Cytotherapy最新文献

{"title":"Charge-reversed small extracellular vesicles from human adipose-derived mesenchymal stromal cells attenuate renal fibrosis postacute kidney injury by inhibiting epithelial-mesenchymal transition progression in SD rat model.","authors":"Wenwen Ping, Xiaoyan Xu, Yan Jiang, Rong Yang, Luwei Xu","doi":"10.1016/j.jcyt.2025.02.004","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.004","url":null,"abstract":"<p><p>Approximately 25% of patients with acute kidney injury (AKI) progress to chronic kidney disease, driven by the transition of renal tubular epithelial cells from epithelial to mesenchymal cells. Recent studies show that adipose-derived mesenchymal stromal cell-derived small extracellular vesicles (AMEV) can ameliorate renal fibrosis and injury. However, owing to poor retention, the limited bioavailability of AMEV hamper their therapeutic application. In this study, AMEV were extracted and modified with an ε-polylysine-polyethylene-distearoylphosphatidylethanolamine (PPD) polymer, which facilitated the reversal of the AMEV surface charge, thereby generating positively charged AMEV for the treatment of AKI. In a rat model of AKI, PPD modification significantly enhanced the renal retention of AMEV and effectively alleviated renal pathological damage. Further, RNA sequencing revealed that AMEV derived from adipose-derived mesenchymal stromal cells contains abundant microRNAs. We found that PPD modification significantly enhanced the bioavailability of AMEV and improved therapeutic effects in both in vivo and in vitro experiments. Furthermore, miR-100 enriched in AMEV targeted mTOR and suppressed the epithelial-mesenchymal transition phenotype of renal tubular epithelial cells, thereby alleviating renal fibrosis and promoting recovery of renal function postischemia-reperfusion. Overall, this study presents a promising therapeutic strategy and identifies clinical targets to combat renal fibrosis.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Controlled activation modulates T-cell expansion and phenotype in stirred-tank bioreactors.","authors":"Margarida S Costa, Constança M Costa, Leonor N Matos, Maria João Sebastião, Nádia Duarte, Marta H G Costa, Margarida Serra","doi":"10.1016/j.jcyt.2025.02.003","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.003","url":null,"abstract":"<p><strong>Background aims: </strong>Autologous cell therapies using chimeric antigen receptor (CAR) T cells have shown significant clinical success in hematologic cancers. However, current production platforms face challenges in scaling up to produce sufficient numbers of cells to meet the demands of multi-dose regimens. Additionally, tight control over critical process parameters during the distinct stages of cell production is required to maximize key phenotypic characteristics of CAR T-cell products that correlate with improved clinical responses. To address these issues, we propose an integrated manufacturing process in stirred-tank bioreactors (STBs) for controlled T-cell activation and expansion.</p><p><strong>Methods: </strong>By tailoring the stirring profile of STBs (Ambr 15 bioreactors; Sartorius, Göttingen, Germany), microbeads functionalized with anti-CD3/CD28 antibodies allow control over the initiation/termination of T-cell activation without requiring additional washing steps to remove the activation signaling cues.</p><p><strong>Results: </strong>This strategy resulted in up to a 10-fold increase in T-cell numbers compared with conventional static culture systems, resulting in a final cell concentration of 2.5 × 10⁷ cells/mL after 10 days of culture. Importantly, a higher proportion of CD8⁺ T cells and lower expression of exhaustion markers programmed cell death protein 1, lymphocyte activation gene 3 and T-cell immunoglobulin and mucin domain 3 (<8%) were obtained in STBs relative to static cultures. Additionally, the anti-CD3/CD28-functionalized microbeads were as efficient as the standard TransAct (Miltenyi Biotec, Bergisch Gladbach, Germany) stimuli in activating and expanding T cells in STBs.</p><p><strong>Conclusions: </strong>Overall, this approach presents a promising strategy for the scalable and tightly controlled manufacturing of T-cell therapies, particularly focusing on the T-cell activation step while minimizing manual operations, thus contributing to more and cost-effective immunotherapies.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted knockdown of MSC-sEVs biogenesis regulator proteins to elucidate the mechanisms of their production: a step towards translational applications.","authors":"Yashvi Sharma, Sujata Mohanty","doi":"10.1016/j.jcyt.2025.02.002","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.002","url":null,"abstract":"<p><p>In the intricate landscape of cellular communication, small extracellular vesicles (sEVs) originating from endosomes play crucial roles as mediators and have garnered significant attention in theranostics. Our understanding of sEV biogenesis largely stems from studies on cancer cells, which are vital for diagnostics. However, in therapeutics, where mesenchymal stromal cell (MSC)-derived sEVs are emerging as investigational new drugs, their biogenesis pathways remain largely unexplored. This article