Science Translational Medicine最新文献

{"title":"Nasal and systemic immune responses correlate with viral shedding after influenza challenge in people with complex preexisting immunity","authors":"Kathie-Anne Walters, Charles A. Blatti, Ruoqing Zhu, Barbara Banbury, Luca T. Giurgea, Rachel Bean, Eugene Han, Yuhan Li, Kelsey Scherler, Jenna Sherry, Sarah Formentini, Wenzhuo Zhou, Adriana Cervantes-Medina, Monica Gouzoulis, Luz Angela Rosas, Alison Han, Lisa Gatzke, Colleen Bushell, Ned Sherry, Jeffery K. Taubenberger, Matthew J. Memoli, John C. Kash","doi":"10.1126/scitranslmed.adt1452","DOIUrl":"https://doi.org/10.1126/scitranslmed.adt1452","url":null,"abstract":"Each year in the United States, ~50% of adults ≥18 years old are vaccinated against influenza viruses, with protective efficacy averaging 40.5% over the past 20 years. To model annual seasonal influenza, a cohort of 74 adults, who were unscreened for preexisting A/H1N1 immunity and half of whom were recently immunized with licensed QIV (mean of 64 days), were challenged with A/H1N1 influenza virus. Transcriptomic, proteomic, and VDJ repertoire analyses were performed on nasal and peripheral blood samples from participants to identify nasal mucosal and systemic immune responses that correlated with viral shedding and immune correlates of protection. Viral-shedding participants showed increased T cell, but not B cell, VDJ diversity with expansion of low-frequency B cell clones postchallenge, including broadly neutralizing motifs. Nonshedding participants demonstrated decreased clonality and increased richness of B and T cell VDJ clones, increased preinoculation nasal mucosal immune gene and serum protein expression, and increased ex vivo peripheral blood mononuclear cell responses. Nasal mucosal responses in participants shedding virus for 2 or more days showed higher early viral loads and exhibited stronger induction of antiviral responses compared with those in participants who shed virus for 1 day. Last, participants with a single day of viral shedding were three times more likely to be female. These data shed light on the complex immune responses in the nasal mucosa and the periphery after influenza vaccination and infection, which will be critical for next-generation vaccine development.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"30 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787488","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}

{"title":"Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models","authors":"Xinyue Zhou, Steven Moreira, Cecilia Restelli, Hong Wang, Soheil Jahangiri, Sajesan Aryal, Emily Tsao, Pengcheng Zhang, Mingming Niu, Harish Kumar, Zaldy Balde, Ana Vujovic, Lina Liu, Nicholas Wong, Andrea Arruda, Mark D. Minden, Yang Zhou, Bhatia Ravi, Jun Qi, Chunliang Li, Kristin J. Hope, Rui Lu","doi":"10.1126/scitranslmed.adn5400","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn5400","url":null,"abstract":"Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, as a critical regulator of MYC expression and BET inhibitor sensitivity in human acute myeloid leukemia (AML). Constitutive or pharmacological activation of AHR repressed MYC and synergized with BET inhibitors to inhibit MYC transcription and suppress leukemia growth across diverse AML models. Mechanistically, AHR directly up-regulated a noncanonical target, ELMSAN1, a component of the MiDAC histone deacetylase complex, which promotes histone deacetylation at MYC regulatory elements. ELMSAN1 depletion led to up-regulation of MYC and impaired AHR signaling–induced BET inhibitor sensitization. In vivo, AHR agonists enhanced BET inhibitor efficacy in patient-derived xenografts and murine leukemia models, enabling the use of lower BET inhibitor doses while preserving therapeutic benefit and reducing toxicity. This combination suppressed leukemia stem cell (LSC) gene signatures and reduced LSC frequency, with minimal impact on normal hematopoietic stem and progenitor cells in both human cord blood xenografts and immunocompetent mouse models. Together, these findings uncover a MYC-repressive, nongenetic AHR-ELMSAN1 axis that enhances BET-targeting therapies and selectively impairs LSCs, providing a compelling rationale for clinical translation in AML and potentially other MYC-driven cancers.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"20 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787507","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}

