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A step-wise directed differentiation protocol generates organoids from induced pluripotent stem cells into mesenchymal, endothelial, and hematopoietic lineages. These 3D structures model marrow stroma, sinusoid lumen, and myeloid cells including proplatelet-forming megakaryocytes. Organoids support patient-derived blood malignancy cell engraftment and reveal TGFβ-driven fibrosis in myelofibrosis contexts, enabling ex vivo target discovery.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/human-bone-marrow-organoids-for-disease-modeling-discovery-and-validation-of-therapeutic-targets-in-hematologic-malignancies/383293/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/human-bone-marrow-organoids-for-disease-modeling-discovery-and-validation-of-therapeutic-targets-in-hematologic-malignancies/383293.png","ImageObject",300,407,{"name":92,"@type":93},"mieayamfan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What platform is described for modeling hematologic diseases?","Question",{"text":112,"@type":113},"The document describes a human bone marrow organoid system generated from induced pluripotent stem cells using a step-wise directed-differentiation protocol.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which cell types and structural features do the organoids reproduce?",{"text":117,"@type":113},"The organoids capture bone marrow stroma, lumen-forming sinusoids, and myeloid cells, including proplatelet-forming megakaryocytes.",{"name":119,"@type":110,"acceptedAnswer":120},"How does the organoid model contribute to therapeutic target discovery?",{"text":121,"@type":113},"It supports engraftment and survival of primary patient cells and provides an ex vivo microenvironment for mechanistic studies and prioritization of new therapeutics.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},383293,1790571203,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090893677,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","RESEARCH ARTICLE  \nHuman Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies   \nAbdullah O. Khan1,2, Antonio Rodriguez-Romera2, Jasmeet S. Reyat1, Aude-Anais Olijnik2,  \nMichela Colombo2, Guanlin Wang2,3, Wei Xiong Wen2,3, Nikolaos Sousos2,4, Lauren C. Murphy2, Beata Grygielska1, Gina Perrella1, Christopher B. Mahony5, Rebecca E. Ling6, Natalina E. Elliott6, Christina Simoglou Karali2, Andrew P. Stone7, Samuel Kemble5, Emily A. Cutler8, Adele K. Fielding8, Adam P. Croft5, David Bassett9, Gowsihan Poologasundarampillai10, Anindita Roy6, Sarah Gooding2,4, Julie Rayes1, Kellie R. Machlus7, and Bethan Psaila2,4  \nIllustration by Bianca Dunn  \nABSTRACT  A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the  \nvalidation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow—stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers.  \nSIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.  \nSee related commentary by Derecka and Crispino, p. 263.  \nINTRODUCTION  \nThe specialized bone marrow microenvironment maintains and regulates hematopoiesis, enabling an adequate supply of blood cells to meet changing physiologic requirements throughout life. Perturbations in the bone marrow hematopoietic niche contribute to the initiation and propagation of hematologic malignancies. In addition, the stromal remodeling that occurs as a consequence of blood cancers contributes to bone marrow failure (1–4) . Modeling bone marrow dysfunction is challenging, particularly in the context of human diseases. In vitro studies are often limited to 2D systems and simple cocultures, in which the relevant cell types are absent, and many human diseases are inadequately reproduced by mouse models. Patient-derived xenografts have been used to model disease and validate targets in vivo, but some malignancies and hematologic cell subtypes do not engraft well, even when humanized murine models are used (5–11) .  \n1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom. 2MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom. 3Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.  \n4Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. 5Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. 6MRC Weatherall Insti","cbCaiaB2F4l5D4xb","https://ap.wps.com/l/cbCaiaB2F4l5D4xb","pdf",37272202,22,"English","# Abstract\n# Significance\n# Introduction\n## Bone marrow niche and hematopoiesis\n## Limitations of current modeling approaches\n## Need for improved in vitro systems","[{\"question\":\"What platform is described for modeling hematologic diseases?\",\"answer\":\"The document describes a human bone marrow organoid system generated from induced pluripotent stem cells using a step-wise directed-differentiation protocol.\"},{\"question\":\"Which cell types and structural features do the organoids reproduce?\",\"answer\":\"The organoids capture bone marrow stroma, lumen-forming sinusoids, and myeloid cells, including proplatelet-forming megakaryocytes.\"},{\"question\":\"How does the organoid model contribute to therapeutic target discovery?\",\"answer\":\"It supports engraftment and survival of primary patient cells and provides an ex vivo microenvironment for mechanistic studies and prioritization of new therapeutics.\"}]","Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies | PDF",1790255724,55]