由免疫調節及血管新生所誘導之周邊神經修復

黃子婕

doi:10.6844/NCKU202001510

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由免疫調節及血管新生所誘導之周邊神經修復

Immunomodulation- and angiogenesis-led peripheral nerve regeneration

黃子婕 , Ph.D　　Advisor：吳佳慶　　

英文 DOI： 10.6844/NCKU202001510

周邊神經修復；凝血調節蛋白；巨噬細胞極化；內皮導向細胞；胞外體； Peripheral nerve regeneration ； Thrombomodulin ； macrophage polarization ； Endothelial lineage cell ； Exosome

Abstract │ Reference (102) │ Altmetrics

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Excessive inflammation within damaged tissue usually leads to delayed and insufficient regeneration. In peripheral nervous system, where fully recovery doesn’t occur frequently, modulating the inflammatory response to promote nerve regeneration has become more and more promising, however, there is a lack of practical therapeutic strategy for doing so. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. Amount all the domains, lectin-like domain of TM shows ability in suppressing inflammatory response. In the current study, we revealed the potential of TM in switching pro-inflammatory type1 macrophages (M1) to anti-inflammatory type2 macrophage (M2) by using THP1 cell. We also evaluated the therapeutic effect of TM-enhanced M2 transition on transected sciatic nerve. Our in vivo finding showed that TM treatment led to a better nerve regeneration and further preserved the effector muscle function. Furthermore, the supplementation of TM also exhibits a remark function in promoting axon elongation and remyelination through increasing the number of M2. Beside immunomodulation, we also found that enhancing angiogenesis and creating a pro-angiogenetic microenvironment is critical for nerve regeneration. In the current study, we also evaluated the potential of endothelial lineage cell (ELC) –derived exosome in enhancing nerve recovery. In comparison to adipose-derived stem cell (ASC), ELC exhibited higher expression of the angiogenetic microRNA (miR)-126. Correspondently, the miR-126 was also enriched in ELC-derived exosomes. We found the ELC conditional medium increased the number of outgrowing neurite in the DRG explants. Concurrently, ELC-exosome exhibited ability in promoting Schwann cell (SC) maturation. Taken together, the current study proved novel therapeutic strategies for peripheral nerve regeneration by immunomodulation and enhancing angiogenesis.

Reference ( 102 ) 〈TOP〉

1. Millesi H: Bridging defects: autologous nerve grafts. Acta Neurochir. Suppl. 100:37-38, 2007.
2. Mukhatyar V, Karumbaiah L, Yeh J, Bellamkonda R: Tissue engineering strategies designed to realize the endogenous regenerative potential of peripheral nerves. Adv. Mater. 21:4670-4679, 2009.
3. Gaudet AD, Popovich PG, Ramer MS: Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J. Neuroinflammation 8:110, 2011.
4. Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S, Lacroix S: Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J. Neurosci. 27:12565-12576, 2007.
5. Barrette B, Hebert MA, Filali M, Lafortune K, Vallieres N, Gowing G, Julien JP, Lacroix S: Requirement of myeloid cells for axon regeneration. J. Neurosci. 28:9363-9376, 2008.

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