Abstract
A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation 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. SIGNIFICANCE: 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.
Original language | English |
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Pages (from-to) | 364-385 |
Number of pages | 22 |
Journal | Cancer Discovery |
Volume | 13 |
Issue number | 2 |
DOIs | |
Publication status | Published - 6 Feb 2023 |
Bibliographical note
Funding Information:A.O. Khan and B. Psaila are coinventors on a pending patent (GB2202025.9 and GB2216647.4) relating to data in this article. A.-A. Olijnik reports grants from Cancer Research UK during the conduct of the study. N. Sousos reports personal fees from Bristol Myers Squibb, and grants from Bristol Myers Squibb and AOP Orphan outside the submitted work. C. Simoglou Karali reports grants and personal fees from Bristol Myers Squibb outside the submitted work. D. Bassett reports other support from CLEXBio outside the submitted work. S. Gooding reports grants from Bristol Myers Squibb, Innovate UK (UKRI), and Cancer Research UK outside the submitted work. B. Psaila reports grants from Cancer Research UK Advanced Clinician Scientist Fellowship and British Research Council Senior Research Fellowship during the conduct of the study, as well as grants, personal fees, and other support from Alethiomics, personal fees from Novartis and Blueprint Medicines, and grants from Galecto and Constellation Therapeutics outside the submitted work. No disclosures were reported by the other authors.
A.O. Khan is funded by a Sir Henry Wellcome fellowship (218649/Z/19/Z). K.R. Machlus is supported by grants from the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (R03DK124746), and the National Heart, Lung, and Blood Institute (R01HL151494) and is an American Society of Hematology Scholar. G. Wang was supported by an Oxford Centre for Haematology Pump Priming Award and a Medical Science Division Pump Priming Award (009800) from the Nuffield Benefaction for Medicine and the Wellcome Institutional Strategic Support Fund (ISSF). A.K. Fielding is supported by the Cancer Research UK award C27995/A21019 (also awarded to Anthony V. Moorman), which allowed for biobanking and specimen collection from UKALL14. G. Perrella is supported by funding from the Engineering and Physical Sciences Research Council (EP/V051342/1). S. Gooding receives funding from a Cancer Research UK Clinician Scientist Fellowship (RCCCSF-Nov21\100004) and unit funding from the Medical Research Council (awarded to the MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine). B. Psaila receives funding from a Cancer Research UK Advanced Clinician Scientist Fellowship (C67633/A29034), a British Research Council (BRC) Senior Research Fellowship, the Haematology and Stem Cells Theme of the Oxford BRC, a Kay Kendall Leukemia Fund Project Grant, and unit funding from the Medical Research Council (awarded to the MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine). A CC BY or equivalent license is applied to the author accepted manuscript arising from this submission in accordance with the funders’ open access conditions. We thank all the patients who kindly donated samples and Nawshad Hayder and Sophie Reed who helped with sample banking; the University of Birmingham TechHub Imaging Core Facilities and staff; the MRC WIMM Flow Cytometry Facility; the MRC WIMM Single Cell Facility; Daniel Royston for input and advice on bone marrow architecture and histology; Zewen Kelvin Tuong for assistance with KT Plots Scripting; and Arturs Habirovs and Ashleigh Danks for computational advice.
Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
ASJC Scopus subject areas
- Oncology