Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells.
Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells.
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DOI：
10.1097/nen.0b013e3181d68d12
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发表时间：
2010-04
影响因子：
3.2
通讯作者：
Shubayev VI
中科院分区：
文献类型：
--
作者：
Liu H;Kim Y;Chattopadhyay S;Shubayev I;Dolkas J;Shubayev VI
周围神经损伤后，雪旺细胞(SCs)旺盛分裂以存活，并产生足够数量的细胞伴随再生轴突。基质金属蛋白酶(MMPs)是干细胞信号转导和有丝分裂的调节因子。利用5-溴-2-脱氧尿苷(BrdU)掺入试验，我们先前发现广谱基质金属蛋白酶抑制剂(MMPI)GM6001(或Ilomastat)可促进原代培养的SCs分裂。在这里，我们测试了一种假设，即MMPI刺激SC有丝分裂的能力可能促进体内神经再生。通过神经挤压实验和生长相关蛋白-43(GAP-43)的表达，GM6001在大鼠坐骨神经挤压后即刻和此后每天给予GM6001可增加神经再生。MMPI促进了神经内BrdU的掺入，相对于车辆控制。分裂细胞主要为干细胞，与GAP-43阳性再生轴突有关。基质金属蛋白酶抑制后，髓鞘碱性蛋白mRNA表达(Taqman RT-qPCR检测)和髓鞘形成干细胞的活跃有丝分裂减少，表明MMPs抑制了有丝分裂前的去分化。MMPI可逆转Sc有丝分裂抑制因子丝裂霉素抑制神经再生的作用，提示其促进轴突生长的作用依赖于其在SCs中的促有丝分裂作用。这些研究确定了MMPs通过控制SC有丝分裂、分化和髓鞘蛋白mRNA的表达在周围神经修复中的新作用。
Following peripheral nerve injury, Schwann cells (SCs) vigorously divide to survive and produce a sufficient number of cells to accompany regenerating axons. Matrix metalloproteinases (MMPs) have emerged as modulators of SC signaling and mitosis. Using a 5-bromo-2-deoxyuridine (BrdU) incorporation assay, we previously found that a broad-spectrum MMP inhibitor (MMPi), GM6001 (or Ilomastat), enhanced division of cultured primary SCs. Here, we tested the hypothesis that the ability of MMPi to stimulate SC mitosis may advance nerve regeneration in vivo. GM6001 administration immediately after rat sciatic nerve crush and daily thereafter produced increased nerve regeneration as determined by nerve pinch test and growth-associated protein-43 (GAP-43) expression. MMPi promoted endoneurial BrdU incorporation relative to vehicle control. The dividing cells were mainly SCs and were associated with GAP-43-positive regenerating axons. After MMP inhibition, myelin basic protein mRNA expression (determined by Taqman RT-qPCR) and active mitosis of myelin-forming SCs were reduced, indicating that MMPs suppressed their de-differentiation preceding mitosis. Intra-sciatic injection of the inhibitor of SC mitosis mitomycin suppressed nerve regrowth is reversed by MMPi, suggesting that its effect on axonal growth promotion depends on its pro-mitogenic action in SCs. These studies establish novel roles for MMPs in peripheral nerve repair via control of SC mitosis, differentiation and myelin protein mRNA expression.