DIRECT ADHESION TO BONE-MARROW STROMA VIA FIBRONECTIN RECEPTORS INHIBITS HEMATOPOIETIC PROGENITOR PROLIFERATION
DIRECT ADHESION TO BONE-MARROW STROMA VIA FIBRONECTIN RECEPTORS INHIBITS HEMATOPOIETIC PROGENITOR PROLIFERATION
复制标题
DOI：
10.1172/jci118063
复制
发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
VERFAILLIE, CM
中科院分区：
文献类型：
--
作者：
HURLEY, RW;MCCARTHY, JB;VERFAILLIE, CM
在长期骨髓培养中，基质-粘附祖细胞的增殖明显低于非粘附祖细胞，因此，密切的祖细胞-基质相互作用可能有助于调节或限制而不是促进造血祖细胞的增殖。我们假设，当祖细胞与基质接触时，通过造血细胞粘附受体传递的信号可能有助于抑制增殖。我们证明，在transwell中与基质物理分离培养的祖细胞比粘附在基质上的祖细胞增殖明显更多。此外，特异性粘附于基质、代谢失活的戊二醛固定基质、基质-细胞外基质或纤维连接蛋白的cooh末端肝素结合域后，集落形成细胞（CFC）的增殖减少，非特异性粘附于聚l-赖氨酸不能抑制CFC的增殖。通过阻断抗α -4单体F（ab）片段表明，VLA-4整合素是传递增殖抑制信号的受体之一。当在dexter型骨髓培养物中加入代表纤维连接蛋白肝素结合区域内特定细胞附着位点的合成肽时，观察到CFC的恢复和增殖显著增加，这表明这些肽破坏了粘附介导的增殖抑制事件。造血功能的负调控可能不仅依赖于生长抑制因子的作用，还依赖于祖细胞与骨髓基质之间直接粘附相互作用产生的生长抑制信号。
In long-term bone marrow cultures, stroma-adherent progenitors proliferate significantly less than nonadherent progenitors, Thus, close progenitor-stroma interactions may serve to regulate or restrict rather than promote hematopoietic progenitor proliferation, We hypothesized that signaling through adhesion receptors on hematopoietic cells may contribute to the inhibition of proliferation observed when progenitors are in contact with stroma. We demonstrate that progenitors cultured physically separated from stroma in a transwell proliferate significantly more than progenitors adherent to stroma. Furthermore, proliferation of colony forming cells (CFC) is reduced after specific adhesion to stroma, metabolically inactivated glutaraldehyde-fixed stroma, stromal-extracellular matrix, or the COOH-terminal heparin-binding domain of fibronectin, Nonspecific adhesion to poly-L-lysine fails to inhibit CFC proliferation, That the VLA-4 integrin is one of the receptors that transfers proliferation inhibitory signals was shown using blocking anti-alpha 4 monomeric F(ab) fragments, Furthermore, when synthetic peptides representing specific Cell attachment sites within the heparin-binding domain of fibronectin were added to Dexter-type marrow cultures, significantly increased recovery and proliferation of CFC was observed, suggesting that these peptides disrupt adhesion-mediated proliferation inhibitory events, Thus, negative regulation of hematopoiesis may not only depend on the action of growth inhibitory cytokines but also on growth inhibitory signals resulting from direct adhesive interactions between progenitors and marrow stroma.