Translational Research最新文献

{"title":"Enhancing specific thymic Treg activation and function with 4-1BB monomeric streptavidin-based CARs","authors":"Jorge Gallego-Valle ,&nbsp;Verónica Astrid Pérez-Fernández ,&nbsp;Ana Pita ,&nbsp;Jesús Rosales-Magallares ,&nbsp;Rocío López-Esteban ,&nbsp;Sergio Gil-Manso ,&nbsp;Diego Carbonell ,&nbsp;Ramón Pérez-Caballero ,&nbsp;Carlos Pardo ,&nbsp;Juan-Miguel Gil-Jaurena ,&nbsp;Rafael Correa-Rocha ,&nbsp;Marjorie Pion","doi":"10.1016/j.trsl.2025.09.004","DOIUrl":"10.1016/j.trsl.2025.09.004","url":null,"abstract":"<div><div>Hyperinflammatory diseases arise from excessive immune activation, causing tissue damage and systemic inflammation. Regulatory T (Treg) cells play a key role in maintaining immune homeostasis, but their function or numbers may be impaired in pathological conditions. Conventional immunosuppressive therapies often fail to restore immune balance and are associated with significant adverse effects. An emerging therapeutic strategy involves the use of chimeric antigen receptor (CAR)-engineered Tregs to suppress aberrant immune responses. However, antigen-specific CAR-Tregs may be insufficient due to the heterogeneity of inflammatory diseases. Universal CAR-Tregs (UniCAR-Tregs), which may recognize broad immune markers, represent a more flexible and potentially effective alternative. In this study, second- and third-generation UniCAR constructs containing a monomeric streptavidin extracellular domain were introduced into human thymus-derived Tregs (thyTregs) via lentiviral transduction. The phenotype and transcriptomic profile of engineered thyTregs were characterized and compared to unmodified controls. Their suppressive capacity was assessed in vitro using a mixed lymphocyte reaction with a biotinylated intermediary, followed by evaluation in a preclinical graft-versus-host disease (GvHD) mouse model. CARs incorporating CD28 co-stimulation resulted in non-specific activation or failed to enhance suppression. In contrast, the UniCAR41BB construct more specifically activated thyTregs and augmented their suppressive function. In vivo, UniCAR41BB thyTregs delayed GvHD onset and improved survival. This study demonstrates, for the first time, that thyTregs can be effectively transduced without compromising their regulatory phenotype. Furthermore, second-generation UniCAR41BB construct enhances antigen-dependent suppressive function, highlighting its potential as a versatile therapeutic platform for GvHD and other inflammatory disorders</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 1-16"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenic and reparative potency of a human cardiac CD90− mesenchymal subpopulation in heart ischemic model","authors":"Elisa Gambini ,&nbsp;Erica Rurali ,&nbsp;Veronica Barbagallo ,&nbsp;Sergio Pirola ,&nbsp;Alessandro Scopece ,&nbsp;Andrea Biondi ,&nbsp;Beatrice Bassetti ,&nbsp;Manuel Casaburo ,&nbsp;Luana Eramo ,&nbsp;Giorgio Pio Alberto Marinelli ,&nbsp;Diego Farinello ,&nbsp;Simona Rodighiero ,&nbsp;Yuri D’alessandra ,&nbsp;Mattia Chiesa ,&nbsp;Gabriella Spaltro ,&nbsp;Veronica Ricci ,&nbsp;Aoife Gowran ,&nbsp;Elisa Castiglioni ,&nbsp;Daniele Fileccia ,&nbsp;Giuseppe Nanci ,&nbsp;Giulio Pompilio","doi":"10.1016/j.trsl.2025.08.004","DOIUrl":"10.1016/j.trsl.2025.08.004","url":null,"abstract":"<div><h3>Background</h3><div>Despite recent significant therapeutic progress, cardiovascular diseases (CVD) remain an unmet clinical, economic, and social burden worldwide. Cell-based therapies have been proposed as therapeutic strategies, however, the overall efficacy was modest.</div></div><div><h3>Objective</h3><div>We aimed to fully characterize a novel subpopulation of CD90⁻ mesenchymal cells derived from human heart tissue (hCmPC90^-) and evaluate its ability to induce cardiac tissue repair and functional recovery.