Cytotherapy最新文献

{"title":"Enrichment of CD4+ and CD8+ T lymphocytes with a column-free flow-based device for clinical cell manufacturing","authors":"Paulina Langa ,&nbsp;Kriti Sharma ,&nbsp;David L. Sellers ,&nbsp;Veronica Placencia ,&nbsp;Eric A. Smith ,&nbsp;Dan Fick ,&nbsp;John R. Wilson ,&nbsp;Silin Sa ,&nbsp;Nathaniel Ortega ,&nbsp;Liping Yu ,&nbsp;Yuchen Zhou ,&nbsp;Ignacio Núñez ,&nbsp;Amittha Wickrema","doi":"10.1016/j.jcyt.2024.12.009","DOIUrl":"10.1016/j.jcyt.2024.12.009","url":null,"abstract":"<div><div>In recent years, adoptive T cell-based immunotherapies have been developed to treat a wide range of hematologic malignancies, including relapsed or refractory non-Hodgkin lymphoma, B-cell leukemia, and multiple myeloma. Most of the commercially approved adoptive T cell therapies are composed of chimeric antigen receptor (CAR)–based T cells, which are a patient's own T cells engineered for recognition of a specific surface antigen, such as CD19 or CD20. Unselected peripheral blood mononuclear cells (PBMCs) have recently been used in several manufacturing protocols, but the vast majority of protocols still use CD4/CD8-selected T cells. The first step in manufacture of these CAR-T products involves simultaneous selection/purification of CD4⁺ and CD8⁺ (or CD4/CD8 positive) T cells. The typical approach for selection of CD4/CD8 subsets for clinical manufacturing involves immunomagnetic labeling followed by selection of positively labeled cells using static column-based approaches that are prone to cell clogging events and typically take approximately 2 to 3 hours in a closed system. Here, we used a new column-free, flow-based, fully closed system suitable for clinical cell manufacturing for isolation of CD4/CD8 cells with high purity in a rapid fashion that could accommodate varying capacities without compromising cell recovery. This new approach allows markedly faster cell selection, preserving the quality of the cells that are used for downstream CAR-T cell manufacture. We report the results of our successful validation runs using the new MARS Bar enrichment platform using human apheresis-derived leukocytes for CD4/CD8 isolation in a selection buffer or directly in T cell culture media for subsequent CAR-T cell production. Our data show a rapid and robust CD4/CD8 enrichment with an enrichment time shortened to 1 hour or less. Overall purity (based on CD3⁺ expression) of the cells was 95.51 ± 1.23% and 93.13 ± 0.30% for fresh and thawed T cells, respectively. Cell recoveries were 64.68 ± 14.05% and 57.06 ± 6.28% for fresh and thawed cells, respectively. We then further tested the MARS Bar enrichment platform after cell wash/volume reduction using the LOVO Automated Cell Processing System, leading to a higher consistency in CD3⁺ purity and increased cell recovery of 68.50 ± 3.54%. Enriched cells were characterized by high viability, ie. 90.5 ± 0.05% for fresh leukopaks when used together with the LOVO device. Altogether, the new approach using the MARS Bar platform allows one to customize and standardize the selection process by using a stand-alone instrument in a clinical manufacturing setting together with cGMP grade reagents and buffers.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 4","pages":"Pages 534-543"},"PeriodicalIF":3.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076221","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":"Comprehensive characterization of cytopenia after chimeric antigen receptor-T cell infusion in patients with relapsed or refractory multiple myeloma","authors":"Hai Cheng ,&nbsp;Lingyan Shao ,&nbsp;Dandan Wang ,&nbsp;Yegan Chen ,&nbsp;Yingjun Sun ,&nbsp;Zihan Chen ,&nbsp;Jiaying Liu ,&nbsp;Xue Wang ,&nbsp;Wei Chen ,&nbsp;Wei Sang ,&nbsp;Kunming Qi ,&nbsp;Zhenyu Li ,&nbsp;Cai Sun ,&nbsp;Ming Shi ,&nbsp;Jianlin Qiao ,&nbsp;Qingyun Wu ,&nbsp;Lingyu Zeng ,&nbsp;Junnian Zheng ,&nbsp;Li Li ,&nbsp;Kailin Xu ,&nbsp;Jiang Cao","doi":"10.1016/j.jcyt.2024.08.007","DOIUrl":"10.1016/j.jcyt.2024.08.007","url":null,"abstract":"<div><h3>Background</h3><div>Many studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized.</div></div><div><h3>Methods</h3><div>A total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors.