Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Development. 2010 Jul;137(13):2205-14. doi: 10.1242/dev.048926.
HB-EGF, a member of the EGF family of growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. Here, we show that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function in this process. In developing valves, HB-EGF is synthesized in endocardial cells but accumulates in the mesenchyme by interacting with HSPGs. Disrupting the interaction between HB-EGF and HSPGs in an ex vivo model of endocardial cushion explants resulted in increased mesenchymal cell proliferation. Moreover, homozygous knock-in mice (HB(Delta)(hb/)(Delta)(hb)) expressing a mutant HB-EGF that cannot bind to HSPGs developed enlarged cardiac valves with hyperproliferation of mesenchymal cells; this resulted in a phenotype that resembled that of Hbegf-null mice. Interestingly, although Hbegf-null mice had abnormal heart chambers and lung alveoli, HB(Delta)(hb/)(Delta)(hb) mice did not exhibit these defects. These results indicate that interactions with HSPGs are essential for the function of HB-EGF, especially in cardiac valve development, in which HB-EGF suppresses mesenchymal cell proliferation.
HB-EGF 是 EGF 家族生长因子的成员，通过抑制间质细胞增殖在心脏瓣膜发育中发挥重要作用。在这里，我们表明 HB-EGF 必须与硫酸乙酰肝素蛋白聚糖（HSPGs）相互作用才能在这个过程中正常发挥作用。在发育中的瓣膜中，HB-EGF 在内皮细胞中合成，但通过与 HSPGs 相互作用在间质中积累。在心脏心垫外植体的体外模型中破坏 HB-EGF 和 HSPGs 之间的相互作用，导致间质细胞增殖增加。此外，表达不能与 HSPGs 结合的突变 HB-EGF 的纯合敲入小鼠（HB(Delta)(hb/)(Delta)(hb)）表现出心脏瓣膜增大和间质细胞过度增殖；这导致了一种类似于 Hbegf 缺失小鼠的表型。有趣的是，尽管 Hbegf 缺失小鼠有异常的心脏腔室和肺肺泡，但 HB(Delta)(hb/)(Delta)(hb) 小鼠没有表现出这些缺陷。这些结果表明与 HSPGs 的相互作用对于 HB-EGF 的功能至关重要，特别是在心脏瓣膜发育中，HB-EGF 抑制间质细胞增殖。
