Neuropilin-1 Is an Important Niche Component and Exerts Context-Dependent Effects on Hematopoietic Stem Cells
Neuropilin-1 Is an Important Niche Component and Exerts Context-Dependent Effects on Hematopoietic Stem Cells
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DOI：
10.1089/scd.2016.0096
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Kale, Vaijayanti P.
中科院分区：
文献类型：
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作者：
Ghode, Suprita S.;Bajaj, Manmohan S.;Kale, Vaijayanti P.
由于骨髓脂肪细胞对造血再生的负面影响，骨髓脂肪细胞在移植后造血再生中构成了一个重要问题。然而，这种消极调节的确切机制尚不清楚。在这项研究中，我们发现骨髓脂肪细胞表达神经纤毛蛋白-1（neuropilin-1，NRP 1）作为分化的功能，并通过三种主要机制抑制造血再生：一是通过死亡受体介导的途径诱导造血干/祖细胞（HSPCs）凋亡;二是通过配体介导的内化下调HSPCs上CXCR 4的表达;第三，通过分泌大量的转化生长因子β 1（TGF β 1），一种已知的造血抑制剂。NRP 1在这些脂肪细胞中的沉默拯救了共培养的HSPCs的凋亡，并提高了它们表面CXCR 4的表达，显示NRP 1在这些过程中的积极作用。然而，这种沉默对TGF β 1的分泌和随后的造血抑制没有影响，这表明脂肪细胞分泌TGF β 1不依赖于它们表达NRP 1。令人惊讶的是，用NRP 1修饰的间充质基质细胞支持具有增强的功能的HSPC的扩增，表明NRP 1对造血发挥背景依赖性作用。我们的数据表明，NRP 1是一个重要的生态位组成部分，并施加上下文依赖性影响HSPCs。基于这些数据，我们推测抗体或肽介导的NRP 1-HSC相互作用的阻断加上TGF β 1信号传导的药理学抑制可能有助于以更有效的方式对抗移植后造血再生的负调控。
Marrow adipocytes pose a significant problem in post-transplant regeneration of hematopoiesis owing to their negative effects on regeneration of hematopoiesis. However, the precise mechanism operative in this negative regulation is not clear. In this study, we show that marrow adipocytes express neuropilin-1 (NRP1) as a function of differentiation and inhibit regeneration of hematopoiesis by three principal mechanisms: one, by inducing apoptosis in hematopoietic stem/progenitor cells (HSPCs) through the death receptor-mediated pathway; two, by downregulating CXCR4 expression on the HSPCs through ligand-mediated internalization; and three, by secreting copious amounts of transforming growth factor beta 1 (TGF beta 1), a known inhibitor of hematopoiesis. Silencing of NRP1 in these adipocytes rescued the apoptosis of cocultured HSPCs and boosted the CXCR4 surface expression on them, showing an active role of NRP1 in these processes. However, such silencing had no effect on TGF beta 1 secretion and consequent inhibition of hematopoiesis by them, showing that secretion of TGF beta 1 by adipocytes is independent of NRP1 expression by them. Surprisingly, mesenchymal stromal cells modified with NRP1 supported expansion of HSPCs having enhanced functionality, suggesting that NRP1 exerts a context-dependent effect on hematopoiesis. Our data demonstrate that NRP1 is an important niche component and exerts context-dependent effects on HSPCs. Based on these data, we speculate that antibody-or peptide-mediated blocking of NRP1-HSC interactions coupled with a pharmacological inhibition of TGF beta 1 signaling may help in combating the negative regulation of post-transplant regeneration of hematopoiesis in a more effective manner.