explores the parallel narratives of sEV biogenesis in cancer cells and stem cells, specifically using HeLa cells and MSCs as model cell lines. This study investigated the roles of key proteins-hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), signal-transducing adaptor molecule (STAM), tumor susceptibility gene 101 (TSG101), and ALG-2-interacting protein X (ALIX)-as identified in HeLa cells, in the context of MSC-sEV biogenesis. While these proteins show similarities across cell types, a discernible difference arises in their primary functions in regulating sEV biogenesis. The critical role of ALIX in MSC-sEV biogenesis, in particular, underscores its potential as a target for modulating sEVs' yield in regenerative therapies. Through this comparative analysis, we identified shared molecular signatures, offering insights to guide therapeutic interventions and unlock the regenerative potential of stem cells.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The current state of Cytotherapy and the field of cell and gene therapy.","authors":"William Y K Hwang, Ezzah Mohamed Muzammil","doi":"10.1016/j.jcyt.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.01.017","url":null,"abstract":"<p><p>2024 marked a transformative phase for cell and gene therapy (CGT) with significant advancements in scientific innovation, regulatory approvals and commercialization milestones. This review highlights key developments in CGT, including innovations in chimeric antigen receptor (CAR)-T therapies, mesenchymal stromal cells (MSCs), gene editing and regenerative medicine, alongside challenges in scalability, regulation and safety. Prominent breakthroughs in CAR-T technology extended its applications beyond oncology to autoimmune diseases, including lupus and systemic sclerosis. Gene therapies achieved major milestones, exemplified by regulatory approval for the treatment of hemophilia, sickle cell disease and other genetic diseases. Further advancements in delivery systems, including lipid nanoparticles and engineered viral vectors were achieved. Refinements in clustered regularly interspaced short palindromic repeats-Cas9 and base-editing tools improved precision and reduced off-target effects, enabling new approaches for genetic disorders. Global collaboration underscored the collective effort to accelerate CGT progress. MSCs remain central to CGT research, focusing on their immunomodulatory properties and clinical applications in autoimmune diseases and graft-versus-host disease. Economic and policy landscapes evolved alongside scientific advancements. Record-breaking approvals and biotech IPOs underscored CGT's economic potential, while affordability and equitable access emerged as critical challenges. Regulatory agencies advanced harmonized guidelines for manufacturing and clinical evaluation, streamlining global access to these therapies. Ethical considerations, including the affordability of therapies and the need for diverse clinical trial representation, remained prominent. Despite progress, challenges persist in scalability, safety and regulatory harmonization. Manufacturing improvements are essential to meet growing demand, while addressing safety concerns, such as off-target gene-editing effects and tumorigenicity in MSC therapies, remains paramount.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aims and Scope","authors":"","doi":"10.1016/S1465-3249(25)00041-6","DOIUrl":"10.1016/S1465-3249(25)00041-6","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 3","pages":"Page A1"},"PeriodicalIF":3.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143351045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subscription information","authors":"","doi":"10.1016/S1465-3249(25)00044-1","DOIUrl":"10.1016/S1465-3249(25)00044-1","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 3","pages":"Page A5"},"PeriodicalIF":3.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143351048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Society for Cell & Gene Therapy Expanded Access Working Group position paper: key considerations to support equitable and ethical expanded access to investigational cell- and gene-based interventions.","authors":"Elena Maryamchik, Laertis Ikonomou, Beth E Roxland, Felix Grignon, Bruce L Levine, Bambi J Grilley","doi":"10.1016/j.jcyt.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.01.016","url":null,"abstract":"<p><p>This position paper reviews the Expanded Access pathway for cell and gene therapies, examining its critical role at the nexus of patient need, regulatory frameworks, and scientific advancement. Spearheaded by the International Society for Cell & Gene Therapy's Expanded Access Working Group, it explores how investigational therapies are accessed outside of clinical trials for patients with serious or life-threatening conditions when no approved alternatives exist. Access to cell and gene therapy products are of specific interest to patients because many times the products are bespoke, being used to treat serious and/or incurable conditions, and are potentially curative. As the field of cell and gene therapy rapidly progresses, healthcare professionals face mounting challenges in navigating the balance between access and oversight. Key considerations include transparent communication with patients, robust data reporting, and a discussion of cost recovery models and their implications for long-term commercialization strategies. Equity and inclusivity are central themes, highlighting the need to design pathways that are accessible to diverse patient populations while upholding high scientific and ethical standards. This position paper is presented as a resource for clinicians, researchers, and policymakers navigating the evolving landscape of investigational cell and gene therapies. It emphasizes the importance of ethical frameworks and equitable practices in delivering transformative treatments to patients in need.