Rescuing repair Schwann cells from senescence

Schwann cells ensheath the long extensions (axons) of peripheral nerve cells, also known as neurons, to protect them similar to a cable insulation. If axons are severed by a nerve injury, the regenerative functions of Schwann cells are of great importance to support the survival and regrowth of axons on their long way towards their target organ. However, Schwann cells cannot maintain this so-called repair mode forever; they age and lose their regeneration-promoting functions over time. The axons then stop growing and cannot reconnect with their target organ, for example a muscle or the skin. This leads to paralysis or numbness in the area that was supplied by the injured nerve. Hence, it is of upmost interest to identify therapeutic approaches that preserve the repair mode of Schwann cells and thus encourage axon regrowth and their reconnection with the target organ. Interestingly, Schwann cells are not only found in peripheral nerves, but also in benign forms of neuroblastic tumors. These tumors consist of neuronal tumor cells and Schwann cells that are not derived from tumor cells but have migrated into the tumor. In our previous study, we found that the tumor-associated Schwann cells show a similar repair mode as Schwann cells after a nerve injury. Hence, the tumor-associated Schwann cells may act on the neuronal tumor cells in similar way as on injured neurons and thus be responsible for the benign course of these tumors. Of note, these results also imply that the tumor cells are able to attract Schwann cells and to keep them in this repair mode over a long period of time. In this project, we want to investigate how the neuroblastic tumor cells induce and maintain the repair mode in Schwann cells to exploit this knowledge and develop novel therapies for injured nerves. For this purpose, we will isolate different tumor cell-derived signaling molecules (proteins, lipids or extracellular vesicles) to investigate their effect on cultured human Schwann cells. Signaling molecules that support the regenerative functions of Schwann cells - such as the formation of certain repair mode- associated proteins or their growth-promoting effect on axons - are selected to elucidate the underlying mechanism. How do these signaling molecules mediate their effect? How does the signal change the cellular status of Schwann cells? And which signaling molecules do Schwann cells produce in response? The answers to these questions contain valuable information that will serve as a basis for therapies and future translational research projects to improve treatment options for patients that suffer from peripheral nerve injuries.