Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, TexasA&M University Health Science Center, Houston, Texas, USA.
Stem Cells. 2013 Nov;31(11):2492-505. doi: 10.1002/stem.1484.
Mechanisms modulating prostate cell fate determination remain unexplored. The leucine-rich repeat containing G-protein-coupled receptors (Lgr) have been identified as important stem cell markers in various tissues. Here, we investigated the roles of Lgr4/Gpr48 in prostate stem cells (PSCs) and development. Lgr4 was ubiquitously expressed during early prostate development prior to lineage specification, with adult expression restricted to a few basal cells (principally Lin(-)Sca1(+)CD49f(+)). Lgr4(-/-) mice had compromised branching morphogenesis and delayed epithelial differentiation, leading to decreased prostate size and impaired luminal cell function. In vitro prostate sphere culture revealed that Lgr4(-/-) Lin(-)/Sca1(+)/CD49f(+) cells failed to generate p63(low) cells, indicating a differentiation deficiency. Furthermore, Lgr4 ablation arrested PSC differentiation of in vivo kidney capsule prostate grafts, suggesting that Lgr4 modulates PSC properties independent of hormonal and mesenchymal effects. Analysis of neonatal prostates and prostate spheres revealed a decrease in Wnt, Sonic Hedgehog, and Notch1 expression in Lgr4(-/-) cells. Lgr4 loss blocked differentiation of prostate sphere p63(hi) cells to p63(low). Treatment with exogenous Sonic Hedgehog partially restored the differentiation of p63(hi) cells in Lgr4(-/-) spheres. Taken together, our data revealed the roles of Lgr4 in early prostate development and in stem cell differentiation through regulation of the Wnt, Notch, and Sonic Hedgehog signaling pathways.
调控前列腺细胞命运决定的机制仍未被探索。富含亮氨酸重复序列的 G 蛋白偶联受体（Lgr）已被鉴定为多种组织中的重要干细胞标志物。在这里，我们研究了 Lgr4/Gpr48 在前列腺干细胞（PSCs）和发育中的作用。Lgr4 在早期前列腺发育过程中在谱系特化之前广泛表达，在成年后仅局限于少数基底细胞（主要是 Lin(-)Sca1(+)CD49f(+))表达。Lgr4(-/-) 小鼠的分支形态发生受损，上皮分化延迟，导致前列腺体积减小和管腔细胞功能受损。体外前列腺球体培养表明，Lgr4(-/-)Lin(-)/Sca1(+)/CD49f(+)细胞无法产生 p63(low)细胞，表明分化缺陷。此外，Lgr4 缺失阻断了体内肾包膜前列腺移植中 PSC 的分化，表明 Lgr4 调节 PSC 特性独立于激素和间质效应。对新生前列腺和前列腺球体的分析表明，Lgr4(-/-)细胞中 Wnt、Sonic Hedgehog 和 Notch1 的表达减少。Lgr4 的缺失阻断了前列腺球体 p63(hi)细胞向 p63(low)细胞的分化。外源性 Sonic Hedgehog 的处理部分恢复了 Lgr4(-/-)球体中 p63(hi)细胞的分化。总之，我们的数据揭示了 Lgr4 在早期前列腺发育和干细胞分化中的作用，通过调节 Wnt、Notch 和 Sonic Hedgehog 信号通路。