</div></div><div><h3>Results</h3><div>Patients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS.</div></div><div><h3>Conclusions</h3><div>The majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 16-24"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247976","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":"Enriching central memory T cells using novel bioreactor design for T cell manufacturing","authors":"Sixun Chen,&nbsp;Akshaya V. Prabhu,&nbsp;Ahmad Amirul Bin Abdul Rahim,&nbsp;Kang-Zheng Lee,&nbsp;Dan Liu","doi":"10.1016/j.jcyt.2024.10.001","DOIUrl":"10.1016/j.jcyt.2024.10.001","url":null,"abstract":"<div><h3>Background</h3><div>The manufacturing of T cell therapies aims to achieve high yields of product with potent phenotypes. We have developed a novel bioreactor, bioreactor with expandable culture area—dual chamber (BECA-D), which has previously demonstrated functionality for scaled T cell manufacturing.</div></div><div><h3>Methods and Results</h3><div>Methods and Results: In this study, incorporation of a stirring mechanism into the double-chamber bioreactor design was tested to homogenize the media components between the two chambers. In addition to the improved media homogenization, the stirring culture was observed to have higher yield and enrichment of central memory T cells, a T cell subpopulation that has been associated with improved therapeutic efficacy compared with a static control. BECA-D with a stirring mechanism was evaluated for its performance in culturing T cells in comparison with a static control, BECA-D, and an industry benchmark, G-Rex10 (Wilson Wolf Manufacturing). BECA-D with a stirring mechanism was able to preferentially promote the enrichment of central memory T cells compared with the static cultures, indicative of the effect of the stirring mechanism.</div></div><div><h3>Conclusion</h3><div>By achieving high T cell yields with a favorable subpopulation profile, the mechanical method of incorporating stirring into a double-chamber bioreactor such as BECA-D carries great potential as a useful research and manufacturing tool to support advanced T-cell therapy manufacturing.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 128-134"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479807","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}

{"title":"Late-onset relapsing neurotoxicity after Brexucabtagene autoleucel associated with high chimeric antigen receptor T cells in cerebrospinal fluid","authors":"Chiara De Philippis ,&nbsp;Arianna Giacomel ,&nbsp;Umberto Pensato ,&nbsp;Chiara Pinton ,&nbsp;Daniela Taurino ,&nbsp;Daniele Mannina ,&nbsp;Jacopo Mariotti ,&nbsp;Barbara Sarina ,&nbsp;Simona Marcheselli ,&nbsp;Inna Timofeeva ,&nbsp;Rossana Capizzuto ,&nbsp;Armando Santoro ,&nbsp;Stefania Bramanti","doi":"10.1016/j.jcyt.2024.07.015","DOIUrl":"10.1016/j.jcyt.2024.07.015","url":null,"abstract":"<div><h3>Background aims</h3><div>Mounting evidence suggests that persistent cell expansion is the main driver for both efficacy and toxicity of chimeric antigen receptor (CAR) T-cell therapy. Hereby, we describe a case of delayed recurrent neurotoxicity associated with late CAR T-cells re-expansion.</div></div><div><h3>Case description</h3><div>A 44-year-old man suffering from mantle cell lymphoma received brexu-cel. After infusion, he developed grade 2 cytokine release syndrome. On day +11, grade 3 neurotoxicity was reported and high-dose methylprednisolone was started with a complete resolution of neurological manifestations. On day +30, he experienced a late-onset CAR T-cell toxicity associated with CAR T-cell re-expansion. The patient was treated with tocilizumab and dexamethasone, with resolution of symptoms. On day +58, he was readmitted for new onset of neurotoxicity. Notably, a new CAR T-cell expansion was observed, with an unexpectedly elevated cerebrospinal fluid/blood ratio. The patient was promptly treated with dexamethasone and then escalated to high-dose methylprednisolone and anakinra, with resolution of his neurologic condition noted.