Amphiregulin in lung branching morphogenesis: interaction with heparan sulfate proteoglycan modulates cell proliferation.
Amphiregulin in lung branching morphogenesis: interaction with heparan sulfate proteoglycan modulates cell proliferation.
复制标题
DOI：
--
复制
发表时间：
1996-06
期刊：
影响因子：
4.6
通讯作者：
Lucia Schuger;Gibbes R. Johnson;Kevin Gilbride;Gregory D. Plowman;Richard Mandel
中科院分区：
文献类型：
--
作者：
Lucia Schuger;Gibbes R. Johnson;Kevin Gilbride;Gregory D. Plowman;Richard Mandel
从小鼠胚胎肺中分离的上皮细胞和间充质细胞合成并以不同的方式对双调节蛋白（AR）产生反应。间充质细胞产生和沉积的AR是上皮细胞的3- 4倍，在外源性AR存在下增殖，其自发生长被抗AR抗体阻断高达85%。相反，上皮细胞对这种生长调节因子表现出广泛的反应，这取决于它们是否补充了细胞外基质（ECM），以及这种ECM是上皮细胞还是间充质细胞。ar处理的上皮细胞在间质沉积的ECM存在下增殖高达3倍，在上皮沉积的ECM存在下保持不变，并且在没有补充ECM的情况下其增殖率低于对照组。用糖胺聚糖降解酶肝素酶和肝素酶处理可消除这种作用，这表明硫酸肝素蛋白多糖（HSPG）特异性参与ar介导的细胞增殖。在全肺外植体中，抗AR硫酸肝素结合位点的抗体抑制了分支形态的形成，外源性AR刺激了分支形态的形成。由于在发育过程中，上皮细胞在生长芽的尖端和基底膜旁与间充质ECM接触，上皮细胞和间充质HSPG比例的局部变化将局部影响上皮细胞的增殖率。因此，AR-HSPG相互作用可能通过诱导分化细胞增殖而成为分支形态发生过程的基础。
Epithelial and mesenchymal cells isolated from mouse embryonic lungs synthesized and responded to amphiregulin (AR) in a different fashion. Mesenchymal cells produced and deposited 3- to 4-fold more AR than epithelial cells, proliferated in the presence of exogenous AR, and their spontaneous growth was blocked by up to 85% by anti-AR antibodies. In contrast, epithelial cells exhibited a broad response to this growth regulator factor depending on whether they were supplemented with extracellular matrix (ECM) and whether this ECM was of epithelial or mesenchymal origin. AR-treated epithelial cells proliferated by up to 3-fold in the presence of mesenchymal-deposited ECM, remained unchanged in the presence of epithelial-deposited ECM, and decreased in their proliferation rate below controls in the absence of ECM supplementation. This effect was abolished by treatment with the glycosaminoglycan-degrading enzymes heparinase and heparitinase suggesting the specific involvement of heparan sulfate proteoglycan (HSPG) in AR-mediated cell proliferation. In whole lung explants, branching morphogenesis was inhibited by antibodies against the AR heparan sulfate binding site and stimulated by exogenous AR. Since during development, epithelial cells are in contact with mesenchymal ECM at the tips of the growing buds and alongside the basement membrane, focal variations in the proportion of epithelial and mesenchymal HSPG will focally affect epithelial proliferation rates. Therefore, AR-HSPG interaction may underlie the process of branching morphogenesis by inducing differential cell proliferation.