Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.
Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.
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DOI：
10.1016/j.stem.2015.05.003
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发表时间：
2015-07-02
期刊：
影响因子：
23.9
通讯作者：
Passegué E
中科院分区：
文献类型：
--
作者：
Pietras EM;Reynaud D;Kang YA;Carlin D;Calero-Nieto FJ;Leavitt AD;Stuart JM;Göttgens B;Passegué E
尽管在理解血液产生的机制方面取得了很大进展，但在多能祖细胞（MPPs）水平上的谱系特化仍然知之甚少。在这里，我们表明，MPP2和MPP3是不同的骨髓偏向MPP亚群，与淋巴引发的MPP4细胞一起控制血液生产。我们发现，所有MPPs是由造血干细胞（HSC）平行产生的，但具有不同的动力学和不同的水平，取决于造血需求。我们还表明，通常罕见的骨髓偏向MPP是短暂的造血干细胞在再生条件下过度生产，因此支持骨髓扩增重建造血系统。这种转变伴随着再生HSC中自我更新活性的降低和MPP4命运向髓系的重编程。我们的研究结果支持一个动态的血液发育模型，其中造血干细胞通过独立产生不同的谱系偏向的MPP子集，反过来支持谱系扩增和分化来传递谱系特化。
Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate towards the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.