Alan Y Hsu, Qingxiang Huang, Fei Liu, Arumugam Balasubramanian, Hongbo R Luo
{"title":"Neutrophil Death-More Than Meets The Eye.","authors":"Alan Y Hsu, Qingxiang Huang, Fei Liu, Arumugam Balasubramanian, Hongbo R Luo","doi":"10.1016/j.exphem.2025.104857","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104857","url":null,"abstract":"<p><p>Neutrophils play an indispensable role in the innate immune system as the body's first line of defense against pathogens. These highly specialized cells are rapidly recruited to infection sites, where they execute a variety of critical functions essential for pathogen clearance. These functions include phagocytosis, degranulation, the release of antimicrobial peptides and reactive oxygen species (ROS), as well as the formation of neutrophil extracellular traps (NETs), which serve to directly neutralize pathogens or restrict their spread. Despite their abundance-accounting for 40-70% of total white blood cells in human circulation, neutrophils have a relatively short lifespan. To maintain immune homeostasis, approximately 1 billion neutrophils per kilogram of body weight are produced and cleared each day, a highly regulated and energy-intensive process. Neutrophil death is a highly heterogeneous process, with neutrophils undergoing different forms of cell death depending on the stimuli, signaling, and microenvironment. Even during aging or cell death, neutrophils continue to exert significant effects on the immune landscape. In this review, we discuss the dynamics of neutrophil turnover during homeostasis and inflammation, the diversity of mechanisms governing their death, and the multifaceted roles of neutrophils in modulating the immune environment both during and after their demise.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104857"},"PeriodicalIF":2.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625615","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":"Fetal heart as a new local site for hematopoiesis and macrophage formation.","authors":"Norika Liu, Haruko Nakano, Atsushi Nakano","doi":"10.1016/j.exphem.2025.104818","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104818","url":null,"abstract":"<p><p>Cardiac tissue macrophages are crucial components of the immune system and tissue homeostasis. Traditionally, these macrophages have been classified into three primary lineages: yolk sac blood island-derived erythromyeloid progenitor (EMP), yolk sac hemogenic endothelial-derived late-EMP, and hematopoietic stem cell (HSC)-derived macrophages. These classifications have shaped our understanding of the developmental origin of macrophages in the heart. However, recent studies have significantly shifted this perspective by revealing that the heart itself possesses an intrinsic source of macrophages, independent of the traditionally recognized hematopoietic sources. This discovery has added a new dimension to our understanding of macrophage biology in the context of cardiac development. Our recent work has provided compelling evidence that endocardial cells exhibit hematopoietic potential during embryonic day (E)8.5 to E10. This discovery challenges the previously held belief that macrophages in the heart are exclusively derived from EMP or HSC. Endocardial cells give rise to a distinct population of cardiac tissue macrophages that play vital roles in heart morphogenesis. These findings open up new avenues for understanding how macrophages contribute to heart formation, homeostasis, and their disruption. This review summarizes the latest findings on the role of endocardial-derived macrophages, along with other macrophage lineages, in contributing to heart development and the maintenance of cardiac homeostasis.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104818"},"PeriodicalIF":2.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567355","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}
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