{"title":"An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer","authors":"Meriem Bahri, Taha Al-Adhami, Emre Demirel, Jit Sarkar, Karen T. Feehan, Joanne E. Anstee, Tik Shing Cheung, Dominika Sosnowska, Chloé A. Woodman, William Macmorland, Dorothy D. Yang, James Rosekilly, Renee Gitsaki-Taylor, Cheryl E. Gillett, Cheryl L. Scudamore, James Spicer, Khondaker Miraz Rahman, James N. Arnold","doi":"10.1126/scitranslmed.ads3085","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads3085","url":null,"abstract":"A subset of perivascular tumor-associated macrophages (PvTAMs) expressing lymphatic vessel endothelial hyaluronan receptor–1 (LYVE-1) relies on heme oxygenase–1 (HO-1) activity to maintain an immunologically cold tumor microenvironment, which suppresses the efficacy of chemotherapy. Consequently, HO-1 inhibition represents a strategy to target immunosuppressive LYVE-1 <jats:sup>+</jats:sup> PvTAMs and improve therapeutic responses. We developed and characterized KCL-HO-1i, a small-molecule, orally bioavailable HO-1 inhibitor. In chemotherapy-resistant spontaneous murine <jats:italic toggle=\"yes\">MMTV-PyMT</jats:italic> breast cancer and subcutaneous MN/MCA1 sarcoma models, targeting the PvTAM function with KCL-HO-1i enhanced chemotherapy effects and sensitized tumors to treatment. KCL-HO-1i combined with chemotherapy promoted an immunologically hot tumor microenvironment characterized by increased infiltration of CD8 <jats:sup>+</jats:sup> T cells exhibiting effector function. These findings identify KCL-HO-1i as a nontoxic, orally bioavailable small-molecule immunotherapeutic targeting a key subset of protumoral PvTAMs, offering a combinatorial strategy to enhance chemotherapy efficacy in cancer.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787487","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}

{"title":"Hematopoietic loss of Y chromosome activates immune checkpoints and contributes to impaired senescent cell clearance and renal disease","authors":"Yohei Arai, Nicholas W. Chavkin, Yuka Arai, Jonatan Halvardson, Josefin Bjurling, Heather Doviak, Jesse D. Cochran, Megan A. Evans, Keita Horitani, Yoshimitsu Yura, Emiri Miura-Yura, Soichi Sano, Lars A. Forsberg, Kenneth Walsh","doi":"10.1126/scitranslmed.adv4071","DOIUrl":"https://doi.org/10.1126/scitranslmed.adv4071","url":null,"abstract":"The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"8 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787508","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}

{"title":"Regulatory KIR + CD8 + T cells are elevated during human pregnancy","authors":"Jing Li, Xuerui Wang, Andreas I. Lackner, Purnima Narasimhan, Lin Li, Vamsee Mallajosyula, Mary M. Johnson, Anna-Lena Höbler, Adam S. Kirosingh, Amy E. Braun, Felistas Nankya, Kenneth Musinguzi, Abel Kakuru, Moses Kamya, Philip J. Rosenthal, Grant Dorsey, Prasanna Jagannathan, Michael Angelo, Jürgen Pollheimer, Stephanie L. Gaw, Virginia D. Winn, Kari C. Nadeau, Mark M. Davis","doi":"10.1126/scitranslmed.adm7697","DOIUrl":"https://doi.org/10.1126/scitranslmed.adm7697","url":null,"abstract":"During pregnancy, immune responses must balance protection from infections with tolerance of the semiallogeneic fetus. However, the mechanisms regulating maternal-fetal tolerance remain poorly understood. Recently, we identified CD8 <jats:sup>+</jats:sup> T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) as a regulatory subset important for suppressing self-reactivity in human autoimmune and infectious diseases. To better understand what other roles these cells might play, we asked whether they are active during pregnancy. We first observed an increased frequency of KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells in the peripheral blood of pregnant people in the second trimester, especially in those carrying a male fetus. In vitro, KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells inhibited the alloreactive responses of maternal T cells against irradiated cord blood cells and selectively suppressed CD8 <jats:sup>+</jats:sup> T cells targeting male-specific proteins in mothers with male pregnancies. Therefore, the higher induction of KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells in mothers carrying a male fetus may help suppress additional allogeneic responses triggered by male-specific alloantigens. Longitudinal analysis showed that KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells undergo expansion and differentiate into functional cytotoxic cells during pregnancy. Single-cell RNA sequencing of decidual CD8 <jats:sup>+</jats:sup> T cells from early pregnancy revealed elevated numbers and increased expression of activation markers in KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells at the maternal-fetal interface. In addition, a higher frequency of KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells was associated with spontaneous abortion and preeclampsia. Together, our findings suggest that KIR <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells may contribute to maternal tolerance by modulating fetal-specific alloreactive T cell responses. They may also be useful as candidate biomarkers or therapeutic targets for human pregnancy disorders.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787506","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}