</div></div><div><h3>Conclusions</h3><div>CAR T-cell–related neurotoxicity usually has an early monophasic course. To our knowledge, this is the first case of late-onset, recurrent neurotoxicity. Moreover, an elevated level of cerebrospinal fluid CAR T cells was observed, which may suggest that the delayed neurotoxicity was primarily caused by the brain infiltration of CAR T cells rather than driven by cytokine-mediated neuroinflammation.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 25-28"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996870","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(24)00954-X","DOIUrl":"10.1016/S1465-3249(24)00954-X","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Page A5"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148152","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":"Advancing immunomodulatory functions in mesenchymal stem/stromal cells through targeting the GATA6-mediated pathway","authors":"Eric Chang-Yi Lin ,&nbsp;Madison P. Davis ,&nbsp;Ming-Song Lee ,&nbsp;Gui Ma ,&nbsp;Wei Xu ,&nbsp;Yuan-I Chang ,&nbsp;Wan-Ju Li","doi":"10.1016/j.jcyt.2024.08.001","DOIUrl":"10.1016/j.jcyt.2024.08.001","url":null,"abstract":"<div><h3>Background aims</h3><div>The immunomodulatory capacity of mesenchymal stem/stromal cells (MSCs) is a key feature that makes them particularly valuable for regenerative medicine. However, this potential is affected by the chronological aging of the donors and the cell expansion procedures in culture. We have demonstrated that GATA binding protein 6 (GATA6) plays a pivotal role in the aging of MSCs and inhibiting GATA6 rejuvenates the characteristics of MSCs.</div></div><div><h3>Methods</h3><div>In this study, we compared the immunomodulatory capabilities of young and old MSC models, using induced pluripotent stem cells-derived rejuvenated MSCs (rMSCs) and their parental MSCs (pMSCs), respectively, to identify a key mechanism involved in the differential regulation of these capabilities. Additionally, we explored the role of GATA6 in mediating the mechanism.</div></div><div><h3>Results</h3><div>Our results demonstrated that rMSCs exhibited downregulated aging-associated regulators, including p53, p21 and GATA6, and showed enhanced suppression of T cell proliferation compared to pMSCs. Through analyzing our previous RNA-seq data and employing target gene knockdown, we determined both suppressors of cytokine signaling 3 (SOCS3) and interleukin 6 were involved in GATA6-induced regulation, collectively affecting the expression of programmed death ligand 1 (PDL1) in both pMSCs and rMSCs.</div></div><div><h3>Conclusions</h3><div>Our findings underline the significance of the GATA6/SOCS3/PDL1 pathway in regulating aging-associated changes in MSC immunomodulatory activity, providing valuable insights into the potential use of rMSCs in the treatment of immune diseases and regenerative medicine.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 85-97"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114410","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":"Using qPCR and ddPCR to study biodistribution of cell therapy products: a multi-site evaluation","authors":"Eriko Fujita ,&nbsp;Syunsuke Yamamoto ,&nbsp;Takeshi Hanada ,&nbsp;Shingo Jogasaki ,&nbsp;Yoshiyuki Koga ,&nbsp;Yukinori Yatsuda ,&nbsp;Yoshiyuki Kakizaki ,&nbsp;Yoshinori Jo ,&nbsp;Yuya Asano ,&nbsp;Koichi Yonezawa ,&nbsp;Yuu Moriya ,&nbsp;Miyu Nakayama ,&nbsp;Yukiko Arimura ,&nbsp;Yurie Okawa ,&nbsp;Hiroyuki Komatsu ,&nbsp;Masahiko Ito ,&nbsp;Syunsuke Suzuki ,&nbsp;Takuya Kuroda ,&nbsp;Satoshi Yasuda ,&nbsp;Yoshiteru Kamiyama ,&nbsp;Yoji Sato","doi":"10.1016/j.jcyt.2024.09.003","DOIUrl":"10.1016/j.jcyt.2024.09.003","url":null,"abstract":"<div><h3>Backgroud aims</h3><div>Regenerative therapies employing cell therapy products (CTPs) have attracted considerable attention. Biodistribution (BD) evaluation of CTPs is mainly performed to clarify the cell survival time, engraftment, and distribution site. This evaluation is crucial for predicting the efficacy and safety profiles of clinical studies based on non-clinical BD study outcomes. However, no internationally unified method has been established for assessing cell BD after administration. Here, we aimed to standardize the BD assay method used for CTPs, conducting the following evaluations using the same protocol across multiple study facilities: (1) <em>in vitro</em> validation of quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR) analyses using the primate-specific Alu gene, and (2) <em>in vivo</em> BD studies after the intravenous administration of human mesenchymal stem cells (hMSCs) to immunodeficient mice, commonly used in non-clinical tumorigenicity studies.