{"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":"<div><div>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.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"147 ","pages":"Article 104786"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","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":"Remembering James Till, 1931-2025.","authors":"Norman Iscove, Alan Bernstein, Ron Worton","doi":"10.1016/j.exphem.2025.104843","DOIUrl":"https://doi.org/10.1016/j.exphem.2025.104843","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104843"},"PeriodicalIF":2.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527036","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":"A new anchor point for gut microbiome to regulate complications of allogeneic hematopoietic stem cell transplantation: oxidative stress.","authors":"Wenxuan Bai, Tiebin Jiang, Lanlan Tang, Chuhan Shao, Mamingxi Wei, Zisai Wang, Mingyi Zhao","doi":"10.1016/j.exphem.2025.104833","DOIUrl":"10.1016/j.exphem.2025.104833","url":null,"abstract":"<p><p>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cure for many malignant hematologic and metabolic diseases, whose complications are an unignorable cause of long-term prognosis. Pretreatment chemoradiotherapy administered before and after transplantation alters the state of the bone marrow hematopoietic microenvironment. Under the stress of hematopoietic injury, a large number of hematopoietic stem cells (HSCs) proliferate and differentiate, producing large amounts of reactive oxygen species (ROS). In addition, the chemotherapeutic pretreatment drugs also cause oxidative stress (OS) themselves, which can indirectly exacerbate OS of the bone marrow microenvironment. The bone marrow hematopoietic microenvironment and local OS affect the development of infections, relapse, graft-versus-host disease (GVHD), poor graft function (PGF), persistent thrombocytopenia (PT), chronic fatigue syndrome (CFS), bronchiolitis obliterans syndrome (BOS), and transplant-associated thrombotic microangiopathy (TA-TMA). Recent studies have demonstrated that the gut microbiome (GM) and its metabolites such as short-chain fatty acids (SCFAs), secondary bile acids, trimethylamine (TMA) and signaling molecules such as H<sub>2</sub>S and NO can enter the bloodstream through the intestinal epithelium and reach all parts of the body. This review describes the impact of OS on the development of allo-HSCT complications. In this article, we will elucidate the mechanism of OS on allo-HSCT complications, summarize the interaction between GM and OS in the body, and highlight the role of GM regulation of OS in allo-HSCT complications to offer new strategies for the prevention and treatment of allo-HSCT complications.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104833"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309736","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}
Justine R Clark, Vasilios Panagopoulos, Jacqueline E Noll, Krzysztof M Mrozik, Alanah L Bradey, Peter I Croucher, Andrew C W Zannettino, Kate Vandyke, Duncan R Hewett
{"title":"Mer receptor expression promotes multiple myeloma disease development via a cell-extrinsic mechanism.","authors":"Justine R Clark, Vasilios Panagopoulos, Jacqueline E Noll, Krzysztof M Mrozik, Alanah L Bradey, Peter I Croucher, Andrew C W Zannettino, Kate Vandyke, Duncan R Hewett","doi":"10.1016/j.exphem.2025.104842","DOIUrl":"10.1016/j.exphem.2025.104842","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the uncontrolled proliferation of bone marrow resident plasma cells (PCs). Two members of the TAM (TYRO3, AXL, and MER) receptor family have previously been implicated in distinct aspects of neoplastic PC biology. AXL expression in MM PCs has been associated with the induction of a dormant, noncycling state within the bone marrow, whereas expression of MER has been implicated in PC proliferation and survival. Here, the generation of single TAM receptor-expressing 5TGM1 murine MM cell lines enabled the individual functional assessment of the effects of Axl and Mer receptor expression on MM development. Axl expression did not affect proliferation, cell cycling, or stromal cell-induced dormancy in vitro. Development of 5TGM1 tumors in C57BL/KaLwRij mice was also unaltered by Axl expression. By contrast, Mer expression conferred an increase in cell proliferation to 5TGM1 cells in vitro and increased 5TGM1 tumor burden in C57BL/KaLwRij mice. The protumorigenic properties of Mer were only observed following intravenous cell delivery into mice with an intact adaptive immune system. Thus, Axl is neither necessary nor sufficient for the induction of MM cancer cell dormancy, whereas MER remains a promising target for therapeutic intervention in patients with MM.