Clonal dynamics of native haematopoiesis

摘要

人们普遍认为，很少数量的造血干细胞通过稳定生成不同层次的短寿命祖细胞来维持多细胞系造血功能。这一理论历史上是根据在接受致命辐射的宿主身上所做的移植实验建立的。现在，利用一个新的、基于转座子的标记方法(该方法使研究人员能够对单个祖细胞和它们的后代在活体中进行独特标记），Fernando Camargo及同事显示，在本体非移植造血过程中可能不是这种情况。作者发现，在成年时期的大部分时间，稳定造血功能的主要驱动因素是大量长寿命祖细胞，而不是人们传统上所认为的造血干细胞。%It is currently thought that life-long blood cell production is driven by the action of a small number of multipotent haematopoietic stem cells. Evidence supporting this view has been largely acquired through the use of functional assays involving transplantation. However, whether these mechanisms also govern native non-transplant haematopoiesis is entirely unclear. Here we have established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address this question. Using this approach, we have performed longitudinal analyses of clonal dynamics in adult mice that reveal unprecedented features of native haematopoiesis. In contrast to what occurs following transplantation, steady-state blood production is maintained by the successive recruitment of thousands of clones, each with a minimal contribution to mature progeny. Our results demonstrate that a large number of long-lived progenitors, rather than classically defined haematopoietic stem cells, are the main drivers of steady-state haematopoiesis during most of adulthood. Our results also have implications for understanding the cellular origin of haematopoietic disease.