THE VLA4/VCAM-1 ADHESION PATHWAY DEFINES CONTRASTING MECHANISMS OF LODGEMENT OF TRANSPLANTED MURINE HEMATOPOIETIC PROGENITORS BETWEEN BONE-MARROW AND SPLEEN
THE VLA4/VCAM-1 ADHESION PATHWAY DEFINES CONTRASTING MECHANISMS OF LODGEMENT OF TRANSPLANTED MURINE HEMATOPOIETIC PROGENITORS BETWEEN BONE-MARROW AND SPLEEN
复制标题
DOI：
10.1073/pnas.92.21.9647
复制
发表时间：
1995-10-10
影响因子：
11.1
通讯作者：
WOLF, NS
中科院分区：
文献类型：
--
作者：
PAPAYANNOPOULOU, T;CRADDOCK, C;WOLF, NS
移植的造血干细胞在受体骨髓（BM）中的选择性寄存或归巢是BM移植后建立长期造血的关键步骤。然而，尽管其具有生物学和临床意义，但对归巢过程知之甚少。在本研究中，我们将重点放在归巢的初始阶段，并探索了一些先前发现的介导造血细胞体外粘附到培养BM基质的粘附途径在体内的功能作用。我们发现，在移植后3小时接受致命辐射的受体，在用一种针对整合素极迟抗原4 （VLA）的抗体预处理供体细胞后，BM的小鼠造血祖细胞的归巢明显减少(4)。骨髓归巢的抑制伴随着血液中循环的造血祖细胞的增加和脾脏对这些祖细胞的摄取增加。用血管细胞粘附分子1 （VCAM-1）抗体（VLA的配体）处理受体也获得了类似的结果(4)。此外，我们发现给正常动物相同的抗体（抗VLA(4)或抗VCAM-1）会引起造血祖细胞动员进入血液，这些数据表明造血细胞在BM中的沉积是一个可调节的过程，可以受到VLA(4)/VCAM-1粘附途径的影响。尽管不排除其他可能的分子途径，但我们的数据表明VCAM-1是骨髓内皮寻址蛋白，类似于粘膜寻址蛋白细胞粘附分子（MAdCAM）在淋巴细胞归巢中的作用。脾对造血祖细胞的摄取是被动的还是通过不同的机制受到控制仍有待澄清。此外，我们提供的实验证据表明，归巢和动员是相关的现象，至少部分涉及相似的分子途径。
Selective lodgement or homing of transplanted hemopoietic stem cells in the recipient's bone marrow (BM) is a critical step in the establishment of long-term hemopoiesis after BM transplantation. However, despite its biologic and clinical significance, little is understood about the process of homing, In the present study, we have concentrated on the initial stages of homing and explored the functional role in vivo of some of the adhesion pathways previously found to mediate in vitro adhesion of hemopoietic cells to cultured BM stroma, We have found that homing of murine hemopoietic progenitors of the BM of lethally irradiated recipients at 3 h after transplant was significantly reduced after pretreatment of the donor cells with an antibody to the integrin very late antigen 4 (VLA(4)). This inhibition of marrow homing was accompanied by an increase in hemopoietic progenitors circulating in the blood and an increased uptake of these progenitors by the spleen. Similar results were obtained by treatment of the recipients with an antibody to vascular cell adhesion molecule 1 (VCAM-1), a ligand for VLA(4). Furthermore, we showed that administration of the same antibodies (anti-VLA(4) or anti-VCAM-1) to normal animals causes mobilization of hemopoietic progenitors into blood, These data suggest that hemopoietic cell lodgement in the BM is a regulatable process and can be influenced by VLA(4)/VCAM-1 adhesion pathway. Although additional molecular pathways are not excluded and may be likely, our data establish VCAM-1 as a BM endothelial addressin, analogous to the role that mucosal addressin cell adhesion molecule (MAdCAM) plays in lymphocyte homing, Whether splenic uptake of hemopoietic progenitors is passive or controlled through different mechanisms remains to be clarified. In addition, we provide experimental evidence that homing and mobilization are related phenomena involving, at Least partly, similar molecular pathways.