{"title":"Circulating epigenetic signatures classifying brain insulin resistance in humans","authors":"Stephanie Kullmann, Amandeep Singh, Ratika Sehgal, Fabian Eichelmann, Leontine Sandforth, Britta Wilms, Markus Jähnert, Andreas Peter, Svenja Meyhöfer, Dirk Walther, Hubert Preissl, Hans-Ulrich Häring, Matthias B. Schulze, Martin Heni, Andreas L. Birkenfeld, Annette Schürmann, Meriem Ouni","doi":"10.1126/scitranslmed.adv7834","DOIUrl":"https://doi.org/10.1126/scitranslmed.adv7834","url":null,"abstract":"Brain insulin action plays an important role in metabolic and cognitive health, but there is no biomarker available to assess brain insulin resistance in humans. Here, we developed a machine learning framework based on blood DNA methylation profiles of participants who did not have type 2 diabetes with and without brain insulin resistance and detailed metabolic phenotyping. We identified 540 DNA methylation sites (CpGs) as classifiers of brain insulin resistance in a discovery cohort ( <jats:italic toggle=\"yes\">n</jats:italic> = 167), results that were validated in two replication cohorts ( <jats:italic toggle=\"yes\">n</jats:italic> = 33 and 24) with high accuracy (83 to 94%). All 540 CpGs were differentially methylated and annotated to 445 genes mapping to neuronal development and axonogenesis processes. Methylation patterns of 98 of 540 CpGs exhibited a strong and significant ( <jats:italic toggle=\"yes\">P</jats:italic> &lt; 0.05) blood-brain correlation, indicating that blood cells are a reliable proxy to capture brain-specific DNA methylation changes. These blood-based epigenetic signatures could potentially serve in the future for the early detection of individuals with brain insulin resistance in a broad clinical setting.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"30 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787489","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}

