Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk
Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk
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DOI：
10.1182/blood-2005-05-2138
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发表时间：
2006-04-01
期刊：
影响因子：
20.3
通讯作者：
Takaki, S
中科院分区：
文献类型：
--
作者：
Takizawa, H;Kubo-Akashi, C;Takaki, S
造血干细胞（HSCs）是维持整个生命过程中血细胞生成和骨髓（BM）移植后淋巴造血重建的关键因素。作为降低伴随BM移植的风险和困难的手段，HSC以及造血祖细胞（HPC）的移植潜力和扩增能力的增强一直是长期的期望。HSC/HPC重建辐射宿主造血系统的能力受到细胞内衔接蛋白Link的负调控。在这里，我们已经确定了连接的功能结构域，并开发了一个显性负（DIN）Lnk突变体，抑制Lnk的功能内源性表达的HSC/HPC，从而加强HSC/HPC的植入。重要的是，DN-Lnk在HSC/HPC中的瞬时表达促进了它们在非清髓性条件下的植入，并完全重建了免疫缺陷宿主动物的淋巴区室。在transwell迁移试验中，固定化血管细胞粘附分子-1（VCAM-1）有效地捕获了表达DN-Lnk的HPC，表明Lnk参与了微环境中细胞迁移或细胞相互作用的调节。瞬时抑制Lnk或Lnk介导的通路可能是增强HSC/HPC植入的有效方法，而没有明显的副作用。
Hematopoietic stem cells (HSCs) are the key elements responsible for maintaining blood-cell production throughout life and for lymphohematopoietic reconstitution following bone marrow (BM) transplantation. Enhancement of the engrafting potential and expansion capabilities of HSCs as well as hematopoietic progenitor cells (HPCs) has been a long-time desire as a means of reducing the risks and difficulties that accompany BM transplantation. The ability of HSCs/HPCs to reconstitute the hematopoietic system of irradiated hosts is negatively regulated by an intracellular adaptor protein, Link. Here we have identified the functional domains of Link and developed a dominant-negative (DIN) Lnk mutant that inhibits the functions of Lnk endogenously expressed in the HSCs/HPCs and thereby potentiates the HSCs/HPCs for engraftment. Importantly, even transient expression of DN-Lnk in HSCs/HPCs facilitated their engraftment under nonmyeloablative conditions and fully reconstituted the lymphoid compartments of immunodeficient host animals. HPCs expressing DN-Lnk were efficiently trapped by immobilized vascular cell adhesion molecule-1 (VCAM-1) in a transwell migration assay, suggesting involvement of Lnk in the regulation of cell mobility or cellular interaction in microenvironments. Transient inhibition of Lnk or Lnk-mediated pathways could be a potent approach to augment engraftment of HSCs/HPCs without obvious side effects.