Cytotherapy最新文献

{"title":"Subscription information","authors":"","doi":"10.1016/S1465-3249(25)00696-6","DOIUrl":"10.1016/S1465-3249(25)00696-6","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Page A5"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098414","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":"SAFETY AND EFFICACY OF MESENCHYMAL STEM CELL THERAPY IN ADULTS WITH INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS.","authors":"J.C. Camacho Barbosa ,&nbsp;E. Nuñez ,&nbsp;L. López Quiceno ,&nbsp;F.A. Barrios Arroyave ,&nbsp;L.A. Palacio ,&nbsp;K. Halpert-Correa","doi":"10.1016/j.jcyt.2025.03.084","DOIUrl":"10.1016/j.jcyt.2025.03.084","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), poses significant treatment challenges. Mesenchymal stem cells (MSC) exhibit anti-inflammatory and immunomodulatory properties, making them a potential therapeutic option for IBD. We aim to synthesize the evidence on the safety and efficacy of MSC therapy in adults (≥18 years) with IBD.</div></div><div><h3>Methodology</h3><div>A systematic literature review was conducted, searching MEDLINE, EMBASE, Cochrane, LILACS, clinical trial registries, and grey literature for randomized controlled trials (RCTs); following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Two independent reviewers screened studies, assessed bias, and synthesized data focusing on disease severity, fistula healing, and serious adverse events (AEs). PROSPERO ID: CRD42022364875.</div></div><div><h3>Results</h3><div>Out of 1273 publications identified, 14 studies from 11 RCTs (n=584 adults) met inclusion criteria. Among these, 50% utilized allogenic bone marrow-derived MSC, 28.57% allogenic adipose-derived MSC (AD-MSC), 14.29% allogeneic umbilical cord-derived MSC, and 7.14% autologous AD-MSC. Cell doses ranged from 10 × 10⁶ to 300 × 10⁶. Twelve studies focused on CD and complications, with follow-ups up to 3 years, reporting two serious AEs: anal abscess and pneumonia. Of those, two studies found MSC therapy reduced disease severity and inflammation. One study on ileal-anal anastomosis and peripouch fistulas showed 31% healing in the MSC group at 6 months, compared to 20% in controls. Seven studies on perianal fistulas showed healing rates of up to 83% in MSC-treated patients. One study on rectovaginal fistulas showed a 50% healing rate in MSC patients. A pooled analysis of 3 RCTs on perianal, rectovaginal, and ileopouch fistulas showed durable responses, with healing rates of 67.7%, 37.5%, and 46.2%, respectively, at 12 months. The other two RCTs were performed on patients with UC with follow-ups for up to 2 years, and they showed MSC therapy to be safe and improved clinical, histological, and endoscopic scores in early disease.</div></div><div><h3>Conclusion</h3><div>This review suggests that MSC therapy is safe and effective in improving clinical outcomes for adults with IBD, particularly in those with Crohn's disease-related complications such as fistulas. The findings support further investigation into MSC therapy as a viable treatment option for IBD, given the high heterogeneity among studies—such as disease severity, cell type, dose, and administration frequency.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Page S51"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888164","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":"MOUSE MESENCHYMAL STROMAL CELL POTENCY ASSAY IN CONTEXT OF USE IN ACUTE LUNG INJURY","authors":"J. Barua ,&nbsp;A. Pennati ,&nbsp;J. Galipeau ,&nbsp;D. Weiss","doi":"10.1016/j.jcyt.2025.03.081","DOIUrl":"10.1016/j.jcyt.2025.03.081","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>Mesenchymal stromal cells (MSCs) due to their anti-inflammatory properties are being actively investigated to treat patients with acute respiratory distress syndrome (ARDS). While the clinical studies have established the safety and tolerability of allogeneic transfer of MSCs in ARDS patients, including COVID-19 ARDS, there remain uncertainties regarding MSC- mechanisms of action. To investigate this both in vitro and in vivo, it is important to determine the efficacy of the cells in addition to meeting the ISCT recommended minimal criteria of phenotypic characterization. We have established a potency assay for mouse bone marrow derived MSCs (mBM-MSCs) to determine their therapeutic fitness. This involves assessing the expression of several genes that have been shown to alter acute lung injury (ALI) outcomes. In addition, the effect of these cells’ secretome on macrophages is also analyzed as a part of potency assay.