Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.
Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.
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DOI：
10.1158/2159-8290.cd-22-0199
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发表时间：
2023-02-06
期刊：
影响因子：
28.2
通讯作者：
Psaila, Bethan
中科院分区：
文献类型：
--
作者：
Khan, Abdullah O.;Rodriguez-Romera, Antonio;Reyat, Jasmeet S.;Olijnik, Aude-Anais;Colombo, Michela;Wang, Guanlin;Wen, Wei Xiong;Sousos, Nikolaos;Murphy, Lauren C.;Grygielska, Beata;Perrella, Gina;Mahony, Christopher B.;Ling, Rebecca E.;Elliott, Natalina E.;Karali, Christina Simoglou;Stone, Andrew P.;Kemble, Samuel;Cutler, Emily A.;Fielding, Adele K.;Croft, Adam P.;Bassett, David;Poologasundarampillai, Gowsihan;Roy, Anindita;Gooding, Sarah;Rayes, Julie;Machlus, Kellie R.;Psaila, Bethan
人类骨髓类器官的开发能够捕获造血组织的关键细胞、分子和结构特征，使疾病建模和利用骨髓和淋巴细胞血癌患者的原代细胞进行靶标筛选成为可能。缺乏概括人类骨髓复杂性的模型阻碍了正常和恶性造血的机制研究和新疗法的验证。在这里，我们描述了一个循序渐进的定向分化方案，其中类器官是由诱导多能干细胞产生的，这些干细胞致力于间充质、内皮和造血谱系。这些3D结构捕捉了人类骨髓基质、形成腔的窦状体和骨髓细胞（包括形成前血小板的巨核细胞）的关键特征。类器官支持血液恶性肿瘤患者的细胞移植和存活，包括众所周知难以在体外维持的癌症类型。类器官纤维化发生在TGFβ刺激和骨髓纤维化植入后，而不是健康供体来源的细胞，验证了该平台作为研究恶性细胞及其在人骨髓样环境中相互作用的有力工具。这种使能技术可能会加速骨髓疾病和血癌新靶点的发现和优先排序。我们提出了一种人类骨髓类器官，支持髓系和淋巴系血癌患者原代细胞的生长。该模型允许在其微环境背景下对血癌进行机制研究，并为新疗法的优先级提供急需的体外工具。见Derecka和Crispino的相关评论，第263页。这篇文章在本期专题第247页突出显示
Development of human bone marrow organoids that capture key cellular, molecular, and architectural features of hematopoietic tissue enables disease modeling and target screening using primary cells from patients with myeloid and lymphoid blood cancers. 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. 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