Notch signaling in Nestin-expressing cells in the bone marrow maintains erythropoiesis via macrophage integrity
Notch signaling in Nestin-expressing cells in the bone marrow maintains erythropoiesis via macrophage integrity
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骨髓中巢蛋白表达细胞中的 Notch 信号通过巨噬细胞完整性维持红细胞生成
DOI：
10.1002/stem.3011
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发表时间：
2019
期刊：
影响因子：
5.2
通讯作者：
Chiba Shigeru
中科院分区：
文献类型：
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作者：
Sakamoto Tatsuhiro;Obara Naoshi;Nishikii Hidekazu;Kato Takayasu;Luan Cao Sy;Fujimura Ryosuke;Yagita Hideo;Sakata-Yanagimoto Mamiko;Takahashi Satoru;Chiba Shigeru
Notch信号通路在造血干/祖细胞及其微环境细胞中起着关键作用。骨髓增殖表型是通过在非造血骨髓（BM）细胞中破坏Notch信号传导而诱导的。据报道，BM中表达巢蛋白的细胞代表造血干细胞小生境的组分。我们建立了小鼠，其中骨髓中罕见的表达Nestin的细胞被绿色荧光蛋白标记，并且Notch信号传导在这些细胞中被特异性地有条件地破坏。我们观察到骨髓红细胞生成障碍伴脾肿大，而其他谱系的骨髓造血程序未受干扰。移植实验表明，微环境，而不是造血细胞归因于这些表型。我们进一步发现BM中央巨噬细胞的红系岛形成能力随着白细胞介素-6的转录上调而沿着受损。各种炎症性疾病阻碍BM红细胞生成，其通常伴随髓外造血。本文所展示的小鼠模型可能与这种常见的病理生理条件相关。Stem Cells 2019;37：924- 936显著性声明Notch信号传导在造血干细胞（HSC）及其小生境细胞中起着至关重要的作用。据报道，在骨髓（BM）中表达巢蛋白的间充质基质细胞（MSC）是HSC巢的组成部分。研究结果表明，表达Nestin的MSC中的Notch信号传导调节BM中的红系分化。表达Nestin的MSC中Notch信号的破坏诱导了中央巨噬细胞中白细胞介素-6（IL-6）的上调，并且IL-6可以导致中央巨噬细胞中红系岛形成能力的损害。结果表明，骨髓中的红细胞生成是通过中央巨噬细胞和表达Nestin的MSC之间的相互作用来调节的。
AbstractNotch signaling plays pivotal roles in both hematopoietic stem/progenitor and their niche cells. Myeloproliferative phenotypes are induced by disruption of Notch signaling in nonhematopoietic bone marrow (BM) cells. Nestin-expressing cells in the BM reportedly represent a component of the hematopoietic stem cell niche. We established mice in which rare Nestin-expressing cells in the BM were marked by green fluorescent protein, and Notch signaling was conditionally disrupted in these cells specifically. We observed impairment of erythropoiesis in the BM accompanying splenomegaly with BM hematopoietic programs in other lineages undisturbed. Transplantation experiments revealed that the microenvironmental rather than the hematopoietic cells were attributable to these phenotypes. We further found that the erythroid-island-forming ability of BM central macrophages was compromised along with the transcriptional upregulation of interleukin-6. Various Inflammatory conditions hamper BM erythropoiesis, which often accompanies extramedullary hematopoiesis. The mouse model demonstrated here may be of relevance to this common pathophysiologic condition.Stem Cells2019;37:924–936SignificanceStatementNotch signaling plays a crucial role in both hematopoietic stem cells (HSCs) and their niche cells. Nestin-expressing mesenchymal stromal cells (MSCs) in a bone marrow (BM) are reported as a component of HSC niche. Results of the study showed that Notch signaling in Nestin-expressing MSCs regulates erythroid differentiation in the BM. Disruption of Notch signaling in Nestin-expressing MSCs induced the upregulation of interleukin-6 (IL-6) in central macrophages, and IL-6 can cause the impairment of erythroid-island-forming capacity in central macrophages. The results suggest that the erythropoiesis in the BM is regulated by interaction between the central macrophages and Nestin-expressing MSCs.