Department of Molecular and Cell Biology, International Center for Research and Education, Antonio Prudente Foundation, A. C. Camargo Hospital and National Institute for Translational Neuroscience (CNPq/MCT), São Paulo, Brazil.
Stem Cells. 2011 Jul;29(7):1126-36. doi: 10.1002/stem.664.
Prion protein (PrP(C) ), when associated with the secreted form of the stress-inducible protein 1 (STI1), plays an important role in neural survival, neuritogenesis, and memory formation. However, the role of the PrP(C) -STI1 complex in the physiology of neural progenitor/stem cells is unknown. In this article, we observed that neurospheres cultured from fetal forebrain of wild-type (Prnp(+/+) ) and PrP(C) -null (Prnp(0/0) ) mice were maintained for several passages without the loss of self-renewal or multipotentiality, as assessed by their continued capacity to generate neurons, astrocytes, and oligodendrocytes. The homogeneous expression and colocalization of STI1 and PrP(C) suggest that they may associate and function as a complex in neurosphere-derived stem cells. The formation of neurospheres from Prnp(0/0) mice was reduced significantly when compared with their wild-type counterparts. In addition, blockade of secreted STI1, and its cell surface ligand, PrP(C) , with specific antibodies, impaired Prnp(+/+) neurosphere formation without further impairing the formation of Prnp(0/0) neurospheres. Alternatively, neurosphere formation was enhanced by recombinant STI1 application in cells expressing PrP(C) but not in cells from Prnp(0/0) mice. The STI1-PrP(C) interaction was able to stimulate cell proliferation in the neurosphere-forming assay, while no effect on cell survival or the expression of neural markers was observed. These data suggest that the STI1-PrP(C) complex may play a critical role in neural progenitor/stem cells self-renewal via the modulation of cell proliferation, leading to the control of the stemness capacity of these cells during nervous system development.
朊病毒蛋白 (PrP(C) ) 与应激诱导蛋白 1 的分泌形式 (STI1) 结合后，在神经存活、神经突生成和记忆形成中发挥着重要作用。然而，PrP(C)-STI1 复合物在神经祖细胞/干细胞生理学中的作用尚不清楚。在本文中，我们观察到，从野生型 (Prnp(+/+) ) 和 PrP(C) 缺失型 (Prnp(0/0) ) 胎鼠前脑中培养的神经球在经过几轮培养后仍能保持自我更新和多能性，其持续生成神经元、星形胶质细胞和少突胶质细胞的能力并未丧失。STI1 和 PrP(C) 的均匀表达和共定位表明，它们可能在神经球衍生的干细胞中结合并发挥作用。与野生型相比，Prnp(0/0) 小鼠形成的神经球明显减少。此外，用特异性抗体阻断 STI1 的分泌及其细胞表面配体 PrP(C) ，会损害 Prnp(+/+) 神经球的形成，而不会进一步损害 Prnp(0/0) 神经球的形成。相反，重组 STI1 的应用增强了表达 PrP(C) 的细胞中的神经球形成，但在 Prnp(0/0) 小鼠的细胞中则没有。STI1-PrP(C) 相互作用能够刺激神经球形成测定中的细胞增殖，而对细胞存活或神经标志物的表达没有影响。这些数据表明，STI1-PrP(C) 复合物可能通过调节细胞增殖在神经祖细胞/干细胞自我更新中发挥关键作用，从而控制这些细胞在神经系统发育过程中的干性能力。
