Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 Synergistically Regenerate Transected Rat Peripheral Nerves by Altering Macrophage Polarity
Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 Synergistically Regenerate Transected Rat Peripheral Nerves by Altering Macrophage Polarity
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DOI：
10.1002/stem.2534
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发表时间：
2017-03-01
期刊：
影响因子：
5.2
通讯作者：
Yamamoto, Akihito
中科院分区：
文献类型：
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作者：
Kano, Fumiya;Matsubara, Kohki;Yamamoto, Akihito
周围神经在单纯挤压伤或切割伤后表现出明显的自我修复能力。然而，涉及神经间隙的神经元横断阻碍了它们的修复活性并导致持续性瘫痪。在这里，我们表明，植入无血清条件培养基从干细胞从人类脱落的乳牙（SHED-CM）浸泡在胶原海绵到神经间隙形成的大鼠面神经横断恢复神经功能。相比之下，特异性耗尽一组抗炎M2巨噬细胞诱导剂、单核细胞趋化蛋白-1（MCP-1）和唾液酸结合Ig样凝集素-9（sSiglec-9）的分泌胞外域的SHED-CM在该模型中失去恢复神经功能的能力。值得注意的是，MCP-1和sSiglec-9的组合在体外诱导了M2巨噬细胞的极化，导致多种营养因子的表达，这些营养因子增强了许旺细胞的增殖、迁移和分化、血管形成和神经纤维延伸。此外，将含有MCP-1/sSiglec-9的胶原移植物植入神经间隙中诱导抗炎性M2巨噬细胞极化，产生施万细胞桥而不是纤维化瘢痕，诱导轴突再生，并恢复神经功能。甘露糖基化的Clodrosome对M2巨噬细胞的特异性消除抑制了MCP-1/sSiglec-9介导的神经恢复。总之，我们的数据表明MCP-1/sSiglec-9通过诱导组织修复M2巨噬细胞再生PN，并可能为严重的周围神经损伤提供治疗益处。
Peripheral nerves (PNs) exhibit remarkable self-repairing reparative activity after a simple crush or cut injury. However, the neuronal transection involving a nerve gap overwhelms their repairing activity and causes persistent paralysis. Here, we show that an implantation of the serum-free conditioned medium from stem cells from human exfoliated deciduous teeth (SHED-CM) immersed in a collagen sponge into the nerve gap formed by rat facial nerves transection restored the neurological function. In contrast, SHED-CM specifically depleted of a set of anti-inflammatory M2 macrophage inducers, monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9) lost the ability to restore neurological function in this model. Notably, the combination of MCP-1 and sSiglec-9 induced the polarization of M2 macrophages in vitro, resulting in the expression of multiple trophic factors that enhanced proliferation, migration, and differentiation of Schwann cells, blood vessel formation, and nerve fiber extension. Furthermore, the implantation of a collagen graft containing MCP-1/sSiglec-9 into the nerve gap induced anti-inflammatory M2 macrophage polarization, generated a Schwann-cell bridge instead of fibrotic scar, induced axonal regrowth, and restored nerve function. The specific elimination of M2 macrophages by Mannosylated-Clodrosome suppressed the MCP-1/sSiglec-9-mediated neurological recovery. Taken together, our data suggest that MCP-1/sSiglec-9 regenerates PNs by inducing tissue-repairing M2 macrophages and may provide therapeutic benefits for severe peripheral nerve injuries.