Abstract：
Emerging evidence has revealed a direct differentiation route from hematopoietic stem cells to megakaryocytes (direct route), in addition to the classical differentiation route through a series of restricted hematopoietic progenitors (stepwise route). This raises the question of the importance of two alternative routes for megakaryopoiesis. Here, we developed fate-mapping systems to distinguish the two routes, comparing their quantitative and functional outputs. We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes, respectively, but contributed to the platelet-producing megakaryocytes together. Megakaryocytes derived from the two routes displayed different activities and were differentially regulated by chemotherapy and inflammation. Our work links differentiation route to the heterogeneity of megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.
摘要：
新的证据已经揭示了从造血干细胞到巨核细胞的直接分化途径（直接途径），除了通过一系列限制性造血祖细胞的经典分化途径（逐步途径）。这提出了巨核细胞生成的两种替代途径的重要性的问题。这里,我们开发了命运地图系统来区分这两条路线，比较它们的数量和功能输出。我们发现，在稳态下，通过两种途径产生的巨核细胞的动力学和数量相当。命运定位的巨核细胞的单细胞RNA测序表明，直接和逐步的途径有助于生态位支持和免疫巨核细胞，分别,而是一起促成了产生血小板的巨核细胞。来自两种途径的巨核细胞表现出不同的活性，并受到化疗和炎症的差异调节。我们的工作将分化途径与巨核细胞的异质性联系起来。替代的分化途径导致针对不同生理需求的功能不同的巨核细胞亚群的可变组合。