</div></div><div><h3>Methodology</h3><div>Mouse bone marrow-derived MSCs (mBM-MSCs) were cultured in DMEM supplemented with 2 mM L-Gln, 20% FBS and 1% Pen-Strep at 5% CO2 and 37°C. Cells between passage 3-5 were used for all experiments. mBM-MSCs were left untreated or treated with IFNγ, or TNFα, or both (10 ng/ml each) for 24 and 48 hrs. Post-treatment, the cells were either harvested for RNA or the media was changed to serum free DMEM for an additional 24 hrs. to collect conditioned media (CM). To assess gene expression, qRT-PCR was performed with targets IDO-1, TSG-6, IL-1RA and IL-6. The CM were used to incubate LPS-treated RAW 264.7 macrophages for 24 hrs. to determine M1/M2 phenotype using targets TNFα and IL-10.</div></div><div><h3>Results</h3><div>Our experiments showed that mBM-MSCs activated with a combination of IFNg and TNFa induce the mRNA expression of IDO-1, IL-1RA and IL-6 significantly after 24 hrs. of incubation, while also significantly upregulating TSG-6 mRNA expression after 48 hrs. CM from doubly primed</div><div>mBM-MSCs were able to upregulate expression of TNFα in RAW cells but did not alter the IL- 10 expression significantly.</div></div><div><h3>Conclusion</h3><div>Together, our data showed that pro-inflammatory cytokine stimulated mBM-MSCs enhanced the expression of genes that are therapeutically relevant for ALI and altered the macrophage phenotype to more M1-like. Further characterizations are needed to ensure the protein expression of these genes. Hereby, we propose this assay pipeline as a preliminary starting point to test the potency of these cells before utilizing to address subsequent research questions.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Page S49"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888225","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":"Mechanistic insights into MSC attenuation of trained immunity in macrophages","authors":"M. Dunlop ,&nbsp;H. Dunbar ,&nbsp;L. Bitterlich ,&nbsp;K. English","doi":"10.1016/j.jcyt.2025.03.086","DOIUrl":"10.1016/j.jcyt.2025.03.086","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>Over the past decade, the original dogma that innate immunity does not have memory has been challenged. Novel research has identified the capacity for macrophages to be trained such that upon a secondary heterologous pathogenic stimulus, a pro-inflammatory macrophage population quickly responds to deal with the pathogen. This trained immunity (TI) of pro-inflammatory macrophages is associated with epigenetic and metabolic imprinting and can be facilitated by exposure to a repeated dose of the BCG vaccine, the fungal chitin β-glucan and other non-pathogenic agents such as oxLDL, lipoprotein(a) and fumarate. On the flip side TI can drive an over-active immune system leading to chronic inflammation or autoimmune disease. Few strategies have been identified to deal with mal-adaptive TI responses. Here we investigated the potential for mesenchymal stromal cells (MSCs) to block TI in vitro and in vivo and to elucidate the mechanisms involved.</div></div><div><h3>Methodology</h3><div>We have developed in vitro and in vivo models to investigate the potential for human BM-MSCs to block TI in mouse bone marrow derived macrophages (BMDMs) in vitro and ex vivo and in human monocyte derived macrophages (MDMs) to a variety of TI inducers including house dust mite (HDM), β-glucan and palmitate. We used epigenetic, metabolic, and chemical antagonists/inhibitors and RNA-seq to identify the mechanisms of action.</div></div><div><h3>Results</h3><div>TI alters macrophage metabolism, reprogammes epigenetics and drives elevated pro-inflammatory cytokine responses. The presence of MSCs in a transwell for as little as 24hrs at the start of a 6-day TI assay blocks TI induced increases in the pro-inflammatory cytokines IL-6, TNFα and IL-1β in both mouse BMDMs and in human MDMs. Importantly, intravenously administered MSCs can block TI induced in vivo in a clinically relevant model of HDM-induced severe asthma. We identified important roles for MSC derived IL-1RA and COX-2 in blocking TI in macrophages and demonstrated that while MSCs significantly alter macrophage metabolism MSCs do not cause a metabolic switch in trained macrophages.</div></div><div><h3>Conclusion</h3><div>In vivo TI induces long term effects mediated by epigenetic and metabolic remodelling in monocyte precursor cells in the bone marrow. Here we show that systemic administration of MSCs 10 days before harvest in a HDM-allergic asthma model, blocks TI and therefore suggests that MSCs mediate this effect centrally in bone marrow precursor cells.