Nature Methods ( IF 36.1 ) Pub Date : 2024-02-19 , DOI: 10.1038/s41592-024-02172-2
Stephanie Frenz-Wiessner 1 , Savannah D Fairley 1, 2 , Maximilian Buser 3 , Isabel Goek 1 , Kirill Salewskij 4, 5 , Gustav Jonsson 4, 5 , David Illig 1 , Benedicta Zu Putlitz 1 , Daniel Petersheim 1 , Yue Li 1 , Pin-Hsuan Chen 1 , Martina Kalauz 1 , Raffaele Conca 1 , Michael Sterr 6, 7, 8 , Johanna Geuder 9 , Yoko Mizoguchi 10 , Remco T A Megens 2, 11, 12 , Monika I Linder 1 , Daniel Kotlarz 1 , Martina Rudelius 13 , Josef M Penninger 4, 14, 15, 16 , Carsten Marr 3 , Christoph Klein 1, 17
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The human bone marrow (BM) niche sustains hematopoiesis throughout life. We present a method for generating complex BM-like organoids (BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist of key cell types that self-organize into spatially defined three-dimensional structures mimicking cellular, structural and molecular characteristics of the hematopoietic microenvironment. Functional properties of BMOs include the presence of an in vivo-like vascular network, the presence of multipotent mesenchymal stem/progenitor cells, the support of neutrophil differentiation and responsiveness to inflammatory stimuli. Single-cell RNA sequencing revealed a heterocellular composition including the presence of a hematopoietic stem/progenitor (HSPC) cluster expressing genes of fetal HSCs. BMO-derived HSPCs also exhibited lymphoid potential and a subset demonstrated transient engraftment potential upon xenotransplantation in mice. We show that the BMOs could enable the modeling of hematopoietic developmental aspects and inborn errors of hematopoiesis, as shown for human VPS45 deficiency. Thus, iPSC-derived BMOs serve as a physiologically relevant in vitro model of the human BM microenvironment to study hematopoietic development and BM diseases.
中文翻译:
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从人类诱导多能干细胞生成复杂的骨髓类器官
人类骨髓 (BM) 生态位维持一生的造血功能。我们提出了一种从人类诱导多能干细胞 (iPSC) 生成复杂 BM 类器官 (BMO) 的方法。 BMO 由关键细胞类型组成,这些细胞类型自组织成空间定义的三维结构,模仿造血微环境的细胞、结构和分子特征。 BMO 的功能特性包括体内样血管网络的存在、多能间充质干细胞/祖细胞的存在、中性粒细胞分化的支持以及对炎症刺激的反应。单细胞 RNA 测序揭示了异质细胞组成,包括表达胎儿 HSC 基因的造血干/祖细胞 (HSPC) 簇的存在。 BMO 衍生的 HSPC 还表现出淋巴潜力,并且其中一部分在小鼠异种移植后表现出短暂植入潜力。我们表明,BMO 可以对造血发育方面和造血先天性缺陷进行建模,如人类 VPS45 缺乏症所示。因此,iPSC 衍生的 BMO 可作为人体骨髓微环境的生理相关体外模型,用于研究造血发育和骨髓疾病。