Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Departments of Psychiatry and Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Sci Transl Med. 2018 May 23;10(442). doi: 10.1126/scitranslmed.aal2563.
Axon regeneration after spinal cord injury (SCI) is attenuated by growth inhibitory molecules associated with myelin. We report that rat myelin stimulated the growth of axons emerging from rat neural progenitor cells (NPCs) transplanted into sites of SCI in adult rat recipients. When plated on a myelin substrate, neurite outgrowth from rat NPCs and from human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) was enhanced threefold. In vivo, rat NPCs and human iPSC-derived NSCs extended greater numbers of axons through adult central nervous system white matter than through gray matter and preferentially associated with rat host myelin. Mechanistic investigations excluded Nogo receptor signaling as a mediator of stem cell-derived axon growth in response to myelin. Transcriptomic screens of rodent NPCs identified the cell adhesion molecule neuronal growth regulator 1 (Negr1) as one mediator of permissive axon-myelin interactions. The stimulatory effect of myelin-associated proteins on rodent NPCs was developmentally regulated and involved direct activation of the extracellular signal-regulated kinase (ERK). The stimulatory effects of myelin on NPC/NSC axon outgrowth should be investigated further and could potentially be exploited for neural repair after SCI.
脊髓损伤 (SCI) 后轴突再生受到与髓鞘相关的生长抑制分子的抑制。我们报告说，大鼠髓鞘刺激了移植到成年大鼠 SCI 部位的大鼠神经祖细胞 (NPC) 中出现的轴突的生长。当在髓鞘底物上培养时，大鼠 NPC 和人诱导多能干细胞 (iPSC) 衍生的神经干细胞 (NSC) 的突起生长增加了三倍。在体内，大鼠 NPC 和人 iPSC 衍生的 NSC 通过成年中枢神经系统白质延伸的轴突数量多于通过灰质延伸的轴突数量，并且优先与大鼠宿主髓鞘相关。机制研究排除了 Nogo 受体信号作为髓鞘对干细胞衍生轴突生长反应的介导物。对啮齿动物 NPC 的转录组筛选鉴定出细胞粘附分子神经元生长调节剂 1 (Negr1) 作为允许轴突-髓鞘相互作用的一种介导物。髓鞘相关蛋白对啮齿动物 NPC 的刺激作用受发育调控，涉及细胞外信号调节激酶 (ERK) 的直接激活。髓鞘对 NPC/NSC 轴突生长的刺激作用应进一步研究，并可能在 SCI 后神经修复中得到利用。
