Nerve regeneration - signal transduktion mechanisms, timing and alternatives to nerve grafts

One of our main topics in experimental animal research is investigation of biological mechanisms which regulate axonal outgrowth. During the last years we have draw our attention to the profound changes that occur in neurons and Schwann cells after nerve transection aiming at putting these cells into a regenerative state. Basic cellular mechanisms by which neuron changes its production machinery towards growth-related substances are not known, but vary signal transduction pathways regulated regrowth and apoptosis in addition, Schwann cells are extremely important for the nerve regeneration process and similar signal transduction pathways are constituted after nerve injury in such cells. We have analysed pathways and their temporal variations, particularly along which MAP kinases are working – JNK pathway – including some of the final steps like up-regulation of the transcription factor ATF3 and the immediate early gene c-jun. Other components of the signal transduction pathways are up-regulated extremely rapidly in Schwann cells after nerve injury like Erk1/2 which are up-regulated extremely rapidly after nerve injury in Schwann cells. More importantly, the up-regulation is crucial for the proliferation of Schwann cells after nerve injury and thus for nerve regeneration. In these studies concerning signal transduction mechanisms in neurons and Schwann cells we have very intense collaboration with Department of Biology.

The up-regulation of various transcription factors may be an important factor for the efficiency of axonal outgrowth. In a number of studies we have focused on these transcription factors in relation to the timing of nerve repair. There is an differential up-regulation of for example ATF3 after a nerve crush and nerve transection. A novel finding is that the up-regulation of ATF3 positively correlates to axonal outgrowth after nerve injury and repair, where the repair is done at different time points after the injury. These studies clearly indicate that timing of nerve repair are crucial and the up-regulation of the transcription factor ATF3 may be more important for motor neurons than sensory neurons. In these studies we had the privilege to work with several guest researchers from universities in Japan and China which has been guest researchers at our department.

Some of the signal transduction pathways decide if a cell will die or survive and regrowth after an injury. Thus, the mechanisms by which apoptosis are initiated is an important issue in nerve regeneration. In delayed nerve repair the number of apoptotic Schwann cells are increased with time and this affect the outgrowth of axons after a nerve injury as shown by increased number of caspase 3 stained Schwann cells. Together with the previously mentioned collaborators we also work to find out other pathways that initiate apoptosis in neurons and Schwann cells.

Finally, our experimental projects are also focused on development of alternatives to nerve grafts. We have previously developed a technique where it is possible to extract nerve iso- and allografts thereby creating acellular nerve grafts which can be used to bridge nerve gap. We have presently characterised these acellular nerve grafts and the mechanisms by which axons grow through such acellular grafts.