Institut de Biologie de Développement de Marseille-Luminy, CNRS UMR 7288, Case 907, Parc Scientifique de Luminy, Aix-Marseille Université, Marseille Cedex 09, France.
Stem Cells. 2012 Sep;30(9):1863-74. doi: 10.1002/stem.1165.
Self-renewal and differentiation of stem cell depend on a dynamic interplay of cell-extrinsic and -intrinsic regulators. However, how stem cells perceive the right amount of signal and at the right time to undergo a precise developmental program remains poorly understood. The cell surface proteins Glypicans act as gatekeepers of environmental signals to modulate their perception by target cells. Here, we show that one of these, Glypican4 (Gpc4), is specifically required to maintain the self-renewal potential of mouse embryonic stem cells (ESCs) and to fine tune cell lineage commitment. Notably, Gpc4-mutant ESCs contribute to all embryonic cell lineages when injected in blastocyts but lose their intrinsic tumorigenic properties after implantation into nude mice. Therefore, our molecular and functional studies reveal that Gpc4 maintains distinct stemness features. Moreover, we provide evidence that self-renewal and lineage commitment of different stem cell types is fine tuned by Gpc4 activity by showing that Gpc4 is required for the maintenance of adult neural stem cell fate in vivo. Mechanistically, Gpc4 regulates self-renewal of ESCs by modulating Wnt/β-catenin signaling activities. Thus, our findings establish that Gpc4 acts at the interface of extrinsic and intrinsic signal regulation to fine tune stem cell fate. Moreover, the ability to uncouple pluripotent stem cell differentiation from tumorigenic potential makes Gpc4 as a promising target for cell-based regenerative therapies.
干细胞的自我更新和分化依赖于细胞外和细胞内调节因子的动态相互作用。然而，干细胞如何感知适量的信号并在适当的时间经历精确的发育程序仍知之甚少。细胞表面蛋白聚糖作为环境信号的守门员，调节靶细胞对其的感知。在这里，我们表明，这些蛋白聚糖中的一种，Glypican4（Gpc4），特异性地维持了小鼠胚胎干细胞（ESCs）的自我更新潜能，并精细地调节细胞谱系的决定。值得注意的是，当注射到囊胚中时，Gpc4 突变的 ESCs 有助于所有胚胎细胞谱系，但在植入裸鼠后失去其内在的致瘤特性。因此，我们的分子和功能研究表明，Gpc4 维持着独特的干性特征。此外，我们提供的证据表明，不同干细胞类型的自我更新和谱系决定是通过 Gpc4 活性精细调节的，表明 Gpc4 是维持体内成年神经干细胞命运所必需的。从机制上讲，Gpc4 通过调节 Wnt/β-catenin 信号活性来调节 ESCs 的自我更新。因此，我们的发现表明，Gpc4 在细胞外和细胞内信号调节的界面上发挥作用，以精细调节干细胞命运。此外，将多能干细胞分化与致瘤潜能分离的能力使 Gpc4 成为细胞再生治疗的有前途的靶点。
