Ragusa Denise, Suen Chun Wai, Torregrosa Cortes Gabriel, Pastorino Fabio, Johns Ayona, Cicirò Ylenia, Dijkhuis Liza, van den Brink Susanne, Cilli Michele, Byrne Connor, Ionescu Giulia-Andreea, Cerveira Joana, Kranc Kamil R, Hernandez-Hernandez Victor, Ponzoni Mirco, Bigas Anna, Garcia-Ojalvo Jordi, Martínez Arias Alfonso, Pina Cristina
College of Health, Medicine and Life Sciences, Centre for Genome Engineering and Maintenance, Brunel University, London, United Kingdom.
Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
Elife. 2025 Sep 11;14:RP102324. doi: 10.7554/eLife.102324.
Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves of hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (haemGx) that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and generates hematopoietic progenitors capable of short-term engraftment of immunodeficient mice upon maturation in an in vivo niche. We took advantage of the haemGx model to interrogate the origins of infant acute myeloid leukemia (infAML). We focused on MNX1-driven leukemia, representing the commonest genetic abnormality unique to the infant group. Enforced MNX1 expression in haemGx promotes the expansion and in vitro transformation of yolk sac-like erythroid-myeloid progenitors at the HE-to-hematopoietic transition to faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional, and transcriptional profiling, including at the single-cell level, we establish the haemGx as a useful new model for the study of normal and leukemic embryonic hematopoiesis.
当前发育性血液形成的体外模型缺乏时空准确性，并且对造血的连续波复制能力较弱。在此，我们描述了一种源自小鼠胚胎干细胞（ES细胞）的三维造血原肠胚样结构（haemGx），它能够捕捉多波血液形成过程，从造血内皮（HE）分化出祖细胞，并产生造血祖细胞，这些祖细胞在体内微环境中成熟后能够短期植入免疫缺陷小鼠体内。我们利用haemGx模型来探究婴儿急性髓系白血病（infAML）的起源。我们聚焦于由MNX1驱动的白血病，这是婴儿组特有的最常见遗传异常。在haemGx中强制表达MNX1可促进卵黄囊样红系-髓系祖细胞在从HE向造血转变过程中的扩增和体外转化，从而忠实地重现患者的转录特征。通过结合表型、功能和转录谱分析，包括单细胞水平的分析，我们将haemGx确立为研究正常和白血病胚胎造血的一种有用的新模型。
