Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies
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 pluripot...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2023
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| _version_ | 1797108739620208640 |
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| author | Khan, AO Rodriguez-Romera, A Reyat, JS Olijnik, A-A Colombo, M Wang, G Wen, WX Sousos, N Murphy, LC Grygielska, B Perrella, G Mahony, CB Ling, RE Elliott, NE Simoglou Karali, C Stone, AP Kemble, S Cutler, EA Fielding, AK Croft, AP Bassett, D Poologasundarampillai, G Roy, A Gooding, S Rayes, J Machlus, KR Psaila, B |
| author_facet | Khan, AO Rodriguez-Romera, A Reyat, JS Olijnik, A-A Colombo, M Wang, G Wen, WX Sousos, N Murphy, LC Grygielska, B Perrella, G Mahony, CB Ling, RE Elliott, NE Simoglou Karali, C Stone, AP Kemble, S Cutler, EA Fielding, AK Croft, AP Bassett, D Poologasundarampillai, G Roy, A Gooding, S Rayes, J Machlus, KR Psaila, B |
| author_sort | Khan, AO |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:32:47Z |
| format | Journal article |
| id | oxford-uuid:060bd246-1787-4b17-9cb4-571253620dc4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:32:47Z |
| publishDate | 2023 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:060bd246-1787-4b17-9cb4-571253620dc42023-02-14T06:27:00ZHuman bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignanciesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:060bd246-1787-4b17-9cb4-571253620dc4EnglishSymplectic ElementsAmerican Association for Cancer Research2023Khan, AORodriguez-Romera, AReyat, JSOlijnik, A-AColombo, MWang, GWen, WXSousos, NMurphy, LCGrygielska, BPerrella, GMahony, CBLing, REElliott, NESimoglou Karali, CStone, APKemble, SCutler, EAFielding, AKCroft, APBassett, DPoologasundarampillai, GRoy, AGooding, SRayes, JMachlus, KRPsaila, BA 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. |
| spellingShingle | Khan, AO Rodriguez-Romera, A Reyat, JS Olijnik, A-A Colombo, M Wang, G Wen, WX Sousos, N Murphy, LC Grygielska, B Perrella, G Mahony, CB Ling, RE Elliott, NE Simoglou Karali, C Stone, AP Kemble, S Cutler, EA Fielding, AK Croft, AP Bassett, D Poologasundarampillai, G Roy, A Gooding, S Rayes, J Machlus, KR Psaila, B Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title | Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title_full | Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title_fullStr | Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title_full_unstemmed | Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title_short | Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies |
| title_sort | human bone marrow organoids for disease modelling discovery and validation of therapeutic targets in hematological malignancies |
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