CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age
CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age
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DOI：
10.1182/blood-2012-09-457929
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发表时间：
2013-05-30
期刊：
影响因子：
20.3
通讯作者：
Graf, Thomas
中科院分区：
文献类型：
--
作者：
Gekas, Christos;Graf, Thomas
造血干细胞（HSC）室是异质的，然而我们对不同HSC亚型的身份的理解是有限的。在这里，我们发现血小板整合素CD41 (α IIb)，目前被认为只是短暂地标记胎儿HSC，在成人HSC亚型上表达，随着年龄的增长而积累。CD41+造血干细胞大部分处于静止状态，并表现出由Gata1控制的髓系和巨核细胞基因启动，而CD41 -造血干细胞更具增殖性，并表现出淋巴细胞基因启动。在不使用阻断抗体的情况下，CD41+造血干细胞在连续移植中具有长期的再生能力，与CD41 -造血干细胞相比，CD41+造血干细胞表现出明显的髓系偏倚，后者产生更偏向淋巴细胞的后代。CD41敲除（KO）小鼠表现出多系造血缺陷，并伴有HSC的静止和存活减少，这表明CD41在功能上与HSC维持和造血稳态相关。移植实验表明，cd41 - ko相关缺陷是长期可移植的、HSC衍生的，并且在一定程度上是通过血小板质量损失介导的，导致HSC暴露于血小板释放的重要细胞因子（如转化生长因子β 1）的减少。总之，我们的数据提供了一种新的标记物来识别随着年龄增长而普遍存在的髓系偏倚HSC亚型，并强调了他们的后代对HSC的调节。
The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (alpha IIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41 - HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity on serial transplantations and showed a marked myeloid bias compared with CD41 - HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout (KO) mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO-associated defects are long-term transplantable, HSC-derived and, in part, mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as transforming growth factor beta 1. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age and highlights the dogma of HSC regulation by their progeny.