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

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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.