Stem Cells Translational Medicine最新文献

{"title":"Efficient and robust generation of functional hematopoietic cells from human pluripotent stem cells in albumin-free conditions.","authors":"Byung Woo Kim, Linyi Zhang, Mo Liu, Supreet Khanal, Ye Eun Jeong, Ge Zheng, Nirjal Bhattarai, Zhaohui Ye","doi":"10.1093/stcltm/szag020","DOIUrl":"https://doi.org/10.1093/stcltm/szag020","url":null,"abstract":"<p><p>Generation of human hematopoietic stem and progenitor cells (HSPCs) from pluripotent stem cells (PSCs) holds significant promise in disease modeling, drug screening, and the development of cell and gene therapies for various hematologic and nonhematologic disorders. However, efficient and consistent derivation of functional HSPCs remains a major challenge hindering their practical use in biomedical research and applications. One of the contributing factors is the use of human serum albumin (HSA), which has been widely regarded as essential for supporting ex vivo maintenance, expansion, and differentiation of human stem cells and their derivatives. The lot-to-lot variation of this critical reagent can contribute to inconsistent laboratory results and high manufacturing costs. In this study, we address the manufacturing and regulatory challenges associated with using HSA in HSPC differentiation and propose an approach using a caprolactam-based polymer as an alternative. Our differentiation method demonstrates robust HSPC generation across various embryonic and induced PSC lines and culture conditions, highlighting its adaptability and reliability. Importantly, PSC-derived HSPCs exhibit functional versatility in differentiation capacity into myeloid and lymphoid lineages, as validated through colony-forming assays as well as directed red blood cell and NK cell differentiations. These findings suggest that HSA is dispensable in HSPC differentiation and replacing it with synthetic polymers has the potential to mitigate lot-to-lot reagent variation, improve HSPC production consistency, lower manufacturing costs, and expedite clinical applications.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles produced by a large-scale protocol are therapeutically effective in preclinical model of Parkinson's disease.","authors":"Agnė Pociūtė, Virginijus Tunaitis, Arūnas Žebrauskas, Vladimirs Pilipenko, Baiba Jansone, Karina Narbute, Marianne Pultar, Matthias Hackl, Augustas Pivoriūnas","doi":"10.1093/stcltm/szag024","DOIUrl":"10.1093/stcltm/szag024","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic applications require large amounts of extracellular vesicles (EVs) that cannot be obtained by standard laboratory protocols. Since culturing parameters and isolation methods can significantly affect the molecular composition and therapeutic efficacy of EVs, the development of a new scale-up protocol should be followed by the molecular fingerprinting and validation of therapeutic potential in vivo.</p><p><strong>Methods: </strong>We developed a new scale-up protocol based on microcarrier culture (3D) of immortalized human dental pulp stem cells in a spinning bioreactor and subsequent isolation of EVs by 2-step tangential flow filtration (TFF) and size exclusion chromatography (SEC).</p><p><strong>Results: </strong>A new scale-up protocol increased EV yields by 463-fold. When compared with ultracentrifugation (UC), isolation using TFF/SEC substantially reduced the complexity of proteomic cargo, whereas culture conditions (2D vs. 3D) affected miRNA, but not mRNA and proteomic content of the EVs. We next compared the therapeutic efficacy of both EV products in 6-hydroxydopamine rat model of Parkinson's disease (PD). The same amounts of EVs derived from standard 2D cultures by UC and a new large-scale protocol were intranasally administered to PD rats, where they similarly improved gait and cognitive functions, preserved nigrostriatal tyrosine hydroxylase density and suppressed neuroinflammation. Notably, both EV preparations were enriched in proteins and miRNAs associated with anti-oxidative and anti-inflammatory responses.</p><p><strong>Conclusion: </strong>Our protocol allows large-scale production of EVs that are therapeutically effective in the pre-clinical model of PD.