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Page S52"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887599","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":"AI-enabled media optimisation enhances T-cell manufacturing process in scalable bioreactors","authors":"M. Kalli ,&nbsp;D.A. Carter ,&nbsp;L. Clarke ,&nbsp;C. Cejas ,&nbsp;A. Espinet ,&nbsp;M. Whittaker ,&nbsp;F.N. Konstanides ,&nbsp;C. Anderson ,&nbsp;A.O. Ward","doi":"10.1016/j.jcyt.2025.03.017","DOIUrl":"10.1016/j.jcyt.2025.03.017","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>The rapid advancement of cell therapies has revolutionised treatment paradigms, yet their clinical and commercial viability remains hindered by manufacturing inefficiencies. T-cell expansion, critical for the production of CAR-T therapies, faces challenges such as suboptimal growth conditions, T-cell exhaustion, and batch variability. Addressing these issues requires innovative approaches to enhance growth and potency while maintaining scalability and cost-effectiveness. This study represents a collaboration between MFX, Tolemy Bio, and AminoAcids.com, leveraging advanced bioreactor technology, combined with phenotypic profiling, and AI-enabled predictive modelling to redefine the T-cell manufacturing process.</div></div><div><h3>Methodology</h3><div>In this study, we culture human T-cells using the MFX-12 novel scalable bioreactor compared to T25 flasks. We perform daily sampling to capture metabolomic and transcriptomic data, providing a comprehensive view of cell metabolism and gene expression dynamics. Then we integrate these data into predictive AI-enabled metabolic models to identify and test optimised media formulations designed uniquely for T-cells in the MFX-12 bioreactor. Finally, we evaluate the impact of novel media on T-cell growth, viability, and functional potency.</div></div><div><h3>Results</h3><div>Early results demonstrate significant expansion (20-fold) in MFX-12 bioreactors with &gt;90% viability compared to conventional systems. Flow cytometry analysis shows that the major T-cell phenotype is effector memory with a small population of memory stem – a less differentiated and more optimal phenotype for CAR-T therapy. Combining these phenotypic input data with predictive modelling, we developed bespoke media formulations that maintain optimal nutrient availability and reduce metabolic stress throughout culture. We continue to evaluate the impact of custom media formulations on T-cell proliferation, phenotype, and production of higher-quality cells for therapeutic applications.</div></div><div><h3>Conclusion</h3><div>This collaboration highlights the transformative potential of bioadaptive analytics for T-cell manufacture; integrating novel bioreactor systems with AI-enabled media optimisation. By addressing inefficiencies in nutrient usage and environmental control, this approach enables a more predictable and scalable manufacturing process for CAR-T and other T-cell therapies. The study demonstrates novel AI-driven solutions in cell therapy, paving the way for cost-effective, high-quality, and scalable manufacturing processes to meeting clinical demands.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages S15-S16"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887857","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":"In vivo inter-mammalian horizontal gene transfer of transiently transfected pet-reporter, tracked in vivo by [18F]-FHBG-PET-CT","authors":"M. Gyöngyösi ,&nbsp;D. Lukovic ,&nbsp;M. Emmert ,&nbsp;S.P. Hoerstrup ,&nbsp;K. Zlabinger","doi":"10.1016/j.jcyt.2025.03.092","DOIUrl":"10.1016/j.jcyt.2025.03.092","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>Spontaneous horizontal jumping gene transfer is common in bacteria and plants, but gene transfer between living mammalians has not yet been reported. We aimed to long-term track in vivo the fate of the xenogeneic porcine mesenchymal stem cells (pig-MSC) transiently transfected with PET-reporter plasmid (pig-MSC-PETr) and implanted in sheep.</div></div><div><h3>Methodology</h3><div>Pig-MSC-PETr were seeded on acellularized tissue-engineered heart valves (TEHV) and implanted in sheep in pulmonary position. After percutaneous placement of TEHV-pig-MSC-PETr, the sheep underwent serial [18F]-FHBG-PET-CT imaging up to 6 months.