</div></div><div><h3>Methods</h3><div>We performed a comprehensive phenotypic characterization of the hCmPC90⁻ by flow cytometry and RNA sequencing. A direct comparison of hCmPC90⁻ with previously clinically tested bone marrow- and cardiac-derived cell types, has been conducted both <em>in vitro</em> by means of various assays of angiogenic potency, and <em>in vivo,</em> by testing the ability to ameliorate left ventricular function in a mouse model of acute myocardial infarction (AMI).</div></div><div><h3>Results</h3><div>hCmPC90⁻ showed distinct surface markers and transcriptional phenotype compared with unselected mesenchymal heart cells (hCmPCs) and the positive CD90 counterpart (hCmPC90⁺). When human hCmPC90⁻, hCmPC90⁺, hCmPC, cardiosphere-derived cells (CDCs), and bone marrow-derived CD34⁺ cells were functionally tested <em>in vitro</em>, hCmPC90⁻ revealed a superior endothelial differentiation ability, higher anti-inflammatory, cardio-protective capacity, and angiocrine activity. Moreover, hCmPC90⁻ showed specific immune-privileged features. When intramyocardially delivered into infarcted mouse hearts, hCmPC90⁻ outperformed three weeks after injection other clinical-grade cell types, as for left ventricular (LV) function and adverse LV remodeling recovery, infarct size reduction, and vascular density augmentation.</div></div><div><h3>Conclusion</h3><div>hCmPC90⁻ shows a superior biological potency which deserves clinical exploitation as an advanced therapy medicinal product in the context of refractory ischemic heart disease.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 22-35"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appendiceal B lymphocytes contribute to the pathogenesis of experimental colitis through fueling colonic CD4+ T polarization","authors":"Yu Zhang ,&nbsp;Shan Cao ,&nbsp;Yun Liu ,&nbsp;Ziliang Ke ,&nbsp;Zhe Wu ,&nbsp;Xiaohui Fang ,&nbsp;Yang Zhang ,&nbsp;Jingyi Chen ,&nbsp;Congyi Yang ,&nbsp;Yiken Lin ,&nbsp;Ning Chen ,&nbsp;Jun Xu ,&nbsp;Yulan Liu","doi":"10.1016/j.trsl.2025.09.001","DOIUrl":"10.1016/j.trsl.2025.09.001","url":null,"abstract":"<div><div>The appendix, a component of the gut-associated lymphoid tissue enriched with B lymphocytes, plays a pivotal role in intestinal mucosal immunity. Previous studies have indicated that prior appendectomy may prevent the onset of ulcerative colitis (UC); however, its therapeutic role in UC remains unclear, and prophylactic appendectomy is not a realistic approach to prevent UC. In this study, we confirmed that appendectomy alleviates dextran sodium sulphate (DSS)-induced chronic murine colitis and further demonstrated that appendiceal B (APB) lymphocytes exacerbate colonic inflammation by migrating to the colon via the CCL20–CCR6 axis and facilitating colonic CD4⁺ T cell-mediated T helper 1 (Th1) and T helper 17 (Th17) immune responses. Single-cell sequencing of colonic tissues revealed IgG⁺ B cell-skewed responses in patients with UC, and APB cell expansion was positively correlated with disease severity. Immunofluorescence co-staining suggested that colonic B cells of UC patients related to the appendix. These findings highlight the therapeutic potential of appendectomy and B cell-targeted immunotherapy in UC treatment and further introduce the hypothesis that UC with appendiceal orifice inflammation may represent a distinct subtype of the disease.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 56-70"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining computational target prioritization and a B cell maturation assay for target evaluation studies in systemic lupus erythematosus","authors":"Ming-Mei Shang ,&nbsp;Zhuang Liu ,&nbsp;Bogdan Knezevic ,&nbsp;Christine Möller Westerberg ,&nbsp;Sudeepta Kumar Panda ,&nbsp;Hai Fang ,&nbsp;Ning Xu Landén ,&nbsp;Michael Sundström ,&nbsp;Julian C. Knight ,&nbsp;Louise Berg","doi":"10.1016/j.trsl.2025.09.002","DOIUrl":"10.1016/j.trsl.2025.09.002","url":null,"abstract":"<div><h3>Background and Purpose</h3><div>Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving production of autoantibodies by B cells. This study aimed at identifying novel drug targets using a computational algorithm to select targets and thereafter validate the top ranked 11 targets by siRNA knockdown in a primary B cell maturation assay.