Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

Autor:	Khan AO; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom.; MRC 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., Rodriguez-Romera A; MRC 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., Reyat JS; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom., Olijnik AA; MRC 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., Colombo M; MRC 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., Wang G; MRC 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.; Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Wen WX; MRC 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.; Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Sousos N; MRC 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.; Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Murphy LC; MRC 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., Grygielska B; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom., Perrella G; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom., Mahony CB; Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Ling RE; MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom., Elliott NE; MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom., Karali CS; MRC 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., Stone AP; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts., Kemble S; Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Cutler EA; University College London Cancer Institute, London, United Kingdom., Fielding AK; University College London Cancer Institute, London, United Kingdom., Croft AP; Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Bassett D; Healthcare Technologies Institute, School of Chemical Engineering, University of Birmingham, Birmingham, United Kingdom., Poologasundarampillai G; School of Dentistry, Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom., Roy A; MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics and National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom., Gooding S; MRC 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.; Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Rayes J; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom., Machlus KR; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts., Psaila B; MRC 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.; Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 Feb 06; Vol. 13 (2), pp. 364-385.
DOI:	10.1158/2159-8290.CD-22-0199
Abstrakt:	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. See related commentary by Derecka and Crispino, p. 263. This article is highlighted in the In This Issue feature, p. 247. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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