Conversion of adult endothelium to immunocompetent haematopoietic stem cells.
Conversion of adult endothelium to immunocompetent haematopoietic stem cells.
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DOI：
10.1038/nature22326
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发表时间：
2017-05-25
期刊：
影响因子：
64.8
通讯作者：
Rafii S
中科院分区：
文献类型：
--
作者：
Lis R;Karrasch CC;Poulos MG;Kunar B;Redmond D;Duran JGB;Badwe CR;Schachterle W;Ginsberg M;Xiang J;Tabrizi AR;Shido K;Rosenwaks Z;Elemento O;Speck NA;Butler JM;Scandura JM;Rafii S
内皮细胞向造血干细胞过渡的发育途径尚不明确。在这里，我们展示了一种简单的方法，通过瞬间表达编码转录因子Fosb、Gfi1、Runx1和Spi1（也称为Fgrs）和血管壁龛衍生的血管分泌因子的基因，将成年小鼠内皮细胞完全转化为造血干细胞（rec - hsc）。转化的诱导期（0-8天）由成熟内皮细胞中Fgrs的表达启动，导致内源性Runx1表达。在分化阶段（第8-20天），Runx1+ Fgrs转导的内皮细胞致力于产生不再需要Fgrs表达的rec - hsc的造血命运。血管生态位驱动rec - hsc的强大自我更新和扩张阶段（第20-28天）。rec - hsc具有与成人造血干细胞相似的转录组和长期自我更新能力，具有克隆植入和一系列初级和次级多谱系重建潜力，包括抗原依赖性适应性免疫功能。抑制TGF-β和CXCR7或激活BMP和CXCR4信号可增强rec - hsc的生成。将内皮细胞转化为可移植的自体造血干细胞有助于治疗血液病。
Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully converting adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of genes encoding the transcription factors Fosb, Gfi1, Runx1, and Spi1 (also known as Fgrs) and vascular-niche-derived angiocrine factors. The induction phase (day 0–8) of conversion is initiated by expression of Fgrs in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (day 8–20), Runx1+ Fgrs-transduced endothelial cells commit to a haematopoietic fate yielding rEC-HSCs that no longer require Fgrs expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (at day 20–28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, are competent for clonal engraftment and serial primary and secondary multi-lineage reconstituting potential, including antigen-dependent adaptive immune function. Inhibition of TGF-β and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.
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影响因子：
23.9
作者：
Butler JM;Nolan DJ;Vertes EL;Varnum-Finney B;Kobayashi H;Hooper AT;Seandel M;Shido K;White IA;Kobayashi M;Witte L;May C;Shawber C;Kimura Y;Kitajewski J;Rosenwaks Z;Bernstein ID;Rafii S
通讯作者：
Rafii S
影响因子：
12.3
作者：
Redmond D;Poran A;Elemento O
通讯作者：
Elemento O
影响因子：
23.9
作者：
Doulatov, Sergei;Vo, Linda T.;Chou, Stephanie S.;Kim, Peter G.;Arora, Natasha;Li, Hu;Hadland, Brandon K.;Bernstein, Irwin D.;Collins, James J.;Zon, Leonard I.;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
64.8
作者：
Rafii S;Butler JM;Ding BS
通讯作者：
Ding BS
影响因子：
20.3
作者：
RAFII, S;SHAPIRO, F;ASCH, AS
通讯作者：
ASCH, AS