</div></div><div><h3>Methods</h3><div>Quality control samples were prepared and analyzed by adding a fixed number of human-derived cells to several mouse tissues. The respective quantitative performances of the qPCR and ddPCR methods were compared for accuracy and precision. hMSCs were intravenously administered to immunodeficient mice, and tissues were collected at 1, 4, and 24 h after administration.</div></div><div><h3>Results</h3><div>Both methods demonstrated an accuracy (relative error) generally within ±50% and a precision (coefficient of variation) generally less than 50%. While differences in calibration curve ranges were observed between qPCR and ddPCR, no significant differences in quantification were found among the assay facilities. The BD of hMSCs in mice was evaluated at seven facilities (qPCR at three facilities; ddPCR at four facilities), revealing similar tissue distribution profiles in all facilities, with the lungs showing the highest cell distribution among the tissues tested.</div></div><div><h3>Conclusions</h3><div>Quantitative evaluation of qPCR and ddPCR using Alu sequences was conducted, demonstrating that the test method can be adapted for BD evaluation.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 51-65"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512323","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}

{"title":"Expansion of tumor-infiltrating and marrow-infiltrating lymphocytes from pediatric malignant solid tumors","authors":"Jonathan Metts ,&nbsp;Madeline Rodriguez-Valentin ,&nbsp;Jonathan Hensel ,&nbsp;Alex Alfaro ,&nbsp;Christopher W. Snyder ,&nbsp;Odion Binitie ,&nbsp;Caroline Chebli ,&nbsp;Hector Monforte ,&nbsp;Shari Pilon-Thomas ,&nbsp;John Mullinax","doi":"10.1016/j.jcyt.2024.08.002","DOIUrl":"10.1016/j.jcyt.2024.08.002","url":null,"abstract":"<div><h3>Introduction</h3><div>The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies. The objective of this study was to demonstrate successful expansion of TIL from pediatric solid tumors for translation in an adoptive cell therapy (ACT) treatment strategy.</div></div><div><h3>Methods</h3><div>A prospective study of TIL/MIL expansion was performed on solid tumors of pediatric patients undergoing standard-of-care procedures. TIL/MIL expansions were performed in the presence of high-dose interleukin 2. To demonstrate a full-scale expansion to clinically-relevant cell doses for TIL therapy, initial TIL culture was followed by a rapid expansion protocol for select patients. Expanded specimens were analyzed for phenotype by flow cytometry and for anti-tumor reactivity by the interferon-gamma release assay.</div></div><div><h3>Results</h3><div>Eighteen tumor samples were obtained. Initial TIL cultures were successfully generated from 14/18 samples (77.7%). A median of 5.52 × 107 (range: 2.5 × 106–3.23 × 108) cells were produced from initial cultures, with 46.9% expressing a CD3 phenotype (46.9%). Eight samples underwent rapid expansion, demonstrating a median 458-fold expansion and a CD3 phenotype of 98%. Initial MIL cultures were successfully generated from five samples, with a predominantly CD3 phenotype (45.2%). Sufficient tumor tissue was only available for seven TIL samples to be tested for reactivity; none demonstrated responsiveness to autologous tumor.</div></div><div><h3>Conclusions</h3><div>TIL and MIL expansion from pediatric solid tumors was successful, including the full-scale expansion process. This data supports translation to an ACT-TIL treatment strategy in the pediatric population and thus a Phase I trial of ACT-TIL in pediatric high-risk solid tumors is planned.