Experimental hematology最新文献

{"title":"Large-Scale Mediator Mendelian Randomization Analysis Identifies Multiple Immune Cells Mediating the Causal Link Between Gut Microbes and Chronic Graft-Versus-Host Disease Risk.","authors":"Yiyin Chen, Xinghao Yu, Yiming Cai, Zhou Jin, Yang Xu","doi":"10.1016/j.exphem.2025.104794","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104794","url":null,"abstract":"<p><strong>Objective: </strong>Disorders of gut microbiota and immune cells have been observed to involve in the occurrence of chronic graft-versus-host disease (cGVHD) following unrelated HLA-matched donor transplantation, but their causal connections have yet to be fully understood.</p><p><strong>Methods: </strong>The study utilized Mendelian randomization (MR), integrating genome-wide association study (GWAS) meta-analyses from the MiBioGen consortium (microbial taxa), the SardiNIA project (immune traits), and disease data from the FHCRC cohort to investigate their complex relationships. The aim was to explore the causal effects of specific gut microbial taxa and immune traits on the incidence of cGVHD, employing mediation analysis to identify which immune traits might mediate the effects of microbiota on this condition.</p><p><strong>Results: </strong>Main analysis observed significant causal associations of three specific microbial taxa with cGVHD after multiple tests adjustment: Lactococcus.id.1851 (OR = 1.989, 95% CI = 1.311 ∼ 3.019, P = 0.001), Ruminiclostridium9.id.11357 (OR = 3.273, 95% CI = 1.604 ∼ 6.679, P = 0.001), and Intestinimonas.id.2062 (OR = 0.400, 95% CI = 0.230 ∼ 0.697, P = 0.001). Complex sensitivity analysis and multivariable MR analysis ruled out possible horizontal pleiotropy and bias. Additionally, after multiple tests adjustment, 10 immune traits (FDR q < 0.1), predominantly covering Tregs and B cells, were identified as influencing cGVHD risk. The two-step mediation MR analysis presented the effect of identified microbial taxa on Tregs and B cells and detailed the pathways through which Intestinimonas impacts cGVHD via CD27 on memory B cells (Proportion mediated = 4.2%). Similarly, the role of interactions between Ruminiclostridium9 and effector memory double-negative (EM DN; CD4^- CD8^-) T cells in mediating cGVHD was quantified, accounting for 9.5% of the total effect.</p><p><strong>Conclusion: </strong>This MR study highlighted the critical interplay between specific microbial taxa and immune cells in cGVHD development, offering insights into potential therapeutic targets and pathways for disease management.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104794"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mtg16 NHR1 mutations cause defects in lymphopoiesis and the response to anemia.","authors":"Monica Bomber, Pankaj Acharya, Anna E Johnson, Shilpa Sampathi, David K Flaherty, Brittany K Matlock, Jacob D Ellis, Luke N Bartlett, Christopher S Williams, Scott W Hiebert, Kristy R Stengel","doi":"10.1016/j.exphem.2025.104793","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104793","url":null,"abstract":"<p><p>The ETO/MTG family of transcriptional co-repressors play a key role in adult stem cell function across multiple tissues and may be affected by mutation, deletion or translocation in solid tumors and leukemia. Structural studies of the first conserved domain identified residues that make specific contacts with E proteins, such as HEB and E2A. We generated mice with a mutation in a critical phenylalanine (F210A) in Mtg16 to test the physiological significance of Mtg16 association with E proteins and compared these mice to mice containing a nearby cancer-associated mutation (P209T). We found that Mtg16^-/- and Mtg16^F210A/F210A mice showed impaired lymphopoiesis following competitive bone marrow transplant, suggesting that the repression of E protein-dependent transcription is critical for B- and T-cell development. While Mtg16^-/-, Mtg16^P209T/P209T, and Mtg16^F210A/F210A animals showed significant defects in burst forming potential (BFU-E) after phenylhydrazine treatment, only Mtg16^-/- mice showed overt signs of anemia. Thus, we propose that, while Mtg16 is a critical regulator of HSPC function, response to hemolytic anemia, and lymphoid development, the interaction between Mtg16 and E-proteins is particularly important for lymphopoiesis.