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and validation of islet regenerative proteins secreted by human multipotent stromal cells.","authors":"Xin Y Xie, Nouran N Al-Banaa, Yina Tian, Gillian I Bell, Miljan Kuljanin, Tyler T Cooper, Caleb J Podgers, Ajaya Sharma, Anargyros Xenocostas, Gilles A Lajoie, David A Hess","doi":"10.1093/stcltm/szag022","DOIUrl":"10.1093/stcltm/szag022","url":null,"abstract":"<p><strong>Introduction: </strong>Diabetes affects >500 million people worldwide. Despite insulin therapy, most patients develop devastating complications, emphasizing the need for curative strategies. Human multipotent stromal/stem cells (MSC) secrete factors that promote islet regeneration. We previously showed that intrapancreatic (iPan) delivery of Wnt-activated MSC-conditioned media (Wnt+ CM) stimulates islet regeneration without cell transfer. This study aimed to identify and functionally validate specific MSC-secreted proteins with islet regenerative potential.</p><p><strong>Methods: </strong>Comprehensive mass spectrometry-based, quantitative proteomic analyses comparing Wnt-pathway activated versus untreated MSC secretomes were cross-referenced with a prior dataset distinguishing regenerative from nonregenerative MSC CM. Proteins enriched in both conditions were iPan-injected individually or in combination into streptozotocin-treated NOD/SCID mice. Nonfasting glucose, glucose tolerance, beta cell mass, islet morphology, and islet cell proliferation were assessed at 4- and 32-days post-treatment.</p><p><strong>Results: </strong>Cross-referenced secretome analyses identified eight proteins implicated in islet regeneration: CALU, CTSB, FAM3C, GAL1, PPIA, PSAP, SOD1, and TGM2. A single iPan-injection of the 8-protein combination significantly lowered hyperglycemia, improved glucose tolerance, and increased beta cell mass, comparable to Wnt+ CM. Regenerative effects such as increased beta cell proliferation appeared as early as day 4. Single-protein testing identified CALU and SOD1 as leading candidates, improving glucose tolerance and reducing nonfasting glucose.</p><p><strong>Conclusion: </strong>This study defines a set of MSC-secreted proteins that promote islet regeneration in vivo, supporting the development of protein-based biologics to preserve or restore beta cell function during diabetes, with potential applications alongside islet replacement therapies to enhance graft survival and function.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intra-articular allogeneic adipose-derived mesenchymal stromal cell injections for stage III knee osteoarthritis: a double-blind placebo-controlled trial with 60-month follow-up.","authors":"Hanan Jafar, Osama Samara, Diana Shahin, Fadwa Daoud, Dana Al-Hattab, Aseel Samara, Lina Al Lawama, Mohammed Hamdan, Huda Qubbaj, Bareqa Salah, Abdalla Awidi","doi":"10.1093/stcltm/szag018","DOIUrl":"10.1093/stcltm/szag018","url":null,"abstract":"<p><p>Knee osteoarthritis (KOA) is a progressive degenerative joint disease with limited treatment options that effectively modify disease progression. This study evaluates the safety and efficacy of allogeneic adipose-derived mesenchymal stromal cells (ADMSCs) injected under ultrasound guidance in patients with symptomatic stage III KOA. In this single-site, randomized, double-blind, placebo-controlled trial, patients were assigned to receive either 2 doses of allogeneic expanded ADMSCs, administered 2 weeks apart (Arm A, mean total dose: 69.58 × 106 ADMSCs), or 2 equal-volume normal saline injections (Arm B). Blinding was maintained for 12 months, after which follow-up of Arm A continued to 60 months. Treatment efficacy was assessed using normalized Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index at 6, 12, 24, 36, 48, and 60 months, while magnetic resonance imaging (MRI) evaluations were performed at baseline and 12 months. A total of 29 subjects (21 in Arm A, 8 in Arm B) completed the study. Adverse events in Arm A were mild and transient, including localized pain and swelling. Patients in Arm A demonstrated significant improvements in clinical scores compared to baseline, with highly significant differences at 6, 12, 24, and 36 months (P < .0001). MRI assessments at 12 months revealed structural improvement (P < .02). However, clinical improvements declined steadily after 36 months, with scores nearing baseline at 60 months. These findings suggest that allogeneic ADMSC therapy is safe and provides sustained clinical and structural benefits for up to 3 years. Larger trials are needed to optimize dosing and assess long-term efficacy.