2009 - 追溯造血干细胞和祖细胞的祖先,揭示其独特的分子特征

IF 2.5 4区 医学 Q2 HEMATOLOGY
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引用次数: 0

摘要

大多数研究都侧重于了解造血内皮细胞(HECs)如何成熟为造血干细胞和祖细胞(HSPCs)。HECs和新生HSPCs可通过内皮和造血标志物的共同表达来识别。然而,大多数启动内皮细胞向造血细胞命运转换的诱导信号必须发生在造血基因表达之前的内皮细胞亚群中。由于难以在体内标记 HEC 的内皮祖先,导致内皮细胞群未被定性,而这些细胞群是造血发育的基础。此外,哺乳动物胚胎中这些发育中间产物在空间上的共存也进一步挑战了它们的表征。在这里,我们利用斑马鱼快速的胚胎发育过程(这种过程会导致同步的发育转换),分离并鉴定了这些中间产物。利用这一系统,结合新型报告基因,我们追溯了 HECs 的内皮祖先。出乎意料的是,我们发现这些内皮前体与周围的内皮前体具有截然不同的分子特征,这表明 HECs 来自一个特定的内皮细胞池,它不同于其他发育中的内皮细胞(ECs)。静止是这些 HEC 前体的特征之一,我们发现 p65 激活在体内和体外都起到了关键的介导作用。此外,当 p65 消融导致静息消失时,HECs 无法特定化。相反,强制静止会增加可用于转分化的 HEC 前体库。我们的工作在体内揭示了作为造血系统基础的欧共体以前神秘的生物学特性。这些知识可用于优化体外生成 HSPC 及其衍生物的方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
2009 – TRACING BACK THE ANCESTORS OF HEMATOPOIETIC STEM AND PROGENITOR CELLS REVEAL THEIR UNIQUE MOLECULAR CHARACTERISTICS

A majority of studies have focused on understanding how hemogenic endothelial cells (HECs) mature into hematopoietic stem and progenitor cells (HSPCs). HECs and nascent HSPCs can be identified by the co-expression of endothelial and hematopoietic markers. However, most of the inductive signals that initiate the switch from endothelial to hematopoietic fate must occur in a subset of endothelial cells prior hematopoietic genes being expressed. Difficulties labelling the endothelial ancestors of HECs in vivo have resulted in uncharacterized endothelial cell populations that serve has the foundation for hematopoietic development. In addition, the spatial coexistence of these developmental intermediates in the mammalian embryo further challenges their characterization. Here, utilizing the rapid embryonic development of the zebrafish, which results in synchronized developmental transitions, we segregated and characterized these intermediates. Using this system, in conjunction with novel reporter lines, we traced back the endothelial ancestry of HECs. Unexpectedly, we found that these endothelial precursors have distinct molecular characteristics from their surrounding endothelial counterparts, indicating that HECs derive from a specific endothelial pool that differs from the rest of developing endothelial cells (ECs). Quiescence was one of the hallmarks of these HEC precursors, and we showed that p65 activation critically mediated it both in vivo and in vitro. In addition, when quiescence was lost by p65 ablation, HECs failed to specify. On the contrary, enforced quiescence increased the pool of HEC precursors available to transdifferentiate. Our work uncovers in vivo the previously enigmatic biology of the ECs that serve as the foundation for the hematopoietic system. This knowledge could be used to optimize in vitro protocols of HSPC generation and their derivatives.

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来源期刊
Experimental hematology
Experimental hematology 医学-血液学
CiteScore
5.30
自引率
0.00%
发文量
84
审稿时长
58 days
期刊介绍: Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.
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