Investigation of lipid metabolism in peripheral nerve regeneration in human vs. mouse nerves

雪旺细胞（SCs）是周围神经系统的髓鞘细胞。损伤后，远端损伤部位的SC去分化，脱落髓磷脂，获得一种新的表型，称为修复SC。修复SC的基因表达谱发生巨大变化，改变形态，进入增殖状态，产生信号分子和炎症因子，促进轴突生长，确保神经再生。从髓鞘形成到修复SC的转变被称为SC重编程。涉及SC重编程的过程主要在啮齿动物中进行了研究。在人类中，对SC对损伤的反应知之甚少，但神经再生的效率远低于啮齿动物。因此，研究人类SCs的损伤反应可能有助于理解小鼠和人类之间不同的再生能力。在我的工作中，我使用人类神经外植体建立了一种新的离体损伤模型，该模型允许在与体内情况非常相似的环境中比较人类和小鼠sc的损伤反应。其目的是找出差异，这可以解释人类神经有限的再生潜力。有趣的是，我发现损伤后小鼠SCs中脂质代谢的主要调节因子PPARg和几个脂质生成基因的表达发生了急剧改变，而人类SCs在这方面几乎没有任何反应。脂质合成先前已被证明对小鼠的髓鞘形成至关重要，因为髓鞘膜含有大量的脂质。考虑到修复SCs必须停止髓磷脂的产生，它们通过下调脂质生成基因来适应脂质代谢是一致的。有趣的是，损伤神经中PPARg活性的药理调节不仅改变了脂肪生成基因的表达，还影响了SC重编程。因此，我假设脂质代谢的适应是周围神经损伤过程中诱导SC重编程的必要过程，并可能解释小鼠和人类之间的差异。为了验证这一假设，我将在小鼠坐骨神经损伤模型中分析PPARg对SC重编程和随后的再分化的影响，方法如下：I)吡格列酮治疗的药理学方法，ii) SC中PPARg缺失的遗传学方法。我认为抑制脂肪生成基因会加速SC重编程并影响髓鞘再生。相反，激活脂质代谢很可能会产生相反的效果。进一步，我将研究损伤后神经和神经瘤组织中人类SCs的形态学变化，以及通过药物治疗来调节脂质代谢。该项目可以确定脂质代谢作为促进人类神经再生的可能治疗靶点。

Schwann cells (SCs) are myelinating cells of the peripheral nervous system. After injury, SCs distal to the injury site dedifferentiate, shed their myelin and obtain a new phenotype described as repair SC. Repair SCs undergo a massive change in their gene expression profile, alter their morphology, enter a proliferative state and produce signalling molecules and inflammatory factors, which promote axonal outgrowth ensuring a proper nerve regeneration. The transition from a myelinating to a repair SC is termed SC reprogramming. Processes involved in SC reprogramming have been mainly studied in rodents. In humans, only little is known about SC reaction to injury, yet nerve regeneration is far less efficient than in rodents. Therefore, investigation of the injury response in human SCs could prove useful in understanding the different regeneration capacities between mice and humans.In my work, I established a novel ex vivo injury model using human nerve explants, which allows for the comparison of injury response in human and murine SCs in an environment closely resembling the in vivo situation. The aim was to identify differences, which could explain the limited regeneration potential of human nerves. Intriguingly, I identified the expression of the major regulator of lipid metabolism PPARg and several lipogenic genes to be drastically altered in murine SCs after injury, while human SCs showed hardly any response in this regard. Lipid synthesis has been previously shown to be crucial for myelination in mice, since myelin membranes contain large amounts of lipids. Considering that repair SCs have to stop myelin production, it is consistent that they adapt lipid metabolism by downregulating lipogenic genes. Interestingly, pharmacological modulation of PPARg activity in injured nerves not only altered the expression of lipogenic genes, but also influenced SC reprogramming. Hence, I hypothesize that adaptation of lipid metabolism is an essential process for the induction of SC reprogramming during peripheral nerve injury and could account for differences between mice and humans.To test this hypothesis, I will analyze the influence of PPARg on SC reprogramming and subsequent redifferentiation in a mouse model of sciatic nerve injury in vivo in the following approaches: i) a pharmacological approach with pioglitazone treatment, ii) a genetic approach with PPARg depletion in SCs. I expect that inhibition of lipogenic genes accelerates SC reprogramming and affects remyelination. In contrast, activation of lipid metabolism will most probably have the opposite effects. Further, I will study morphological changes of human SCs in nerves and neuroma tissue after injury and after pharmacological treatment to modulate lipid metabolism. This project could identify lipid metabolism as a possible therapeutic target for promoting nerve regeneration in humans.