</div></div><div><h3>Results</h3><div>Serial [18F]-FHBG-PET-CT displayed accumulated tracer signal of the TEHV-pig-MSC-PETr at 3 and 24 hours, 2 and 3 weeks, and 5 and 6 months, indicating spontaneous stable transfection of the cytoplasmic PET-reporter plasmid. This was confirmed by ex vivo [18F]-FHBG PET-CT imaging of one explanted TEHV-pig-MSC-PETr after 6-month follow-up. Immunohistochemistry and fluorescence imaging of the explanted TEHV-pig-MSC-PETr showed sheep alpha-smooth muscle actin-positive cells expressing the PET-reporter. While the [18F]-FHBG-PET tracer signal remained almost constant in vivo in TEVH position, the number of pig cells decreased and the sheep fibroblasts colonized the TEVH, proved by histology and pig- and sheep-specific DNA qPCR. The unexpected high PET signal intensity suggested the in vivo lateral gene transfer from the pig cells to host sheep cells, followed by integration into the sheep genome. The mechanism of the cross-species gene jumping in our experiment is curious, because the plasmid PET reporter construct encodes no transposase or reverse transcriptase and is considered to be a non-autonomous transposable element. Intracellular parasitic bacteria or endoparasites (which commonly affect sheep) or other potential carriers such as exosomes, apoptotic bodies, nanotubes, or nucleic acid-binding proteins might have shuttled the PET-reporter between the pig and sheep cells. Although a spontaneous genetic modification of an in vivo organism is difficult to reproduce, the mechanism is currently investigated.</div></div><div><h3>Conclusion</h3><div>In conclusion, we report the first serial in vivo tracking of pig-MSC-PETr seeded on TEHVs that were implanted in sheep, confirming the long-term survival of small amount of xenogeneic pig cells and the in vivo inter-mammalian species horizontal gene transfer between pig MSCs and host sheep myofibroblasts. The work has been supported by the LifeValve EU Grant.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages S54-S55"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888034","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":"A phase 1, open-label study to determine safety and tolerability of the topical application of mesenchymal stem/stromal cell (MSC) exosome ointment to treat psoriasis in healthy volunteers","authors":"Nisha Suyien Chandran ,&nbsp;Monil Nagad Bhupendrabhai ,&nbsp;Thong Teck Tan ,&nbsp;Bin Zhang ,&nbsp;Sai Kiang Lim ,&nbsp;Andre Boon Hwa Choo ,&nbsp;Ruenn Chai Lai","doi":"10.1016/j.jcyt.2025.01.007","DOIUrl":"10.1016/j.jcyt.2025.01.007","url":null,"abstract":"<div><h3>Background</h3><div>Topical application of mesenchymal stem/stromal cell (MSC) exosomes have yielded encouraging results in the treatment of psoriasis in pre-clinical studies. The safety of topical applications of MSC exosome in ointment has not yet been determined in human subjects.</div></div><div><h3>Objective</h3><div>To assess the safety and tolerability of an MSC exosome ointment, PTD2021P, for topical application in healthy adult volunteers.</div></div><div><h3>Methods</h3><div>Ten healthy adult volunteers were enrolled. All subjects received topical treatment with PTD2021P immediately followed by Vesiderm liposome cream ter in die (TID) (thrice a day) on the forearm with a gap of 4 hours between doses for 20 days and underwent another round of screening procedure at end of study (Day 21 + 3 days). Screening procedures included vital signs, blood examinations, photographs and visual assessment of the area of application. All through the treatment period, the subjects completed the daily Subject Diary to capture adverse events, concomitant medications, and time of study product application.</div></div><div><h3>Results</h3><div>One subject was reported with 1 treatment-emergent adverse event (TEAE) of COVID-19 infection during the study. The TEAE was moderate in severity and unlikely related to the study drug. This TEAE was resolved and the subject recovered fully. No subject was reported with clinically significant abnormality for laboratory parameters. As per the visual assessment of the area of application, no subject had dryness, itch, oozing/crusting, redness, scratch marks, skin thickening, sleeplessness, or swelling at the area of application of skin.</div></div><div><h3>Conclusions</h3><div>PTD 2021P was well tolerated for topical application. There were no serious adverse events (SAEs) or TEAEs related to the treatment, and no subject discontinued the study. No clinically significant abnormality was reported for laboratory parameters and vital signs. No abnormality was reported for visual assessment of the area of application of exosome ointment. This ointment could be an alternative therapeutic option for patients who are refractory to current first line therapy.