</div></div><div><h3>Experimental Approach</h3><div>The top 1 % genes (∼150 genes) from SLE genome-wide association studies were ranked by Priority index (Pi), a computational tool integrating genomic and network information to prioritize disease-relevant genes. These were further filtered by network connectivity, drugability, for ranking highly in autoimmune diseases and for not directly interfering with the B cell stimulation cocktail used. From this, 11 genes were selected for validation by siRNA knockdown: <em>IFNGR1, IL-2, IRF4, IL-12A, IL-12B, VCAM-1, ATF6B, RELA, IKBKG, CHUK</em> and <em>MAPK14.</em> Effects on induced maturation and viability of primary blood B cells were analyzed by flow cytometry, and effects on IgG secretion were investigated by ELISA. RNA-sequencing of B cells treated with siRNA was performed to investigate molecular mechanisms underlying the functional alterations.</div></div><div><h3>Key Results</h3><div>Experimental results show that several of the targets (<em>IFNGR1, IL-2, IL-12A, MAPK14, IRF4, CHUK, ATF6B, IKBKG,</em> and <em>RELA</em>) are involved in B cell maturation, as knockdown caused reduced IgG production and/or decreased maturation of B cells. The observed variability of effects on IgG secretion and B cell maturation suggests differences in the mechanistic roles of the proteins encoded by these genes. RNA-seq analysis of cells where expression of the targeted genes had been modulated showed effects on the expression level of hundreds of genes involved in cellular processes important for B cell functions.</div></div><div><h3>Conclusion and Implications</h3><div>Combining the target prioritization algorithm with experimental functional validation studies by gene knockdown and whole transcriptomics profiling constitutes a promising approach to identify potential novel drug targets in immune disorders.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 36-46"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(25)00098-2","DOIUrl":"10.1016/S1931-5244(25)00098-2","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Page IBC"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of thermogenic genes to metabolic tissues: Effects on body weight and glucose tolerance","authors":"Min-Jung Park ,&nbsp;Junhyeong Lee ,&nbsp;Merc Emil Matienzo ,&nbsp;Sangyi Lim ,&nbsp;Keon Kim ,&nbsp;Chang-Min Lee ,&nbsp;Dong-il Kim","doi":"10.1016/j.trsl.2025.09.003","DOIUrl":"10.1016/j.trsl.2025.09.003","url":null,"abstract":"<div><div>Adaptive thermogenesis, particularly via the β3-adrenergic receptor (ADRB3)–protein kinase A catalytic subunit α (PKA Cα)–uncoupling protein 1 (UCP1) pathway, promotes energy expenditure and contributes to metabolic homeostasis, thereby establishing this pathway as a promising therapeutic target for metabolic disorders associated with excessive energy intake. In this study, we aimed to evaluate the therapeutic potential of adeno-associated virus (AAV)-mediated gene therapy targeting thermogenic pathways in metabolic tissues for the treatment of obesity-related dysfunctions. We demonstrated that adipocyte-specific overexpression of UCP1 improved glucose tolerance. Similarly, ADRB3 overexpression significantly enhanced glucose tolerance. Furthermore, ectopic expression of UCP1 in hepatocytes and myofibers also led to improved glucose tolerance. These findings highlight the potential of AAV-mediated gene therapy targeting the ADRB3–PKA Cα–UCP1 axis as a promising strategy for the treatment of obesity-associated metabolic disorders.