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104842"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309787","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":"Gene regulatory complexes: their role and regulation across normal and malignant hematopoiesis","authors":"Gina Sangha , Brian J.P. Huntly","doi":"10.1016/j.exphem.2025.104821","DOIUrl":"10.1016/j.exphem.2025.104821","url":null,"abstract":"<div><div>Transcription is regulated in a multitude of ways to ensure lineage- and context-specific gene expression in a coordinated fashion. Hematopoiesis is an exemplary process for studying the mechanisms of tightly regulated activation and repression of gene expression programs through transcription and gene regulatory complexes. These complexes act by posttranslational modification of histones and nonhistone proteins, epigenetic modifications of DNA, ATP-dependent chromatin remodeling, scaffolding and recruitment of combinatorial protein complexes, and alteration of three-dimensional genome conformation to bring about lineage-specific gene expression. This review will focus on the function of these gene regulatory complexes in hematopoiesis and how they are hijacked in acute myeloid leukemia, highlighting therapeutic progress and opportunities.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"149 ","pages":"Article 104821"},"PeriodicalIF":2.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309786","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":"Advances in RARα fusion genes in acute promyelocytic leukemia","authors":"Ao Zhang , Shaowei Qiu","doi":"10.1016/j.exphem.2025.104822","DOIUrl":"10.1016/j.exphem.2025.104822","url":null,"abstract":"<div><div>Retinoic acid receptor α (RARα) is a ligand-dependent transcription factor that dimerizes with retinoid X receptor α (RXRα) to activate target gene promoters, playing a critical role in normal hematopoiesis and granulocyte differentiation. The translocation of chromosomes 15 and 17 generates the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion gene, the master driver of acute promyelocytic leukemia (APL). The PML-RARα oncoprotein exerts two major effects: transcriptional repression and disruption of promyelocytic leukemia (PML) function. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the complete remission rate in APL, making it a highly treatable disease. However, resistance to ATRA/ATO and the emergence of variant fusion genes remain significant challenges to improving APL prognosis. This review provides an overview of the physiological role of retinoid nuclear receptor signaling in hematopoiesis, the pathological mechanisms of PML-RARα in APL, the pharmacologic effects of ATRA/ATO, and the variant translocations identified in APL. We aimed to provide innovative research perspectives and insights that may be applicable to other hematopoietic malignancies.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"149 ","pages":"Article 104822"},"PeriodicalIF":2.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257689","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}
Juliana Fabiani Miranda , Adam Rogerson , Megan Guthrie , Kimrun Kaur , Emma Apperley , Mary Catherine Dunne , Navin Shridokar , Anjum Khan , William Grey
{"title":"Ex vivo modelling reveals low levels of CKS1 inhibition boost haematopoiesis via AKT/Foxo1 signalling","authors":"Juliana Fabiani Miranda , Adam Rogerson , Megan Guthrie , Kimrun Kaur , Emma Apperley , Mary Catherine Dunne , Navin Shridokar , Anjum Khan , William Grey","doi":"10.1016/j.exphem.2025.104768","DOIUrl":"10.1016/j.exphem.2025.104768","url":null,"abstract":"<div><div>Hematopoietic stem cells (HSCs) are rare cells residing at the top of the haematopoietic hierarchy capable of reconstituting all blood cell populations through their ability of self-renewal and differentiation. Their ability to maintain haematopoiesis can be majorly depleted by chemotherapeutic agents, leading to a long-term bone marrow injury. However, pre-clinical studies have focused on the acute effects of chemotherapy, leaving the lasting impact on healthy cells poorly understood. To study this, we combined rapid <em>ex vivo</em> models to study the long-term/late-stage effects of a cyclin-dependent kinase subunit 1 (CKS1) inhibitor. Inhibition of CKS1 has been shown to protect healthy HSCs from chemotherapy during acute myeloid leukaemia, and here we show a dose-dependent role of long-term CKS1 inhibition on haematopoiesis, either boosting B lymphopoiesis or ablating HSC proliferation capacity, dependent on the context. Mechanistically, low doses of the CKS1 inhibitor (CKS1i) affects AKT-Foxo1 signalling potentiating B-cell differentiation, but impairing HSC proliferation. These results reveal a novel role for CKS1 in boosting B lymphopoiesis and propose the use of rapid <em>ex vivo</em> models to investigate the long-term effects of chemotherapeutic treatments targeting HSCs with the potential of reducing late adverse effects.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"146 ","pages":"Article 104768"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751821","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}