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104793"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct transcriptional changes in hematopoietic progenitor subsets upon LPS-induced emergency granulopoiesis.","authors":"Sladjana Kosanovic, Karolina Vanickova, Mirko Milosevic, Irina Ribeiro Bas, Mateusz Chilinski, Dariusz Plewczynski, Petr Danek, Jakub Rohlena, Katerina Rohlenova, Meritxell Alberich-Jorda","doi":"10.1016/j.exphem.2025.104792","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104792","url":null,"abstract":"<p><p>Emergency granulopoiesis is a critical process by which hematopoietic progenitors and stem cells facilitate enhanced granulocytic production during severe infections. However, the role of distinct multipotent progenitors (MPPs) at early stages of this process remains underexplored. Here, we investigated the contribution of MPPs to granulocytic production following lipopolysaccharide (LPS) administration in wild-type mice, simulating a bacterial infection. Transplantation assays demonstrated that LPS exposure reduces the engraftment capacity of lymphoid-biased MPP4 and enhances lymphoid production, rather than supporting myeloid lineage output. Further, single-cell RNA sequencing (scRNA-seq) of MPPs isolated from control and LPS challenged mice revealed transcriptional reprogramming of non-lineage committed MPPs towards myeloid- and erythroid-biased progenitors. Notably, inflammatory progenitor populations emerged upon activation of LPS-induced emergency granulopoiesis, displaying chromatin accessibility changes that align with a commitment to myeloid and erythroid fates. Pseudotime analysis elucidated cellular trajectories that suggest a developmental pathway where unbiased progenitors, present in non-stress conditions, transition towards myeloid and erythroid lineage outputs upon LPS administration. In line with our functional MPP4 assessment, scRNA-seq suggested that lymphoid-biased progenitors do not transcriptionally rewire during early stages of emergency granulopoiesis. Collectively, our data highlight the critical role of specific MPP subsets in responding to LPS-induced inflammatory signals and underscore the dynamic adaptations that occur during granulocyte production in response to infection.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104792"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hematopoietic stem cells in human fetal liver selectively express CD49f.","authors":"Margarita E MacAldaz, Jeremy Shu, Glenn Edin, Margaret Hale, Connie J Eaves","doi":"10.1016/j.exphem.2025.104788","DOIUrl":"10.1016/j.exphem.2025.104788","url":null,"abstract":"<p><p>Identification of phenotypes of human hematopoietic cells that display long-term mature cell outputs in vitro and repopulating capability in immunodeficient mice has been important to anticipating the therapeutic potential of fresh harvests of bone marrow or cord blood before or after their physical or genetic manipulation. However, characterizing their key properties and strategies for their isolation from multiple sources at increasing cell purities and elucidating the mechanisms that regulate their ability to sustain mature blood cell production continues to be of major interest. Previous studies have shown that fetal and adult human cells with long-term blood cell output potential are highly enriched in their respective glycosylphosphatidylinositol (GPI)-anchored surface protein GPI80+ and CD49f+ subsets of a developmentally preserved CD45+CD34+CD38-CD45RA-CD90+ population. The so-called \"GPI80\" hematopoietic cells found in first-trimester human fetal liver are of particular interest because of their very high regenerative capability compared with their adult or even neonatal (cord blood) \"CD49f\" counterparts. Here, it was hypothesized that high regenerative activity of the GPI80+ cells could be further enriched within a CD49f+ subset. We now demonstrated that coexpression of CD49f within the GPI80+ population identifies a subset with reduced short-term myeloid colony-forming activity in semisolid medium and greater progeny outputs in both 12-week growth factor-supplemented stromal cocultures and in transplanted immunodeficient mice. These findings demonstrated that CD49f is a pervasive marker of human hematopoietic stem cells (HSCs) throughout ontogeny and aging.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104788"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and aging of resident endothelial stem cells in pre-existing blood vessels.","authors":"Fitriana N Rahmawati, Nobuyuki Takakura","doi":"10.1016/j.exphem.2025.104795","DOIUrl":"10.1016/j.exphem.2025.104795","url":null,"abstract":"<p><p>Organ-specific somatic stem cells play an important role in supporting tissue turnover and facilitating regeneration on injury. Hematopoietic stem cells are one of the most established organ-specific somatic cells that have been frequently used for transplantation therapy. Recently, there has been a growing interest in other organ-specific somatic cells, including vascular endothelial stem cells (VESCs). We have previously reported on the use of CD157 and CD200 as markers to isolate VESCs from adult mouse organs, particularly the liver. In this review, we aimed to summarize, based on our previous research, how CD157⁺CD200⁺ VESCs in the liver develop from the fetal stage to postnatal life, what transcriptional regulatory mechanisms govern them, and how VESCs change with aging.