Rezvani Milad, Lewis Kyle, Quach Susanna, Iwasawa Kentaro, Weihs Julian, Reza Hasan, Cai Yuqi, Kimura Masaki, Zhang RanRan, Milton Yuka, Chaturvedi Praneet, Thorner Konrad, Nayak Ramesh C, Munera Jorge O, Kramer Phillip, Davis Brian, Balamurugan Appakalai, Ait Ahmed Yeni, Finke Marcel, Behncke Rose Yinghan, Guillot Adrien, Haegerling Rene, Polansky Julia, Bufler Philip, Cancelas Jose, Wells James, Yoshimoto Momoko, Takebe Takanori
bioRxiv. 2024 Oct 12:2024.10.11.617794. doi: 10.1101/2024.10.11.617794.
The fetal liver is a hematopoietic organ, hosting a diverse and evolving progenitor population. While human liver organoids derived from pluripotent stem cells (PSCs) mimic aspects of embryonic and fetal development, they typically lack the complex hematopoietic niche and the interaction between hepatic and hematopoietic development. We describe the generation of human Fetal Liver-like Organoids (FLOs), that model human hepato-hematopoietic interactions previously characterized in mouse models. Developing FLOs first integrate a yolk sac-like hemogenic endothelium into hepatic endoderm and mesoderm specification. As the hepatic and hematopoietic lineages differentiate, the FLO culture model establishes an autonomous niche capable of driving subsequent progenitor differentiation without exogenous factors. Consistent with yolk sac-derived waves, hematopoietic progenitor cells (HPCs) within FLOs exhibit multipotency with a preference for myeloid lineage commitment, while retaining fetal B and T cell differentiation potential. We reconstruct in FLOs the embryonic monocyte-to-macrophage and granulocyte immune trajectories within the FLO microenvironment and assess their functional responses in the liver niche. In vivo, FLOs demonstrate a liver engraftment bias of hematopoietic cells, recapitulating a key phenomenon of human hematopoietic ontogeny. Our findings highlight the intrinsic capacity of liver organoids to support hematopoietic development, establishing FLOs as a platform for modeling and manipulating human blood-liver niche interactions during critical stages of development and disease.
胎儿肝脏是一个造血器官，容纳着多样且不断演变的祖细胞群体。虽然源自多能干细胞（PSC）的人类肝脏类器官模拟了胚胎和胎儿发育的某些方面，但它们通常缺乏复杂的造血微环境以及肝脏和造血发育之间的相互作用。我们描述了人类胎儿肝脏样类器官（FLO）的生成，该类器官模拟了先前在小鼠模型中表征的人类肝造血相互作用。发育中的FLO首先将卵黄囊样造血内皮整合到肝内胚层和中胚层的特化过程中。随着肝脏和造血谱系的分化，FLO培养模型建立了一个自主微环境，能够在没有外源性因子的情况下驱动后续祖细胞的分化。与源自卵黄囊的细胞群一致，FLO内的造血祖细胞（HPC）表现出多能性，更倾向于髓系谱系定向，同时保留胎儿B细胞和T细胞的分化潜能。我们在FLO微环境中重建了胚胎期单核细胞向巨噬细胞和粒细胞的免疫轨迹，并评估了它们在肝脏微环境中的功能反应。在体内，FLO显示出造血细胞在肝脏中的植入偏好，概括了人类造血个体发生的一个关键现象。我们的研究结果突出了肝脏类器官支持造血发育的内在能力，将FLO确立为在发育和疾病的关键阶段模拟和操纵人类血液-肝脏微环境相互作用的平台。