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation of cord blood-derived Innate Lymphoid Cells 1  into KIR+NKG2A- natural killer cells in a human stem cell niche.","authors":"Sabrina B Bennstein, Julian Reiß, Sandra Weinhold, Nadine Scherenschlich, Özer Degistirici, Katharina Raba, Lutz Walter, Johannes C Fischer, Gesine Kögler, Roland Meisel, Markus Uhrberg","doi":"10.1093/stcltm/szag034","DOIUrl":"10.1093/stcltm/szag034","url":null,"abstract":"<p><p>KIR+NKG2A- natural killer (NK) cells can detect and eliminate malignant and infected cells that have downregulated single HLA class I molecules to escape T cell recognition. So far, these KIRonly NK cells cannot be efficiently expanded in vitro without concomitant co-expression of NKG2A, which modulates their specificity. In this context, we recently demonstrated that circulating innate lymphoid cells 1 (cILC1s) have NK cell progenitor potential and can be differentiated into KIRonly NK cells using murine feeder cells. Here, we established an animal-free culture system enabling the generation and expansion of NK cells from cord blood (CB)-derived cILC1s using human mesenchymal stem cells (MSCs) as feeder cells. Compared to the murine niche provided by the OP9-DL1 cell line, human MSCs generally enabled a much more efficient generation of NK cells, resulting in significantly higher yields of KIR+ NK cells. The frequency of KIRonly NK cells could be further increased by addition of the soluble NOTCH ligand DLL1. Furthermore, we utilized the cILC1/MSC platform to study education of KIRonly NK cells by HLA-C-encoded ligands in a human stem cell niche. This effect was strongest for homozygous (C1/C1) compared to heterozygous (C1/C2) donors, suggesting that cognate KIR/KIR ligand interaction mediates a gene-dosage-dependent education effect. Altogether, this optimized culture protocol overcomes previous limitations by enabling efficient generation of KIR-expressing NK cells in an animal-free, GMP-compatible system. The presented approach may facilitate the clinical translation of NK cell-based strategies for cellular immunotherapy and in addition provides a platform for mechanistic studies of NK cell education.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A selection model for umbilical cord blood units with high isolation yield of total nucleated and CD34+ cells.","authors":"Vuong M Pham, Hung V Nguyen, Qui T Dang, Son K Nguyen, Mi H V Ngo, An P N Tra, Huyen T T Truong, Hung M Pham, Dien V Mai, Oanh H Le, Lan T Huynh","doi":"10.1093/stcltm/szag031","DOIUrl":"https://doi.org/10.1093/stcltm/szag031","url":null,"abstract":"<p><strong>Background: </strong>Cord blood is an important hematopoietic stem cell source for treating over 80 FDA-approved diseases, driving demand for HSC-containing-umbilical cord blood (UCB) unit cryopreservation for future use. Total nucleated cell (TNC) and CD34+ cell amounts are key determinants of transplant success. Predicting processing outcomes is clinically valuable, particularly for public stem cell banks where storing high-quality UCB units is a priority. This study aimed to establish selection models for UCB units with high isolation yields of these critical cellular determinants.</p><p><strong>Methods: </strong>We first performed univariate analysis and multiple linear regression on 3338 UCB units processed at MekoStem Stem Cell Bank (Vietnam) from 2019 to 2023 to explore correlations between potential variables (maternal age, mode of delivery, baby blood type, birth weight, gestational age, infant sex, blood volume, procurement time, and time to processing after collection) and TNC and CD34+ cell counts. Subsequently, Bayesian Model Averaging and exhaustive search were applied to develop predictive models. The developed models were then validated using a dataset of 660 UCB units processed in 2024.</p><p><strong>Results: </strong>Results identified an optimal selection model incorporating birth weight, delivery mode, blood volume, and gestational age for predicting high isolation yields of both TNC and CD34+ cells. Reference values for these variables were birth weight >3200 g, vaginal delivery mode, blood volume >79.22 mL, and gestational age >39 weeks or ≤39 weeks for TNC or CD34+ cell models, respectively.</p><p><strong>Conclusions: </strong>The models proposed in this study demonstrated robust predictive performance in external validation and can be applied to any type of stem cell bank.