{"title":"Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial","authors":"K. Rachael Parks,&nbsp;Zoe Moodie,&nbsp;Mary A. Allen,&nbsp;Catherine Yen,&nbsp;Briana D. Furch,&nbsp;Kellie J. MacPhee,&nbsp;Gabriel Ozorowski,&nbsp;Jack Heptinstall,&nbsp;William O. Hahn,&nbsp;Zihan Zheng,&nbsp;Huiyin Lu,&nbsp;Shannon Grant,&nbsp;Elize Domin,&nbsp;Michael O. Duff,&nbsp;Aaron Seese,&nbsp;Constanza Marini-Macouzet,&nbsp;Lamar Ballweber-Fleming,&nbsp;Wen-Hsin Lee,&nbsp;Christopher A. Cottrell,&nbsp;Alessia Liguori,&nbsp;Erik Georgeson,&nbsp;Nushin Alavi,&nbsp;Michael Kubitz,&nbsp;Nicole Phelps,&nbsp;Kelly E. Seaton,&nbsp;Kristen W. Cohen,&nbsp;Maija A. Anderson,&nbsp;Kajari Mondal,&nbsp;Dagna S. Laufer,&nbsp;James G. Kublin,&nbsp;Andrew B. Ward,&nbsp;Ollivier Hyrien,&nbsp;Stephen C. De Rosa,&nbsp;Sunny Himansu,&nbsp;Brett Leav,&nbsp;Caroline Reuter,&nbsp;Georgia D. Tomaras,&nbsp;David Montefiori,&nbsp;Stephen R. Walsh,&nbsp;Ian Frank,&nbsp;Magdalena E. Sobieszczyk,&nbsp;Paul A. Goepfert,&nbsp;Kathryn E. Stephenson,&nbsp;Lindsey R. Baden,&nbsp;Hong Van Tieu,&nbsp;Michael C. Keefer,&nbsp;Jesse Clark,&nbsp;Sharon A. Riddler,&nbsp;William R. Schief,&nbsp;M. Juliana McElrath","doi":"10.1126/scitranslmed.ady6831","DOIUrl":"10.1126/scitranslmed.ady6831","url":null,"abstract":"<div >mRNA technology might accelerate development of an urgently needed preventive human immunodeficiency virus (HIV) vaccine. We evaluated the safety and immunogenicity of three mRNA-encoded envelope trimers, including two doses of soluble and membrane-anchored forms, in a randomized, open-label, phase 1 clinical trial. Vaccines were generally well tolerated, although 6.5% (7 of 108) of participants developed urticaria, a higher proportion than seen with other mRNA vaccines. mRNA-encoded trimers induced strong envelope-specific B and T cell responses. Immunization with membrane-anchored trimers, intended to obscure epitopes at the trimer base targeted by nonneutralizing antibodies, reduced the frequency of base-binding serum antibodies in comparison with soluble trimers. Three immunizations elicited autologous tier 2 serum neutralizing antibodies in 80% of vaccinees receiving the membrane-anchored trimers, in contrast to only 4% receiving the soluble trimer. Thus, with demonstration of more favorable safety, mRNA-encoded membrane-anchored HIV envelope trimers represent a promising platform for HIV vaccine clinical development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ady6831","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737508","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":"NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis","authors":"Cuicui Wang,&nbsp;Liang Fang,&nbsp;Meng Shi,&nbsp;Xiangfeng Niu,&nbsp;Tiandao Li,&nbsp;Xiaofei Li,&nbsp;Kevin Cho,&nbsp;Yonghua He,&nbsp;Shuang Liu,&nbsp;Aiwu Lu,&nbsp;Xiaoyun Xing,&nbsp;Jessica Lukowski,&nbsp;Young Ah Goo,&nbsp;John R. Speakman,&nbsp;Di Chen,&nbsp;Regis J. O’Keefe,&nbsp;Gary J. Patti,&nbsp;Michael J. Zuscik,&nbsp;Bo Zhang,&nbsp;Jie Shen","doi":"10.1126/scitranslmed.adm9488","DOIUrl":"10.1126/scitranslmed.adm9488","url":null,"abstract":"<div >Osteoarthritis (OA) is a joint disease with an etiology partially rooted in metabolic dysfunction, yet the underlying mechanisms in this context are not determined, limiting opportunities to develop therapeutic treatments. In this study, we used a multiomic approach combining RNA sequencing, ATAC-seq, MRE-seq, and metabolomics to reveal that OA articular chondrocytes induced by imbalanced transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) signaling have increased fatty acid synthesis and oxidation processes regulated by nuclear factor I A (NFIA) up-regulation. Inhibition of <i>NFIA</i> suppressed the elevated gene expression of essential metabolic enzymes, including acetyl-CoA carboxylase A (<i>ACACA</i>) and carnitine palmitoyltransferase 2 (<i>CPT2</i>), leading to the restoration of fatty acid metabolism and cellular homeostasis in both murine and human OA articular chondrocytes. Obese mice displayed metabolic stress with elevated expression of NFIA, ACACA, and CPT2 in joint tissues, and they simultaneously developed profound synovitis, cartilage degeneration, subchondral bone sclerosis, and pain after joint injury. Both <i>Nfia</i> inhibition and pharmacological suppression of fatty acid metabolism in obese mice preserved joint integrity and mitigated synovitis and pain in the context of injury-induced OA settings. Overall, this work identifies a role for NFIA in the regulation of fatty acid metabolism and articular chondrocyte homeostasis and highlights fatty acid metabolism as a potential therapeutic target for OA treatment, particularly under obesity conditions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737637","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}

