Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis.
Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis.
复制标题
DOI：
10.1038/nature21693
复制
发表时间：
2017-04-06
期刊：
影响因子：
64.8
通讯作者：
Passegué E
中科院分区：
文献类型：
--
作者：
Hérault A;Binnewies M;Leong S;Calero-Nieto FJ;Zhang SY;Kang YA;Wang X;Pietras EM;Chu SH;Barry-Holson K;Armstrong S;Göttgens B;Passegué E
虽然血液产生的许多方面现在已经被很好地理解，但骨髓（BM）中髓细胞分化的空间组织仍然未知。在这里，我们使用成像来跟踪粒细胞/巨噬细胞祖细胞（GMP）在急诊和白血病骨髓生成过程中的行为。在稳定状态下，我们发现单个gmp分散在整个BM中。在再生过程中，我们观察到扩大的GMP斑块形成明确的GMP团簇，而这些团簇又局部分化为粒细胞。我们描述了重要BM生态位信号（SCF, IL-1β, G-CSF, TGF-β, CXCL4）的定时释放和诱导的Irf8/β-catenin祖细胞自我更新网络的激活如何控制再生GMP簇的短暂形成。在白血病中，我们发现由于自我更新网络的持续激活和缺乏通常恢复干细胞静止的终止细胞因子，GMP簇不断产生。我们的研究结果揭示了先前未被认识到的gmp原位动态行为，它调节紧急骨髓形成并在白血病中被劫持。
While many aspects of blood production are now well understood, the spatial organization of myeloid differentiation in the bone marrow (BM) remains unknown. Here, we use imaging to track granulocyte/macrophage progenitor (GMP) behavior during emergency and leukemic myelopoiesis. At steady state, we find individual GMPs scattered throughout the BM. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. We describe how the timed release of important BM niche signals (SCF, IL-1β, G-CSF, TGF-β, CXCL4) and activation of an inducible Irf8/β-catenin progenitor self-renewal network controls the transient formation of regenerating GMP clusters. In leukemia, we show that GMP clusters are constantly produced due to persistent activation of the self-renewal network and lack of termination cytokines that normally restore stem cell quiescence. Our results uncover a previously unrecognized dynamic behavior of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukemia.