Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells
Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells
复制标题
DOI：
10.1182/blood-2009-05-224857
复制
发表时间：
2010-07-29
期刊：
影响因子：
20.3
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Hosokawa, Kentaro;Arai, Fumio;Suda, Toshio
在出生后的生活中，骨髓（BM）支持造血干细胞（HSC）在称为干细胞龛的专门微环境中的自我更新和分化。HSC与其小生境之间的细胞-细胞和细胞-细胞外基质相互作用对于维持HSC的特性至关重要。本研究通过转染N-cadherin shRNA，分析了N-cadherin在造血干/祖细胞增殖和长期再增殖活性调控中的作用。抑制N-钙粘蛋白表达可加速体外细胞分裂，减少供体HSPCs在骨内膜表面的沉积，导致长期植入显著减少。共转导的N-钙粘蛋白shRNA和突变的N-钙粘蛋白，引入沉默突变的shRNA靶序列拯救加速细胞分裂和重建表型。此外，HSPC植入对N-钙粘蛋白的需求似乎具有生态位特异性，因为shN-cad转导的谱系（-）Sca-1（+）c-Kit（+）细胞成功植入缺乏成骨细胞生态位的脾脏中。这些发现表明，N-cad介导的细胞粘附是功能上需要的骨髓移植后在骨髓龛造血的建立。（血。2010; 116（4）：554-563）
During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA. Inhibition of N-cadherin expression accelerated cell division in vitro and reduced the lodgment of donor HSPCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. Cotransduction of N-cadherin shRNA and a mutant N-cadherin that introduced the silent mutations to shRNA target sequences rescued the accelerated cell division and reconstitution phenotypes. In addition, the requirement of N-cadherin for HSPC engraftment appears to be niche specific, as shN-cad-transduced lineage (-)Sca-1(+)c-Kit(+) cells successfully engrafted in spleen, which lacks an osteoblastic niche. These findings suggest that N-cad-mediated cell adhesion is functionally required for the establishment of hematopoiesis in the BM niche after BM transplantation. (Blood. 2010; 116(4):554-563)