Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium
Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium
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乳脂肪球-EGF因子8/乳粘素在小鼠肠上皮的维持和修复中发挥着至关重要的作用
DOI：
10.1172/jci31841
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Tan, Xiao-Di
中科院分区：
文献类型：
--
作者：
Bu, Heng-Fu;Zuo, Xiu-Li;Tan, Xiao-Di
乳脂球EGF因子8（MFG-E8）/乳粘附素参与几种细胞表面介导的调节事件。虽然其mRNA存在于肠道中，但MFG-E8在肠粘膜中的生理作用尚未被探索。在这里，我们表明，MFG-E8表达在肠固有层巨噬细胞从小鼠。使用伤口愈合试验，MFG-E8显示通过PKCE依赖性机制促进肠上皮细胞的迁移。MFG-E8与磷脂酰丝氨酸结合，并引发伤口边缘肠上皮细胞中肌动蛋白细胞骨架的重新定向。通过施用抗MFG-E8抗体或靶向缺失MFG-E8基因来消耗小鼠中的MFG-E8导致肠上皮细胞沿隐窝-绒毛轴的迁移沿着和局灶性粘膜损伤减慢。此外，在脓毒症小鼠中，肠MFG-E8表达下调，这与肠损伤、肠上皮细胞迁移中断和恢复受损相关。用重组MFG-E8治疗恢复肠上皮细胞迁移，而MFG-E8的缺失阻碍了脓毒症小鼠的粘膜愈合。这些结果表明，肠MFG-E8的减少损害脓毒症中的肠粘膜修复。总之，我们的数据表明，MFG-E8在维持肠上皮稳态和促进粘膜愈合方面起着重要作用，并表明重组MFG-E8可能有利于治疗肠损伤。
Milk fat globule-EGF factor 8 (MFG-E8)/lactadherin participates in several cell surface-mediated regulatory events. Although its mRNA is present in the gut, the physiological roles of MFG-E8 in the intestinal mucosa have not been explored. Here we show that MFG-E8 was expressed in intestinal lamina propria macrophages from mice. Using a wound-healing assay, MFG-E8 was shown to promote the migration of intestinal epithelial cells through a PKCE-dependent mechanism. MFG-E8 bound to phosphatidylserine and triggered reorientation of the actin cytoskeleton in intestinal epithelial cells at the wound edge. Depleting MFG-E8 in mice by administration of anti-MFG-E8 antibody or targeted deletion of the MFG-E8 gene resulted in a slowing of enterocyte migration along the crypt-villus axis and focal mucosal injury. Moreover, in septic mice, intestinal MFG-E8 expression was downregulated, which correlated with intestinal injury, interrupted enterocyte migration, and impaired restitution. Treatment with recombinant MFG-E8 restored enterocyte migration, whereas deletion of MFG-E8 impeded mucosal healing in mice with sepsis. These results suggest that a decrease in intestinal MFG-E8 impairs intestinal mucosal repair in sepsis. Together, our data indicate that MFG-E8 plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing and suggest that recombinant MFG-E8 may be beneficial for the treatment of bowel injuries.