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 29-35"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146763","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":"Challenges in advancing Schwann cell transplantation for spinal cord injury repair","authors":"James D. Guest ,&nbsp;Andrea J. Santamaria ,&nbsp;Juan. P. Solano ,&nbsp;Juan P. de Rivero Vaccari ,&nbsp;William D. Dietrich ,&nbsp;Damien D. Pearse ,&nbsp;Aisha Khan ,&nbsp;Allan D. Levi","doi":"10.1016/j.jcyt.2024.08.005","DOIUrl":"10.1016/j.jcyt.2024.08.005","url":null,"abstract":"<div><h3>Background Aims</h3><div>In this article we aimed to provide an expert synthesis of the current status of Schwann cell (SC)therapeutics and potential steps to increase their clinical utility.</div></div><div><h3>Methods</h3><div>We provide an expert synthesis based on preclinical, clinical and manufacturing experience.</div></div><div><h3>Results</h3><div>Schwann cells (SCs) are essential for peripheral nerve regeneration and are of interest in supporting axonal repair after spinal cord injury (SCI). SCs can be isolated and cultivated in tissue culture from adult nerve biopsies or generated from precursors and neural progenitors using specific differentiation protocols leading to expanded quantities. In culture, they undergo dedifferentiation to a state similar to “repair” SCs. The known repertoire of SC functions is increasing beyond axon maintenance, myelination, and axonal regeneration to include immunologic regulation and the release of potentially therapeutic extracellular vesicles. Recently, autologous human SC cultures purified under cGMP conditions have been tested in both nerve repair and subacute and chronic SCI clinical trials. Although the effects of SCs to support nerve regeneration are indisputable, their efficacy for clinical SCI has been limited according to the outcomes examined.</div></div><div><h3>Conclusions</h3><div>This review discusses the current limitations of transplanted SCs within the damaged spinal cord environment. Limitations include limited post-transplant cell survival, the inability of SCs to migrate within astrocytic parenchyma, and restricted axonal regeneration out of SC-rich graft regions. We describe steps to amplify the survival and integration of transplanted SCs and to expand the repertoire of uses of SCs, including SC-derived extracellular vesicles. The relative merits of transplanting autologous versus allogeneic SCs and the role that endogenous SCs play in spinal cord repair are described. Finally, we briefly describe the issues requiring solutions to scale up SC manufacturing for commercial use.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 36-50"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479806","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":"Enhancing EV-cell communication through “External Modulation of Cell by EV” (EMCEV)","authors":"Thong Teck Tan ,&nbsp;Ruenn Chai Lai ,&nbsp;Wei Kian Sim ,&nbsp;Bin Zhang ,&nbsp;Sai Kiang Lim","doi":"10.1016/j.jcyt.2024.07.014","DOIUrl":"10.1016/j.jcyt.2024.07.014","url":null,"abstract":"<div><div>Mesenchymal stem/stromal cells (MSC) have displayed promising therapeutic potential. Nonetheless, no United States Food and Drug Administration (FDA)–approved MSC product exists due largely to the absence of a reliable potency assay based on the mechanisms of action to ensure consistent efficacy. MSCs are now thought to exert their effects primarily by releasing small extracellular vesicles (sEVs) of 50–200 nm. While non-living MSC-sEV drugs offer distinct advantages over larger, living MSC drugs, elucidating their mechanism of action to develop robust potency assays remains a challenge. A pivotal prelude to elucidating the mechanism of action for MSC-sEVs is how extracellular vesicles (EVs) engage their primary target cells. Given the inherent inefficiencies of processes such as endocytosis, endosomal escape and EV uncoating during cellular internalization, we propose an alternative EV-cell engagement: EMCEV (<u>E</u>xtracellular <u>M</u>odulation of <u>C</u>ells by <u>EV</u>). This approach involves extracellular modulation by EV attributes to generate signaling/inhibitory molecules that have the potential to affect many cells within the vicinity, thereby eliciting a more widespread tissue response.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 1","pages":"Pages 1-6"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037608","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}