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of increasing intranuclear calcium levels via MCU inhibition on mouse and human PSC-derived cardiomyocyte differentiation and maturation.","authors":"Hyun Ju Seo, Ju-Young Kim, Hyun-Jai Cho, Joo-Eun Lee, Sang-Beom Bang, Mika Jeon, Hyang-Ae Lee, Yoo-Jeong Shin, Han-Mo Yang, Hyo-Soo Kim","doi":"10.1093/stcltm/szag021","DOIUrl":"https://doi.org/10.1093/stcltm/szag021","url":null,"abstract":"<p><p>Background Cardiovascular diseases remain the leading cause of death worldwide, accounting for approximately 19.41 million deaths annually. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for disease modeling and therapy. However, variability in differentiation efficiency and maturation state remains a significant challenge. Calcium signaling plays a pivotal role in cardiac differentiation and maturation, with mitochondrial calcium dynamics closely linked to transcriptional activation. Recent evidence suggests that closure of the mitochondrial permeability transition pore promotes cardiomyocyte differentiation by stabilizing calcium homeostasis and reducing oxidative stress. Methods We investigated the effect of 7-aminoindole (7-AI), a mitochondrial calcium uniporter inhibitor, on cardiomyocyte differentiation. Mouse embryonic stem cells and hiPSCs were treated with 7-AI during the cardiac progenitor stage (day 4). Nuclear calcium levels, Ca2+/calmodulin-dependent protein kinase (CaMK) activation, CREB phosphorylation, and cardiac marker expression were assessed. Results 7-AI increased nuclear calcium levels, activated CaMK and CREB, and upregulated cardiac-specific markers, including cTnT, α-SA, and MYH6/7. The resulting cardiomyocytes exhibited improved sarcomere organization and enhanced contractility. Moreover, CREB-deficient cells failed to exhibit these effects, confirming that CREB activation is essential for 7-AI-mediated cardiac maturation. Conclusions Collectively, our findings demonstrate that inhibition of mitochondrial calcium influx redistributes calcium to the nucleus, thereby activating the CaMK-CREB signaling axis and promoting cardiomyocyte differentiation. Targeting mitochondrial calcium handling at the cardiac progenitor stage provides a mechanistic and pharmacological approach to enhance the structural and functional maturation of cardiomyocytes for therapeutic application.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moderate neuroprotection of combination cell therapy in fetal growth restricted newborns at postnatal day 10.","authors":"Kirat K Chand, Kate Beecher, Rachel Nano, Seen-Ling Sim, Jane Sun, Peytn Stokes-Marshall, Lillian Macfarlane, John Luff, Hannah Musco, Paul B Colditz, Kiarash Khosrotehrani, Jatin Patel, Julie A Wixey","doi":"10.1093/stcltm/szag019","DOIUrl":"https://doi.org/10.1093/stcltm/szag019","url":null,"abstract":"<p><p>Infants with fetal growth restriction (FGR) are at increased risk of adverse neurodevelopmental conditions, including motor, learning, and behavioral deficits. There are currently no treatments to protect the FGR newborn from lifelong neurological conditions. We have previously reported neuroprotective potential of a single dose of combined mesenchymal stromal cells and endothelial colony-forming cells (ECFCs) therapy, termed cECFC, isolated from healthy human term placenta, in treating brain injury in a preclinical model of FGR. We administered cECFCs to newborn FGR pigs and survived to postnatal day 4 (2-week human equivalence). We reported improved gray and white matter integrity, reduced glial-mediated inflammation and improved microvasculature. Here, we aimed to examine whether this novel therapy presented sustained efficacy in newborn pigs that survived to postnatal day 10 (1-month human equivalence). We determined a single dose of cECFC treatment affords moderate neuroprotective capacity in the cortex but limited efficacy in the periventricular white matter. We also report minimal modulation of the inflammatory environment, with ongoing glial activation observed in most regions examined. Our data suggest a diminution in efficacy of single-dose cECFC 10 days after administration. We propose multiple doses of cECFCs may be required to maintain neuroprotective capacity during early post-natal life in FGR newborns. Overall, these findings demonstrate the importance of extended pre-clinical studies to determine the efficacy of treatments prior to translation to clinical trials.