Tissue-Specific Progenitor and Stem Cells Neural Progenitor-Like Cells Induced From Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration-猫眼课题宝

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2016

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Qunzhou Zhang;P. Nguyen;XU Qilin;W. Park;Sumin Lee;A. Furuhashi;Anh;-D.;LEa

周围神经损伤的再生仍然是一个主要的临床挑战。近年来，间充质干细胞（MSCs）被认为是周围神经再生的潜在候选者，然而，其潜在的机制仍然是难以捉摸的。在这里，我们表明，人牙龈来源的骨髓间充质干细胞（GMSC）可以直接诱导成多能NPC（iNPC）在最低限度的操作条件下，不引入外源基因。使用大鼠坐骨神经挤压损伤模型，我们证明移植到损伤部位的GMSCs可以分化为神经元细胞，而iNPC可以分化为神经元和雪旺细胞。挤压损伤后，iNPCs，与GMSCs相比，显示出上级的治疗效果，轴突再生在损伤部位和损伤的坐骨神经的远端段。从机制上讲，移植GMSC，特别是iNPC，显著减弱了损伤触发的c-Jun表达的增加，c-Jun是一种转录因子，其作为髓鞘形成的主要负调节因子发挥作用，并在雪旺细胞的去分化/重编程为祖细胞样状态中发挥核心作用。同时，我们的研究结果还表明，移植GMSC和iNPC一致地增加了Krox-20/EGR 2的表达，Krox-20/EGR 2是一种调控髓鞘蛋白表达并促进髓鞘形成的转录因子。总之，我们的研究结果表明，移植GMSC和iNPC促进周围神经修复/再生，可能是通过促进由拮抗性髓鞘形成调节剂c-Jun和Krox-20/EGR 2的调节介导的许旺细胞的髓鞘再生。干细胞转化医学2016;5：1-13

Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva-derived MSCs (GMSCs) could be directly induced intomultipotent NPCs (iNPCs) underminimally manipulated conditions without the introduction of exogenous genes. Using a crush-injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells. After crush injury, iNPCs, compared with GMSCs, displayed superior therapeutic effects on axonal regeneration at both the injury site and the distal segment of the injured sciatic nerve. Mechanistically, transplantation of GMSCs, especially iNPCs, significantly attenuated injury-triggered increase in the expression of c-Jun, a transcription factor that functions as a major negative regulator of myelination and plays a central role in dedifferentiation/reprogramming of Schwann cells into a progenitor-like state. Meanwhile, our results also demonstrate that transplantation of GMSCs and iNPCs consistently increased the expression of Krox-20/EGR2, a transcription factor that governs the expression of myelin proteins and facilitatesmyelination. Altogether, our findings suggest that transplantation ofGMSCs and iNPCs promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c-Jun and Krox-20/EGR2. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1–13

Tissue-Specific Progenitor and Stem Cells Neural Progenitor-Like Cells Induced From Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration

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