再生微環境是周圍神經損傷後神經功能能否成功恢復的關鍵。神經損傷後，許旺細胞 (Schwann cells, SCs) 處於一去分化過程，以利支持神經修復過程中各個階段的發展。這種轉變是透過 SCs 中，組蛋白脫乙醯酶 (histone deacetylases, HDAC) 的表觀遺傳調控促進的。活化的 SCs 藉由在損傷部位釋放炎性細胞因子和生長因子，來塑造一個，以利遠端軸突退化以及近端軸突形成一朝向去神經支配目標器官之生長錐的微環境。而由 SCs 介導的炎症時間或時序的變化，皆會影響修復和再生相關的後期過程。因此，在我們的研究中，我們研究了 SCs 中，是何種HDAC 控制炎症細胞因子，進而為周圍神經再生提供有利微環境的調節過程。我們在體外 RT4 SC 炎症模型和體內坐骨神經橫斷損傷模型中，使用 HDAC 抑制劑，苯丁酸鈉 (sodium phenylbutyrate, PBA)，來探究 HDAC 抑制對炎症擴展與神經再生潛力的影響。我們發現，使用 PBA 治療得縮短炎症時程，並有利於神經橫斷損傷後，軸突與髓鞘再生。於體外模式中，PBA 亦透過抑制 SCs 中 NFκB-p65 和 HDAC3 的轉錄激活來調節促炎細胞因子的表達。此外，由於內源性生長因子的濃度不足以為神經再生提供營養支持，因此我們在坐骨神經損傷部位加入了自體血小板濃縮生長因子（autologous platelet rich growth factors, PRGF），來提升神經再生過程的速度。PRGF的應用在體內促進血管生成、軸突再生、髓鞘再生和神經再支配以及控制體外炎性細胞因子的表現量方面皆顯示出益處。總結，免疫反應和生長因子水平的優化為受傷後的周圍神經再生提供了一種優越的治療方法。

A regenerative niche is the key to successful functional recovery after a peripheral nerve injury. Schwann cells (SCs) undergo a dedifferentiation process necessary to support various stages of nerve repair after a nerve injury. This transition is facilitated through epigenetic regulation by histone deacetylases (HDACs) in SCs. The activated SCs release inflammatory cytokines as well as growth factors at the injury site to create a permissive microenvironment for the distal axons to degenerate and proximal axons to form a growth cone towards the denervated target organ. However, changes in either the timing or duration of inflammation mediated by SCs can affect later processes associated with repair and regeneration. Therefore, in our study we have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. We employed the HDAC inhibitor sodium phenylbutyrate (PBA) in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the suppression of extended inflammation and its effect on the regenerative potential of nerves. Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro. Additionally, as the concentration of endogenous growth factors are not enough to provide the trophic support for nerve regeneration hence, we incorporated the autologous platelet rich growth factors (PRGF) at the injury site in sciatic nerve to enhance the speed of nerve regeneration processes. PRGF application has shown beneficial roles in promoting angiogenesis, axonal regeneration, remyelination, and reinnervation in vivo and controlling the levels of inflammatory cytokines in vitro. Taken together, optimization of the immune response and levels of growth factors provides a superior therapy for peripheral nerve regeneration post-injury.

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