{"title":"Impairment of stromal-epithelial regenerative cross-talk in Hirschsprung disease primes for the progression to enterocolitis","authors":"Zhen Zhang,&nbsp;Dorothy Lee,&nbsp;Lingya Liu,&nbsp;Yi Xiong,&nbsp;Carol Lee,&nbsp;Ji-Eun Kim,&nbsp;Sinobol Chusilp,&nbsp;Ethan Lau,&nbsp;Yina Tian,&nbsp;Mehrsa Feizi,&nbsp;Mashriq Alganabi,&nbsp;Anthea Lafreniere,&nbsp;Tianran Cheng,&nbsp;Ruijie Zhou,&nbsp;Lu Han,&nbsp;Lihua Wu,&nbsp;Ping Xiao,&nbsp;Ya Gao,&nbsp;Giada Benedetti,&nbsp;Lucy Holland,&nbsp;Lucinda Tullie,&nbsp;Giovanni Giuseppe Giobbe,&nbsp;Long Li,&nbsp;Qi Li,&nbsp;Atsuyuki Yamataka,&nbsp;Vivian S. W. Li,&nbsp;Paolo De Coppi,&nbsp;Qian Jiang,&nbsp;Agostino Pierro,&nbsp;Bo Li","doi":"10.1126/scitranslmed.adp4679","DOIUrl":"10.1126/scitranslmed.adp4679","url":null,"abstract":"<div >Hirschsprung disease (HSCR) is a congenital condition characterized by the improper migration of enteric neural crest cells, leading to aganglionosis most commonly in the rectosigmoid colon. This severe and life-threatening disorder often results in the development of Hirschsprung-associated enterocolitis (HAEC), which can occur either before or after surgical resection of the affected bowel segment. Using colonic tissue from patients with HSCR alongside the well-established endothelin receptor B knockout mouse model, we investigated epithelial regeneration dynamics and stromal-epithelial cross-talk in the distal ganglionic colon, a critical site for HAEC development. In individuals with HSCR but without epithelial damage, the distal ganglionic colon displayed impaired epithelial regeneration and alteration of intestinal stem cell dynamics, characterized by the reduction of leucine-rich repeat-containing G protein–coupled receptor 5 (LGR5⁺) epithelial stem cells. This phenomenon was consistent in the mouse model, where impaired regenerative ability preceded HAEC when epithelial damage occurred on site. Patients with HSCR also exhibited remodeling in stromal cells in this distal ganglionic colon region, with fewer primary sources of Wingless-related integration site (Wnt) signal-releasing stromal cells and the exclusive presence of proinflammatory (matrix metalloproteinase 1⁺) stromal cells. Stromal cells from the HSCR distal ganglionic colon failed to sustain the growth of colonic organoids. However, ibuprofen suppressed the proinflammatory stromal cells, leading to effective restoration of epithelial organoid growth. These observations underscore the crucial role of impaired stromal-epithelial cross-talk in HSCR and the pathogenesis of HAEC and suggest potential therapeutic targets for the prevention or treatment of the condition.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737507","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}

{"title":"Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease","authors":"Ricardo D’Oliveira Albanus,&nbsp;Gina M. Finan,&nbsp;Logan Brase,&nbsp;Nicholas Sweeney,&nbsp;Tae Yeon Kim,&nbsp;Shuo Chen,&nbsp;Yeonsu Ryoo,&nbsp;Joseph Park,&nbsp;Qi Guo,&nbsp;Abhirami Kannan,&nbsp;Mariana Acquarone,&nbsp;Shih-Feng You,&nbsp;Brenna C. Novotny,&nbsp;Emily M. Mace,&nbsp;Patricia M. Ribeiro Pereira,&nbsp;John C. Morris,&nbsp;David M. Holtzman,&nbsp;Eric McDade,&nbsp;Martin Farlow,&nbsp;Jasmeer P. Chhatwal,&nbsp;Bruno A. Benitez,&nbsp;Laura Piccio,&nbsp;Richard J. Perrin,&nbsp;Greg T. Sutherland,&nbsp;Qin Ma,&nbsp;Celeste M. Karch,&nbsp;Doo Yeon Kim,&nbsp;Rudolph E. Tanzi,&nbsp;Hongjun Fu,&nbsp;Oscar Harari,&nbsp;Tae-Wan Kim","doi":"10.1126/scitranslmed.adx0027","DOIUrl":"10.1126/scitranslmed.adx0027","url":null,"abstract":"<div >Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged <i>TREM2</i> knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737636","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}