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科学家揭示TCF15在造血过程中的功能
2020-07-16 17:31

美国哈佛大学Fernando D. Camargo及其团队利用单细胞谱系示踪揭示了TCF15在造血过程中的作用。2020年7月15日出版的《自然》在线发表了这项成果。

为解决测序损害和细胞观察不能同时进行这一难题,研究人员采用了可表达的慢病毒条形码技术,该技术可在长期骨髓重建过程中同时分析单个成熟造血干细胞(HSCs)的谱系、转录组及其克隆轨迹。对具有不同行为克隆的差异基因表达分析揭示了一个内在的分子特征,该特征代表了功能性长期繁殖的HSC。

通过体内CRISPR筛选探索这一特征,研究人员发现转录因子TCF15是必需的,并且其足以促进HSC静止和长期自我更新。原位Tcf15表达标记了真正多能HSC的最原始子集。总之,这项工作阐明了与功能干细胞异质性相关克隆的内在分子机制,并确定了维持HSC自我更新的基础。

据了解,骨髓移植依赖于HSCs的终生再生能力。造血干细胞在克隆水平上表现出多种多样的再生行为,但这种多样性的潜在机制仍未知。单细胞RNA测序的最新进展揭示了HSC之间的转录差异,为它们的功能异质性提供了可能的解释。然而,测序方法的破坏性阻碍了同时观察干细胞的状态和功能。

附:英文原文

Title: Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis

Author: Alejo E. Rodriguez-Fraticelli, Caleb Weinreb, Shou-Wen Wang, Rosa P. Migueles, Maja Jankovic, Marc Usart, Allon M. Klein, Sally Lowell, Fernando D. Camargo

Issue&Volume: 2020-07-15

Abstract: Bone marrow transplantation therapy relies on the life-long regenerative capacity of haematopoietic stem cells (HSCs)1,2. HSCs present a complex variety of regenerative behaviours at the clonal level, but the mechanisms underlying this diversity are still undetermined3,4,5,6,7,8,9,10,11. Recent advances in single-cell RNA sequencing have revealed transcriptional differences among HSCs, providing a possible explanation for their functional heterogeneity12,13,14,15,16,17. However, the destructive nature of sequencing assays prevents simultaneous observation of stem cell state and function. To solve this challenge, we implemented expressible lentiviral barcoding, which enabled simultaneous analysis of lineages and transcriptomes from single adult HSCs and their clonal trajectories during long-term bone marrow reconstitution. Analysis of differential gene expression between clones with distinct behaviour revealed an intrinsic molecular signature that characterizes functional long-term repopulating HSCs. Probing this signature through in vivo CRISPR screening, we found the transcription factor TCF15 to be required and sufficient to drive HSC quiescence and long-term self-renewal. In situ, Tcf15 expression labels the most primitive subset of true multipotent HSCs. In conclusion, our work elucidates clone-intrinsic molecular programmes associated with functional stem cell heterogeneity and identifies a mechanism for the maintenance of the self-renewing HSC state.

DOI: 10.1038/s41586-020-2503-6

Source: https://www.nature.com/articles/s41586-020-2503-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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