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages 633-641"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366614","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 free fatty acid palmitate enhances MSC suppression of macrophages in a ceramide/CCL2/IL-10 dependent manner","authors":"L. Bitterlich ,&nbsp;C. Tunstead ,&nbsp;J.A. Ankrum ,&nbsp;A.E. Hogan ,&nbsp;K. English","doi":"10.1016/j.jcyt.2025.03.087","DOIUrl":"10.1016/j.jcyt.2025.03.087","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>The immunosuppressive activity of human mesenchymal stromal cells (MSCs) is central to the approved and investigational use of MSC therapy in inflammatory conditions such as GvHD. External factors like cytokines and other molecules encountered in the disease microenvironment significantly influence MSC immunosuppressive function. The obese microenvironment including elevated levels of serum free fatty acids, specifically palmitate, have the potential to affect MSC therapy. For T cell suppression, it has already been shown that exposure to palmitate impairs the ability of MSCs to carry out their function. However, we do not yet understand the effects of palmitate on MSC immunosuppression of macrophages. This study focused on investigating the influence of palmitate on MSC functional capacity to suppress macrophages and to elucidate the mechanisms of action at play.</div></div><div><h3>Methodology</h3><div>We used peripheral blood from healthy control and patients with obesity to investigate the immunosuppressive capacity for MSCs or MSCs exposed to plamitate in vitro. Following exposure to palmitate, the capacity for MSCs to alter human monocyte derived macrophage (MDM) production of TNFa and IL-10 and phenotype following LPS stimulation were investigated. Moreover, chemical anatagonists, neutralising antibodies and a biologically active, cell-permeable ceramide analog were used to uncover the mechanisms of action.</div></div><div><h3>Results</h3><div>Palmitate exposure significantly increased expression of the MSC immunomodulatory factors <em>ptgs2, il-6, ccl2</em> and <em>angptl4.</em> Palmitate exposed MSCs had significantly modulated LPS stimulated human MDMs leading to decreased TNFα and increased IL-10 production by MDMs. Using a neutralising antibody, we identified that enhanced suppression mediated by palmitate exposed MSCs involved CCL2. Using the biologically active, cell-permeable ceramide analog C2 as well as the cermide synthases inhibitor (fumonisin B1), we showed that palmitate enhanced MSC immunomodulation of MDMs via activating ceramide de novo synthesis.</div></div><div><h3>Conclusion</h3><div>Palmitate has a beneficial effect on macrophage immunomodulation by MSCs, suggesting that a high concentration of palmitate in the microenvironment likely does not negatively affect MSC therapy in conditions where MSC -macrophage interactions are central to MSC mode of action.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages S52-S53"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888163","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":"A Protocol for Priming MSCs to Produce Conditioned Medium That Reduces Senescence and Enhances Fibroblast Proliferation","authors":"S. Peñaherrera ,&nbsp;A. Benavides-Almeida ,&nbsp;Á. Perez ,&nbsp;A. Haro-Vinueza ,&nbsp;D. Villavicencio ,&nbsp;G. Pazmiño ,&nbsp;A. Caicedo","doi":"10.1016/j.jcyt.2025.03.083","DOIUrl":"10.1016/j.jcyt.2025.03.083","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>Mesenchymal stem cells (MSCs) are a cornerstone of regenerative medicine due to their ability to secrete bioactive factors that modulate cellular behavior and promote tissue repair. However, the culture conditions under which MSCs are expanded significantly influence their secretory profiles and the therapeutic efficacy of their conditioned medium (CM). To address this, we developed an innovative priming protocol involving sequential stimulation with growth factors, emergency signals, and mitochondrial transfer to enhance MSC regenerative capabilities (Patent Pending: SENADI-2024-91641). This protocol generates CM with properties capable of reducing cellular senescence, promoting fibroblast proliferation, and mitigating damage induced by ultraviolet radiation (UVR) and oxidative stress. These advancements hold significant promise for anti-aging therapies and translational research.</div></div><div><h3>Methodology</h3><div>Human Wharton Jelly MSCs were sequentially primed using growth hormone (GH), epinephrine as an emergency signal (E), and artificial mitochondrial transfer (M). Senescent human fibroblasts were generated through a UVR and H2O2 double-shock method. CM or GHEM was collected from primed MSCs and applied to fibroblasts. The effects on senescence markers (β-Galactosidase, P21, P53), proliferation rates, and morphological characteristics were evaluated using flow cytometry, RT-qPCR, and microscopy.