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cell-derived protein extract induces periodontal regeneration","authors":"Yihao Peng ,&nbsp;Kengo Iwasaki ,&nbsp;Yoichiro Taguchi ,&nbsp;Isao Ishikawa ,&nbsp;Makoto Umeda","doi":"10.1016/j.jcyt.2024.10.003","DOIUrl":"10.1016/j.jcyt.2024.10.003","url":null,"abstract":"<div><h3>Background</h3><div>Periodontal disease is characterized by chronic inflammation and destruction of supporting periodontal tissues, ultimately leading to tooth loss. In recent years, “cell-free treatment” without stem cell transplantation has attracted considerable attention for tissue regeneration. This study investigated the effects of extracts of mesenchymal stem cells (MSC-extract) and their protein components (MSC-protein) on the proliferation and migration of periodontal ligament (PDL) cells and whether MSC-protein can induce periodontal regeneration.</div></div><div><h3>Methods</h3><div>MSC-extract and MSC-protein were obtained by subjecting mesenchymal stem cells (MSCs) to freeze–thaw cycles and acetone precipitation. Cell proliferation was examined using a WST-8 assay and Ki67 immunostaining, and cell migration was examined using Boyden chambers. The MSC-protein content was analyzed using liquid chromatography-mass spectrometry, protein arrays, and enzyme-linked immunosorbent assays (ELISAs). Gene expression in MSC-protein-treated PDL cells was examined using RNA-sequencing and Gene Ontology analyses. The regenerative potential of MSC-protein was examined using micro-computer tomography (CT) and histological analyses after transplantation into a rat periodontal defect model.</div></div><div><h3>Results</h3><div>MSC-extract and MSC-protein promoted the proliferation and migration of PDL cells. Protein array and ELISA revealed that MSC-protein contained high concentrations of basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). Exogenous bFGF promoted the proliferation and migration of PDL cells. Furthermore, the transplantation of MSC-protein enhanced periodontal tissue regeneration with the formation of new alveolar bone and PDLs.</div></div><div><h3>Conclusions</h3><div>These results indicate that the MSC-protein promotes the proliferation and migration of PDL cells and induces significant periodontal tissue regeneration, suggesting that the MSC-protein could be used as a new cell-free treatment for periodontal disease.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 2","pages":"Pages 201-212"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subscription information","authors":"","doi":"10.1016/S1465-3249(25)00009-X","DOIUrl":"10.1016/S1465-3249(25)00009-X","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 2","pages":"Page A4"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143336728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders","authors":"Dimitrios Mougiakakos ,&nbsp;Ranjita Sengupta ,&nbsp;Ralf Gold ,&nbsp;Roland Schroers ,&nbsp;Aiden Haghikia ,&nbsp;Mario Lorente ,&nbsp;Michael Pendleton ,&nbsp;Ames Register ,&nbsp;Christoph Heesen ,&nbsp;Nicolaus Kröger ,&nbsp;Georg Schett ,&nbsp;Andreas Mackensen ,&nbsp;Amber Podoll ,&nbsp;Jonathan Gutman ,&nbsp;Richard Furie ,&nbsp;Ruthee Bayer ,&nbsp;Jörg H.W. Distler ,&nbsp;Sascha Dietrich ,&nbsp;Gerhard Krönke ,&nbsp;Lars Bullinger ,&nbsp;Karen Walker","doi":"10.1016/j.jcyt.2024.09.008","DOIUrl":"10.1016/j.jcyt.2024.09.008","url":null,"abstract":"<div><h3>Background</h3><div>B-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases.</div></div><div><h3>Methods</h3><div>KYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across seven autoimmune disease types (neurological autoimmune diseases, n = 13; rheumatological autoimmune diseases, n = 7). Patients ranged from 18 to 75 years of age. Duration of disease ranged from &lt;1 to 23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across nine sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4⁺/CD8⁺ T cells, transduced with a third generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19^+/– target cell lines.</div></div><div><h3>Results</h3><div>KYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11 to 66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37 and 77% with low variation in transgene copy number (two to four per cell). Cell viability of the final KYV-101 drug product ranged from 87 to 97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ.</div></div><div><h3>Conclusions</h3><div>KYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 2","pages":"Pages 236-246"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}