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104795"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-COUNT: a convolutional neural network-based tool for automated scoring of erythroid colonies.","authors":"Rui Li, Ashley Winward, Logan R Lalonde, Daniel Hidalgo, John P Sardella, Yung Hwang, Aishwarya Swaminathan, Sean Thackeray, Kai Hu, Lihua Julie Zhu, Merav Socolovsky","doi":"10.1016/j.exphem.2025.104786","DOIUrl":"10.1016/j.exphem.2025.104786","url":null,"abstract":"<p><p>Despite advances in flow cytometry and single-cell transcriptomics, colony-formation assays (CFAs) remain an essential component in the evaluation of erythroid and hematopoietic progenitors. These assays provide functional information on progenitor differentiation and proliferative potential, making them a mainstay of hematology research and clinical diagnosis. However, the utility of CFAs is limited by the time-consuming and error-prone manual counting of colonies, which is also prone to bias and inconsistency. Here we present \"C-COUNT,\" a convolutional neural network-based tool that scores the standard colony-forming-unit-erythroid (CFU-e) assay by reliably identifying CFU-e colonies from images collected by automated microscopy and outputs both their number and size. We tested the performance of C-COUNT against three experienced scientists and find that it is equivalent or better in reliably identifying CFU-e colonies on plates that also contain myeloid colonies and other cell aggregates. We further evaluated its performance in the response of CFU-e progenitors to increasing erythropoietin concentrations and to a spectrum of genotoxic agents. We provide the C-COUNT code, a Docker image, a trained model, and training data set to facilitate its download, usage, and model refinement in other laboratories. The C-COUNT tool transforms the traditional CFU-e CFA into a rigorous and efficient assay with potential applications in high-throughput screens for novel erythropoietic factors and therapeutic agents.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104786"},"PeriodicalIF":2.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered cytokine-expressing MSCs support ex vivo culture of human HSPCs and AML cells.","authors":"Johannes Foßelteder, Thomas Brauchart, Angelika Schlacher, Tommaso Sconocchia, Erdem Özkaya, Lisa Auinger, Peter Schlenke, Heinz Sill, Armin Zebisch, Andreas Reinisch","doi":"10.1016/j.exphem.2025.104790","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104790","url":null,"abstract":"<p><p>CD34⁺ human hematopoietic stem and progenitor cells and primary patient-derived leukemia cells are important tools for basic and translational research. Their limited availability demands additional expansion ex vivo in many cases. The use of either cytokine cocktails or cocultures with mesenchymal stromal cells (MSCs) has advanced cell expansion but combinations of both have not been addressed extensively so far. Here, we presented a novel approach to generating human cytokine-expressing MSCs (ceMSCs) using genetic engineering. Coculture with ceMSCs and their culture supernatant led to an efficient expansion and maintenance of functional CD34⁺CD45RA^-CD90⁺CD201⁺CD49c⁺ hematopoietic stem cells ex vivo. Similarly, ceMSCs and their culture supernatant support the growth of cytokine-dependent leukemic cell lines in vitro and improve the survival, maintenance, and expansion of patient-derived acute myeloid leukemia cells, a cell population very challenging to be cultured ex vivo. ceMSCs even surpass the support provided by wild-type MSCs or external cytokines alone. Therefore, ceMSCs offer a cost-effective, straightforward alternative to traditional cytokine supplementation, enhancing the feasibility of ex vivo studies on healthy and leukemic stem and progenitor cells, including therapeutic drug testing and mechanistic investigations.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104790"},"PeriodicalIF":2.