</div></div><div><h3>Results</h3><div>MSCs were sequentially primed using growth hormone (GH), epinephrine as an emergency signal (E), and artificial mitochondrial transfer (M). Senescent human fibroblasts were generated through a UVR and H2O2 double-shock method. CM or GHEM was collected from primed MSCs and applied to fibroblasts. The effects on senescence markers (β-Galactosidase, P21, P53), proliferation rates, and morphological characteristics were evaluated using flow cytometry, RT-qPCR, and microscopy. Non-parametric analyses were performed, Mann-Whitney, N=6 ***P &lt; 0.001, ****P &lt; 0.0001, Graph Pad Prism.</div></div><div><h3>Conclusion</h3><div>Our findings show that the sequential priming of MSCs with growth factors, emergency signals, and mitochondrial transfer enhances their secretory profiles, resulting in a potent CM with significant regenerative potential. This scalable and cost-effective approach provides a platform for developing therapeutic applications in tissue repair, anti-aging strategies, and regenerative medicine. Further studies are warranted to explore additional functional and mechanistic insights, paving the way for clinical translation.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages S50-S51"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888227","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":"ENEPC-CLI-01- A PHASE 2 DOUBLE BLIND PLACEBO CONTROLLED STUDY FOR AUTOLOGOUS BGC-101, ENRICHED ENDOTHELIAL PROGENITOR CELLS, FOR CRITICAL LIMB THREATENING ISCHEMIA","authors":"S. Cohen ,&nbsp;Y. Gothelf ,&nbsp;Y. porat ,&nbsp;T. Shitrit ,&nbsp;A. Shicht","doi":"10.1016/j.jcyt.2025.03.036","DOIUrl":"10.1016/j.jcyt.2025.03.036","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><div>EnEPC (BGC-101) is a population of autologous endothelial progenitor cells (EPC) enriched from the peripheral blood of patients with critical limb threatening ischemia (CLTI) by inducing immature Dendritic cells (DC) to specifically direct activation of their Stem/Progenitor cells (SPC). EnEPCs were shown <em>in vitro</em> to secrete proangiogenic chemoattractant as well as anti-inflammatory cytokines that reduce the chronic inflammation typical of ischemic areas. EnEPCs are then injected back intramuscularly to the patient.</div><div>CLTI is a major unmet need. Despite advances in treatment, including surgical and radiological intervention, approximately 35% of CLTI patients will undergo amputation and 20% will die within 6-12 months.</div><div>Preclinical studies in a nude mice limb ischemia model showed that EnEPCs significantly increased blood perfusion and capillary density with high safety profile. After 21 days BGC101 treatment doubled the blood flow to the legs. Cell tracking and biodistribution showed that engraftment was restricted to the ischemic limb (Porat et al. 2014).</div><div>A pilot, single site, open-label study with BGC101 in 5 patients with CLTI (including 3 diabetics) who had not responded to standard pharmacological treatment, with no revascularization option, and 5 compassionate treatments for ‘no-option' CLTI patients (including 3 diabetics), provided initial indications of efficacy by preventing amputations (Niven et al. 2020).</div><div>Results show 80% amputation free survival (AFS) at 12 months with prolonged safety and durable therapeutic effects including wound healing, improved perfusion, walking capability and freedom of pain after over 7 years, to be confirmed in a Phase 2 study.</div></div><div><h3>Methodology</h3><div>The ENEPC-CLI-01 ongoing Phase 2 double blind placebo controlled multicenter multinational study primary endpoints include safety and efficacy, major amputation (below or above the knee) rate at month 12 and major AFS rate at Month 12</div></div><div><h3>Results</h3><div>The study for Rutherford category 4-5 patients with no revascularization option, has enrolled 40 patients including 23 diabetic patients and confirmed the treatment to be safe and well tolerated. Promising results of 80% AFS with no difference between diabetic and non-diabetic patients were observed in the Phase-2 blinded interim analyses.</div><div>Based on BGC101 mode of action as well as preclinical and clinical data review, BGC101 has been granted FDA Fast Track designation.</div></div><div><h3>Conclusion</h3><div>Next steps include completion of Phase 2 and a Phase 3 study bringing the treatment to patients in need</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 5","pages":"Pages S25-S26"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887586","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}