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 47-55"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S1931-5244(25)00096-9","DOIUrl":"10.1016/S1931-5244(25)00096-9","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Page ii"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Guidelines","authors":"","doi":"10.1016/S1931-5244(25)00097-0","DOIUrl":"10.1016/S1931-5244(25)00097-0","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages iii-iv"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of circulating tumor cells and circulating tumor DNA in peritoneal lavage fluid for predicting metachronous peritoneal metastasis of gastric cancer","authors":"Long Bai ,&nbsp;Bo Ni ,&nbsp;Xiaoyao Shen ,&nbsp;Yeqian Zhang ,&nbsp;Yujing Guan ,&nbsp;Jiayi Gu ,&nbsp;Haoyu Zhang ,&nbsp;Muerzhate Aimaiti ,&nbsp;Shuchang Wang ,&nbsp;Ben Yue ,&nbsp;Yanying Shen ,&nbsp;Zebing Liu ,&nbsp;Xiang Xia ,&nbsp;Zizhen Zhang","doi":"10.1016/j.trsl.2025.08.003","DOIUrl":"10.1016/j.trsl.2025.08.003","url":null,"abstract":"<div><h3>Background</h3><div>Peritoneal metastasis is a leading cause of death in gastric cancer (GC) patients, highlighting the need for early diagnosis and high-risk population identification. While circulating tumor DNA(ctDNA) and circulating tumor cells (CTC) have been widely studied in blood, their role in peritoneal lavage fluid (PLF) remains unexplored.</div></div><div><h3>Methods</h3><div>Patients with stage III GC were enrolled, and preoperative/postoperative PLF was collected in this study. ctDNA in PLF supernatant was analyzed via next-generation sequencing (NGS), while CTC in the pellet were detected using Epithelial Cell Adhesion Molecule (EpCAM), Folate Receptor (FR), and Cytokeratin (CK) immunofluorescence.</div></div><div><h3>Results</h3><div>ctDNA-positive patients had higher peritoneal metastasis risk (preoperative HR: 4.82, 95% CI 1.03–22.54, p = 0.04; postoperative HR: 4.83, 95% CI 1.03–22.54, p = 0.04). CTC-positive patients also showed higher risk (preoperative HR: 6.76, 95% CI 0.92–49.74, p = 0.003; postoperative HR: 7.41, 95% CI 1.67–32.87, p = 0.02). Postoperative ctDNA had higher predictive efficacy for peritoneal metastasis compared to preoperative ctDNA, with AUC values of 0.93 and 0.86. Combined ctDNA/CTC positivity identified the highest recurrence risk (preoperative HR: 8.07, 95% CI 0.96–67.51, p = 0.0012; postoperative HR: 18.14, 95% CI 3.27–100.70, p = 0.0002).</div></div><div><h3>Conclusions</h3><div>The combination of postoperative ctDNA and CTC in PLF offered the highest accuracy (85%) and risk stratification in predicting peritoneal metastasis (30.30% vs. 66.67%, p = 0.0063). This method may guide the postoperative prophylactic intraperitoneal chemotherapy.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 13-21"},"PeriodicalIF":5.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvasive in vivo tracking of SPIONs-labeled CLDN18.2-targeted CAR-T cells in gastric cancer via magnetic particle imaging","authors":"Meng He ,&nbsp;Lijie Ge ,&nbsp;Hui Hui ,&nbsp;Yali Zhou ,&nbsp;Yingxiu Tang ,&nbsp;Lin Shen ,&nbsp;Jie Tian ,&nbsp;Bo Wu ,&nbsp;Changsong Qi ,&nbsp;Yang Du ,&nbsp;Lei Tang","doi":"10.1016/j.trsl.2025.08.002","DOIUrl":"10.1016/j.trsl.2025.08.002","url":null,"abstract":"<div><div>This study aims to employ magnetic particle imaging (MPI) for in vivo tracking and quantitative assessment of targeting capability of CLDN18.2-specific CAR-T cells. CLDN18.2-targeted CAR-T cells were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic particle imaging (MPI), and with the near-infrared fluorescent dye DiR for fluorescence molecular imaging (FMI) before infusion. SPIONs-labeled and unlabeled CAR-T cells were administered intravenously to NOD/SCID mice bearing HGC27 xenograft tumors, either independently or in combination with anti-PD-L1 (aPD-L1) antibody (n = 3 for imaging and n = 5 for treatment). The FMI and MPI successfully monitored the dynamic migration and tumor targeting of CAR-T cells towards CLDN18.2-overexpressing tumors. On the fifth day post-infusion, the MPI signal of SPIONs-labeled CAR-T cells was significantly higher in the tumor than that of labeled normal T cells. MPI combined with FMI successfully monitored the targeting of CLDN18.2-specific CAR-T cells in gastric cancer, providing a potential framework for evaluating CAR-T therapy combined with aPD-L1 immunotherapy.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"283 ","pages":"Pages 3-12"},"PeriodicalIF":5.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}