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic immune reconstitution and clinical outcomes in different chimerism statuses of HLA-matched transplantation for severe aplastic anemia.","authors":"Ming-Hao Lin, Zheng-Li Xu, Ying-Jun Chang, Hui-Dong Guo, Lan-Ping Xu, Yu Wang, Xiao-Hui Zhang, Yi-Fei Cheng, Yuan-Yuan Zhang, Xiao-Dong Mo, Yu-Qian Sun, Ting-Ting Han, Jing-Zhi Wang, Yao Chen, Yu-Hong Chen, Huan Chen, Wei Han, Xiao-Jun Huang","doi":"10.1093/stcltm/szag009","DOIUrl":"10.1093/stcltm/szag009","url":null,"abstract":"<p><p>This retrospective study examines the clinical outcomes and immune reconstitution dynamics in patients with severe aplastic anemia (SAA) exhibiting mixed chimerism (MC) compared with those with full donor chimerism (FDC) following HLA-matched hematopoietic stem cell transplantation (HSCT). Analysis of propensity score-matched cohorts (23 MC vs 69 FDC) revealed comparable 5-year overall survival (OS: 87.0% vs 92.8%, P = .433) but significantly inferior failure-free survival (FFS: 47.8% vs 87.0%, P < .001) in patients with MC due to a higher incidence of graft failure (52.2% vs 8.7%, P < .001). Longitudinal immune profiling revealed delayed recovery of myeloid and lymphoid lineages in patients with MC at 12 months post-HSCT, with pronounced deficits in adaptive immunity. Specifically, CD8+CD28+ T cell counts were consistently reduced at 1 month (median, 20 vs 41 cells/μL, P = .049), 3 months (median, 86 vs 153 cells/μL, P = .024), and 6 months (median, 109 vs 160 cells/μL, P = .001), and CD4+CD25+ T cells were diminished at 6 months (median, 11 vs 20 cells/μL, P = .006). Multivariate analysis revealed that elevated CD8+CD28+ T cell levels at 3 months (≥140 cells/μL) were an independent predictor of improved FFS (HR = 0.30, P = .035). These findings highlight MC-associated immune dysregulation, particularly impaired CD28-costimulated T cell and CD4+CD25+ T cell reconstitution, as a key mediator of graft instability. This study underscores the prognostic value of early immune monitoring and suggests therapeutic strategies that target T cell recovery to mitigate MC-related risk in patients with SAA.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13026414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147532756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-genome CRISPR screening identifies genetic modifiers of stem cell-derived islet transplantation.","authors":"Marlie M Maestas, Kameron Bradley, Mira Shunkarova, Noyonika Mukherjee, Matthew Ishahak, James Lu, Jeffrey R Millman","doi":"10.1093/stcltm/szag012","DOIUrl":"https://doi.org/10.1093/stcltm/szag012","url":null,"abstract":"<p><strong>Introduction: </strong>Genetically engineering human pluripotent stem cell (hPSC)-derived islets is a promising strategy for improving transplantation for diabetes cell therapy; however, genetic perturbations that modulate transplantation outcomes have yet to be systematically explored.</p><p><strong>Methods: </strong>To identify potential targets, we performed an unbiased whole-genome CRISPR-activation screen in transplanted stem cell-derived islets (SC-islets). Specifically, we created a stem cell line with CRISPR-activation components (HUES8-VPR) and then transduced these stem cells with a lentiviral guide RNA library targeting the whole human genome. Following transduction, the stem cells were differentiated into SC-islets, which were subsequently transplanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) immunodeficient mice. After transplantation, SC-islets were extracted for next-generation sequencing.</p><p><strong>Results: </strong>The screen identified multiple candidates, including the Fc alpha/mu receptor (FCAMR). In vitro characterization revealed that FCAMR overexpression did not negatively affect SC-islet function or transcriptomic identity. Mice subcutaneously transplanted with SC-islets overexpressing FCAMR had reduced blood glucose levels and increased C-peptide compared to controls. Additionally, mice receiving FCAMR-modified grafts into the kidney capsule or hindleg muscle maintained a higher body weight compared to controls in a diabetic setting.</p><p><strong>Conclusions: </strong>In conclusion, this study demonstrats improved glucose regulation at a subcutaneous transplant site. In addition, we show that FCAMR SC-islets could play a role in systemic metabolism when transplanted into the kidney capsule or hindleg muscle. Overall, our study establishes a functional screening approach to identify gene candidates to improve SC-islet transplantation.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522022","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}