Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro
Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro
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DOI：
10.1016/j.yexcr.2005.02.004
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发表时间：
2005-05-15
影响因子：
3.7
通讯作者：
Southgate, J
中科院分区：
文献类型：
--
作者：
Varley, C;Hill, G;Southgate, J
尿道鞘的再生是快速和有效的，以维持组织损伤后的尿液屏障。而正常人尿路上皮（NHU）细胞是nitotically静止的，并且GO原位停滞，它们在接种于原代培养物中后迅速进入细胞周期，并且在汇合时显示可逆的生长停滞。我们以此为模型来研究EGF受体信号在尿路上皮再生和伤口愈合中的作用。HER-1、HER-2和HER-3的转录物由静止的人尿激酶原位表达。HER-I的表达在增殖培养物中上调，而HER-2和HER-3与生长停滞表型更相关。NHU细胞可以在没有外源性EGF的情况下增殖，但通过HER-1通过MAPK和P13激酶途径的自分泌信号对于尿路上皮创伤修复过程中的增殖和迁移至关重要。HB-EGF在原位表达于尿路上皮细胞，HB-EGF、表皮调节蛋白、TGF-α和双调蛋白在增殖的NHU细胞中表达。体外尿路上皮伤口修复通过针对HER-I配体的中和抗体，特别是双调蛋白而减弱。相比之下，相同的配体外源性地促进迁移，但抑制增殖，这意味着HER-I配体在NHU细胞中引起不同的作用，这取决于它们是作为可溶性配体还是作为非他克林配体存在。我们的结论是，在NHU细胞伤口愈合过程中的增殖和迁移介导的EGFR自分泌信号环，我们的研究结果牵连双调蛋白作为一个关键的调解人。(c)2005年爱思唯尔公司All rights reserved.
Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are rnitotically quiescent and GO arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing. Transcripts for HER-1, HER-2, and HER-3 were expressed by quiescent human urothelium in situ. Expression of HER-I was upregulated in proliferating cultures, whereas HER-2 and HER-3 were more associated with a growth-arrested phenotype. NHU Cells Could be propagated in the absence of exogenous EGF, but autocrine signaling through HER-1 via the MAPK and P13kinase pathways was essential for proliferation and migration during urothelial wound repair. HB-EGF was expressed by urothelium in situ and HB-EGF, epiregulin, TGF-alpha, and amphiregulin were expressed by proliferating NHU cells. Urothelial wound repair in vitro was attenuated by neutralizing antibodies against HER-I ligands, particularly amphiregulin. By contrast, the same ligands applied exogenously promoted migration, but inhibited proliferation, implying that HER-I ligands provoke differential effects in NHU cells depending upon whether they are presented as soluble or juxtacrine ligands. We conclude that proliferation and migration during wound healing in NHU cells are mediated through an EGFR autocrine signalling loop and our results implicate amphiregulin as a key mediator. (c) 2005 Elsevier Inc. All rights reserved.