Cadherin-Based Adhesion Is a Potential Target for Niche Manipulation to Protect Hematopoietic Stem Cells in Adult Bone Marrow
Cadherin-Based Adhesion Is a Potential Target for Niche Manipulation to Protect Hematopoietic Stem Cells in Adult Bone Marrow
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DOI：
10.1016/j.stem.2009.04.013
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发表时间：
2010-03-05
期刊：
影响因子：
23.9
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Hosokawa, Kentaro;Arai, Fumio;Suda, Toshio
在出生后的生命中，造血干细胞（HSC）维持在专门的骨髓（BM）小生境中（莫里森和Spradling，2008; Wilson和Trumpp，2006; Yin和Li，2006）。钙粘蛋白是负责Ca 2+依赖性细胞-细胞相互作用的主要细胞粘附分子（Gumbiner，1996），但钙粘蛋白功能，更具体地说是N-钙粘蛋白在HSC-小生境相互作用中的作用一直存在争议（Li和Zon，2010）。在这项研究中，我们分析了各种钙粘蛋白（cad）基因在长期HSC（LT-HSC）和从骨内膜分离的细胞亚群的表达。我们发现，LT-HSC表达低水平的N-cad，而骨内膜细胞群，包括间充质祖细胞（MPC），未成熟的OBs和成熟OBs表达不同水平的各种钙粘蛋白。我们通过表达显性阴性突变体N-cad（DN-N-cad）探索钙粘蛋白功能对HSC的影响，发现它减少了HSC的沉积（锚定到骨内膜表面），并显着抑制其长期植入。同时，在连续骨髓移植过程中，HSC中N-cadherin的过表达促进了HSC的静止并维持了HSC的活性。这些数据表明，增强的细胞粘附可以保护HSC免受各种压力，并促进HSC池的长期维持。因此，通过粘附相互作用操纵干细胞及其小生境之间的信号传导可能会成为再生或癌症医学的新型小生境相关疗法的基础。
During postnatal life, hematopoietic stem cells (HSCs) are maintained in specialized bone marrow (BM) niches (Morrison and Spradling, 2008; Wilson and Trumpp, 2006; Yin and Li, 2006). Cadherins are major cell adhesion molecules responsible for Ca2+-dependent cell-cell interaction (Gumbiner, 1996), but the role of cadherin function, and more specifically N-cadherin, in HSC-niche interactions has been controversial (Li and Zon, 2010). In this study, we analyzed the expression of various cadherin (cad) genes in longterm HSCs (LT-HSCs) and subpopulations of the cells isolated from the endosteum. We found that LT-HSCs expressed a low level of N-cad, whereas endosteal cell populations including mesenchymal progenitor cells (MPCs), immature OBs, and mature OBs expressed a variety of cadherins at different levels. We explored the influence of cadherin function on HSCs by expressing a dominant-negative mutant N-cad (DN-N-cad) and found that it reduced the lodgment of HSCs (anchoring to the endosteal surface) and significantly inhibited their long-term engraftment. Meanwhile, overexpression of N-cadherin in HSCs promoted quiescence and maintained HSC activity during serial BM transplantation. These data suggest that enhanced cell adhesion may protect HSCs against various stresses and promote long-term maintenance of the HSC pool. Thus, manipulation of the signaling between stem cells and their niche through adhesive interactions could potentially form a basis of novel nicherelated therapies for regenerative or cancer medicine.