Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation.
Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation.
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DOI：
10.1038/s41467-021-27161-3
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发表时间：
2021-11-29
影响因子：
16.6
通讯作者：
Koch PS
中科院分区：
文献类型：
--
作者：
Heil J;Olsavszky V;Busch K;Klapproth K;de la Torre C;Sticht C;Sandorski K;Hoffmann J;Schönhaber H;Zierow J;Winkler M;Schmid CD;Staniczek T;Daniels DE;Frayne J;Metzgeroth G;Nowak D;Schneider S;Neumaier M;Weyer V;Groden C;Gröne HJ;Richter K;Mogler C;Taketo MM;Schledzewski K;Géraud C;Goerdt S;Koch PS
在骨髓微环境中，内皮细胞（EC）发挥着重要的功能。动脉EC支持造血，而H型毛细血管诱导骨形成。在这里，我们表明，BM正弦EC（BM-SEC）积极控制红细胞生成。通过使用BM-SEC限制性Cre小鼠系（Stab 2-iCreF 3）生成的BM-SEC（Ctnnb 1 OE-SEC）中β-连环蛋白稳定的小鼠发生致命性贫血。虽然BM-SEC中Wnt信号传导的激活导致成红细胞亚群（PII-PIV）增加，但成熟红细胞（PV）减少，表明终末红细胞分化/网织红细胞成熟受损。将Ctnnb 1 OE-SEC造血干细胞移植到野生型受体中证实了致死性贫血是由细胞外源性内皮介导的效应引起的。Ctnnb 1 OE-SEC BM-SEC显示异常的窦状隙分化，伴有EC基因表达改变和窦周ECM沉积，以及血管分泌失调，伴有FGF 23和DKK 2的新生内皮表达，分别在贫血中升高和参与血管稳定。我们的研究表明，BM-SEC在健康和疾病的骨髓微环境中发挥重要作用。与造血细胞的生态位串扰是正常造血和骨髓疾病的基础。在这里，作者报告了Cre活性仅限于骨髓窦内皮细胞的Stabilin 2-Cre驱动小鼠，并且Stabilin 2-Cre驱动的b-连环蛋白过度活化导致红系分化缺陷和贫血。
Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC (Ctnnb1OE-SEC) generated by using a BM-SEC-restricted Cre mouse line (Stab2-iCreF3) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII–PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease. Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.
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影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
9.8
作者：
Filipowska J;Tomaszewski KA;Niedźwiedzki Ł;Walocha JA;Niedźwiedzki T
通讯作者：
Niedźwiedzki T
影响因子：
23.9
作者：
Duarte D;Hawkins ED;Akinduro O;Ang H;De Filippo K;Kong IY;Haltalli M;Ruivo N;Straszkowski L;Vervoort SJ;McLean C;Weber TS;Khorshed R;Pirillo C;Wei A;Ramasamy SK;Kusumbe AP;Duffy K;Adams RH;Purton LE;Carlin LM;Lo Celso C
通讯作者：
Lo Celso C