Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies
Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies
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用于疾病建模、发现和验证血液恶性肿瘤治疗靶点的人骨髓类器官
DOI：
10.1101/2022.03.14.483815
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Khan A
中科院分区：
文献类型：
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作者：
Khan A
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，我们描述了一个逐步的，定向分化的协议，其中类器官是从诱导多能干细胞致力于间充质，内皮和造血谱系。这些3D结构捕获了人骨髓基质、管腔形成窦状隙和骨髓细胞（包括前血小板形成巨核细胞）的关键特征。这些类器官支持血液恶性肿瘤患者的细胞植入和存活，包括众所周知难以体外培养的癌症类型。类器官的纤维化发生在TGFβ刺激和骨髓纤维化而不是健康供体来源的细胞移植后，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发现和优先考虑骨髓疾病和血癌的新靶点。Significance我们提出了一种人骨髓类器官，它支持骨髓和淋巴血癌患者的原代细胞生长。该模型允许在其微环境的背景下进行血癌的机制研究，并为新疗法的优先级提供急需的活体工具。参见Derecka和Crispino的相关评论，第263页。本文在本期专题中突出显示，第247页
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 maintainex 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.SignificanceWe 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-neededex vivotool 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