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unbiased analysis of NUP98-KDM5A-induced murine leukemia reveals phenotypic heterogeneity recapitulating human disease subtypes.","authors":"Marilaine Fournier, Marion Dubuissez, Mathieu Neault, Jean-Sébastien Delisle, Frédérick A Mallette, Heather J Melichar","doi":"10.1016/j.exphem.2025.104791","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104791","url":null,"abstract":"<p><p>NUP98-KDM5A (NK5) is an oncogenic fusion protein implicated in the development of several types of acute myeloid leukemia (AML) in humans, including rare pediatric acute megakaryoblastic leukemia (AMKL). NK5 expression in murine hematopoietic progenitor cells can induce AML in mice. However, the limited number of animals and phenotypic markers used in previous studies preclude the full characterization of the AML subtypes that develop. We used NK5-transduced hematopoietic progenitor cells from murine fetal liver to generate a large cohort of mice. We then assessed the expression of a panel of myeloid markers to characterize the lineage of leukemic blasts using flow cytometry. Finally, we used bioinformatic tools to perform an unbiased analysis of mouse-to-mouse heterogeneity in leukemic cellular phenotypes. We identified phenotypically distinct subgroups among the NK5 leukemias that were predominantly segregated based on the expression of the AMKL-associated marker CD41. Our findings indicate that NK5 expression in fetal liver cells causes different types of leukemia similar in proportion to that observed in pediatric patients. The heterogeneity and mixed phenotypes observed might explain the difficulty in accurately diagnosing leukemia in some patients carrying the NK5 fusion. In addition, this approach may enable the identification of the molecular or cellular basis of the diverse NK5-driven AML types.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104791"},"PeriodicalIF":2.5,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patterns of hemolysis, erythropoiesis, and iron distribution define unique disease trajectories in three mouse models of genetic anemia.","authors":"Irina L Dubach, Raphael M Buzzi, Dominik J Schaer, Florence Vallelian","doi":"10.1016/j.exphem.2025.104787","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104787","url":null,"abstract":"<p><p>Hemolytic anemias involve premature red blood cell (RBC) destruction and present complex phenotypes, including disturbances in iron metabolism, extramedullary erythropoiesis, and systemic organ involvement. To guide the selection of appropriate murine models for studying pathophysiology and pharmacological treatments of human hemolytic disorders, we systematically characterized three genetic mouse models commonly used to investigate such conditions: sickle cell disease (SCD), beta-thalassemia (THAL), and hereditary spherocytosis (SPH). We sought to clarify how these models differ in the severity and nature of hemolysis, the balance between erythropoietic responses and iron regulation, and the long-term patterns of iron distribution. Our findings reveal that SPH mice exhibit severe intravascular hemolysis and suppressed hepcidin levels, leading to unopposed intestinal iron absorption and extensive tissue iron loading, especially in the liver. In contrast, SCD and THAL mice display predominantly extravascular hemolysis, moderate anemia, relatively stable hepcidin levels, and balanced erythropoiesis with partially regulated iron overload. Single-cell RNA sequencing of spleens highlighted distinct erythropoietic progenitor distributions, while iron isotope tracing experiments confirmed divergent RBC turnover kinetics and tissue distribution. This study defines distinct disease trajectories for common hemolytic disease models by providing a unique comparative framework. Our work will support more informed model selection and refined experimental design to investigate hemolytic anemia pathobiology and therapeutics. TEASER ABSTRACT: We compared three genetic mouse models - sickle cell disease, beta-thalassemia, and hereditary spherocytosis - to reveal distinct disease mechanisms in hemolytic anemia. Our findings show that hereditary spherocytosis induces severe intravascular hemolysis and iron overload, while sickle cell and beta-thalassemia models exhibit extravascular hemolysis with more regulated iron distribution. This study offers critical insights into model selection for hemolytic anemia research and provides a framework for studying pathophysiology and treatments.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104787"},"PeriodicalIF":2.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to A novel lymphoid progenitor cell population (LSKlow) is restricted by p18INK4c Experimental Hematology Volume 44 Issue 9 (2016), 874-844.e5","authors":"Fang Dong ,&nbsp;Sha Hao ,&nbsp;Shihu Ma ,&nbsp;Hui Cheng ,&nbsp;Yajie Wang ,&nbsp;Wen Zhou ,&nbsp;Weiping Yuan ,&nbsp;Hideo Ema ,&nbsp;Tao Cheng","doi":"10.1016/j.exphem.2025.104770","DOIUrl":"10.1016/j.exphem.2025.104770","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"145 ","pages":"Article 104770"},"PeriodicalIF":2.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}