Hoeber Jan, König Niclas, Trolle Carl, Lekholm Emilia, Zhou Chunfang, Pankratova Stanislava, Åkesson Elisabet, Fredriksson Robert, Aldskogius Håkan, Kozlova Elena N
1 Department of Neuroscience, Uppsala University , Uppsala, Sweden .
2 Department of Pharmaceutical Biosciences, Uppsala University , Uppsala, Sweden .
Stem Cells Dev. 2017 Jul 15;26(14):1065-1077. doi: 10.1089/scd.2017.0019. Epub 2017 May 31.
Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.
脊髓神经根损伤会导致新形成的胶质瘢痕形成，这会阻止感觉轴突再生，从而导致永久性感觉丧失。先前的研究表明，给予神经营养因子或植入人类神经祖细胞可支持感觉轴突再生并部分恢复感觉功能。在本研究中，我们阐明了背根撕脱（DRA）后干细胞介导的感觉轴突向内生长的机制。我们发现，人类脊髓神经干细胞/祖细胞（hscNSPC）以及负载生长因子模拟物的介孔二氧化硅颗粒（MesoMIM）均支持感觉轴突再生。然而，当hscNSPC和MesoMIM联合使用时，感觉轴突再生失败。形态学和追踪分析表明，感觉轴突沿着迁移的干细胞形成的“桥”穿过新形成的胶质瘢痕生长。MesoMIM的共植入阻止了干细胞迁移，“桥”未形成，感觉轴突无法进入脊髓。单独应用MesoMIM可支持感觉轴突向内生长，但不影响胶质瘢痕形成。在体外，MesoMIM的存在显著损害了hscNSPC的迁移，但不影响其分化水平。我们的数据表明：（1）干细胞迁移到脊髓并在新形成的界面中组织细胞“桥”的能力对于成功的感觉轴突再生至关重要；（2）介孔二氧化硅递送的神经营养因子模拟物可能是诱导感觉轴突再生的一种便捷替代方法；（3）单独有益成分的组合方法不一定具有累加性，反而可能对轴突生长产生反作用。
