Hérault Aurélie, Binnewies Mikhail, Leong Stephanie, Calero-Nieto Fernando J, Zhang Si Yi, Kang Yoon-A, Wang Xiaonan, Pietras Eric M, Chu S Haihua, Barry-Holson Keegan, Armstrong Scott, Göttgens Berthold, Passegué Emmanuelle
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
Cambridge University Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
Nature. 2017 Apr 6;544(7648):53-58. doi: 10.1038/nature21693. Epub 2017 Mar 29.
Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1β, G-CSF, TGFβ and CXCL4) and activation of an inducible Irf8 and β-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.
尽管血液生成的许多方面已为人所熟知，但骨髓中髓系分化的空间组织仍不清楚。在此，我们利用成像技术追踪小鼠在应急和白血病性髓系造血过程中粒细胞/巨噬细胞祖细胞（GMP）的行为。在稳态下，我们发现单个GMP分散于整个骨髓中。在再生过程中，我们观察到不断扩大的GMP斑块形成明确的GMP簇，这些簇进而在局部分化为粒细胞。重要的骨髓微环境信号（SCF、IL-1β、G-CSF、TGFβ和CXCL4）的定时释放以及可诱导的Irf8和β-连环蛋白祖细胞自我更新网络的激活控制着再生GMP簇的短暂形成。在白血病中，我们表明由于自我更新网络的持续激活以及缺乏通常可恢复造血干细胞静止状态的终止细胞因子，GMP簇不断产生。我们的结果揭示了GMP在原位一种先前未被认识的动态行为，这种行为调节应急髓系造血，且在白血病中被劫持。
