin C. Ling,&nbsp;Alison Heffer,&nbsp;Xingxuan He,&nbsp;Vamsi K. Gullapalli,&nbsp;Brent A. Johnson,&nbsp;Richard T. Libby,&nbsp;Danielle S. W. Benoit,&nbsp;Anthony L. Cook,&nbsp;Vera L. Bonilha,&nbsp;Edward H. Schuchman,&nbsp;Jennifer J. Hunter,&nbsp;Ruchira Singh","doi":"10.1126/scitranslmed.ady7616","DOIUrl":"10.1126/scitranslmed.ady7616","url":null,"abstract":"<div >Disruption of the photoreceptor–retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, is a pathological hallmark of several neurodegenerative and retinal diseases, including lysosomal storage disorders like juvenile neuronal ceroid lipofuscinosis (CLN3) disease. However, in vitro stem cell models that enable investigation of the photoreceptor-RPE interface are lacking. Here, we developed a 3D human pluripotent stem cell–derived retina organoid–RPE (hPSC-RO-RPE) model to investigate the photoreceptor-RPE interface in healthy and diseased tissues. Using this 3D hPSC-RO-RPE retina model, we showed that the most common disease-causing CLN3 mutation (<i>CLN3</i>^{Δ<i>ex7-8</i>}) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus <i>CLN3</i> mutant (<i>CLN3</i>^{Δ<i>ex7-8</i>}) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 disease pathobiology, and (ii) we showed a cell autonomous role of the RPE dysfunction in promoting POS loss/retina degeneration in CLN3 disease. We validated the molecular and structural changes observed in the <i>CLN3</i>^{Δ<i>ex7-8</i>} hPSC-RO-RPE model in the CLN3 miniswine model (<i>CLN3</i>^{Δ<i>ex7-8</i>}) and donor eyes from two patients with CLN3 disease. High-resolution retinal imaging of the living eye in two patients with CLN3 disease suggested decreased RPE autofluorescence in early-stage CLN3 disease. Treatment with recombinant human acid ceramidase (rhAC) ameliorated photoreceptor degeneration in both the CLN3 disease RO-RPE model and CLN3 miniswine eyes. These findings suggest that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 864","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibodies against MLC1 found in patients with NMOSD-like disease mediate astrocytopathy in rodent models","authors":"Hoi Kiu Wong,&nbsp;Samantha Ho,&nbsp;Qian Yu,&nbsp;Katherine S. Given,&nbsp;Dorina Shqau,&nbsp;Selia Baier,&nbsp;Stephan Winklmeier,&nbsp;Heike Rübsamen,&nbsp;Arek Kendirli,&nbsp;Kathrin Schanda,&nbsp;Eva Oswald,&nbsp;Katharina Bräuer,&nbsp;Franziska S. Thaler,&nbsp;Lisa Ann Gerdes,&nbsp;Regina Feederle,&nbsp;Martin Kerschensteiner,&nbsp;Markus Reindl,&nbsp;Mohsen Khademi,&nbsp;Fredrik Piehl,&nbsp;Tomas Olsson,&nbsp;Jeffrey L. Bennett,&nbsp;Tania Kümpfel,&nbsp;Naoto Kawakami,&nbsp;Monika Bradl,&nbsp;Edgar Meinl,&nbsp;Simone Mader","doi":"10.1126/scitranslmed.ady0403","DOIUrl":"10.1126/scitranslmed.ady0403","url":null,"abstract":"<div >The identification of autoantibodies against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) has been essential in distinguishing neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody–associated disease (MOGAD) from classical multiple sclerosis (MS), with important implications for treatment. However, for several patients within this disease spectrum, the target of the autoimmune response remains unknown. Here, we describe the modulator of VRAC current 1 (MLC1), a membrane protein with extracellular epitopes enriched at astrocytic end feet, as an autoantigen. Serum MLC1 antibodies were verified with a cell-based assay, identifying four MLC1 immunoglobulin G (IgG)–positive patients among 297 patients with inflammatory autoimmune diseases of the central nervous system who were screened. All four MLC1 IgG–positive patients exhibited overlapping yet atypical clinical features of MS and NMOSD and tested negative for AQP4 and MOG antibodies. Moreover, treatment with a monoclonal MLC1 antibody induced astrocytopathy in mouse cerebellar slice cultures and in a rat encephalitis model. Thus, MLC1 antibodies identify a subset of patients with an NMOSD-like phenotype, underscoring their potential as a disease marker with pathogenic relevance.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 864","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148815555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}