Leveraging epigenetics to improve peripheral nerve regeneration

Unlike the brain and spinal cord, the peripheral nervous system (PNS) harbors an immense capacity for plasticity after nerve injury. Peripheral nerves must travel precariously towards their target tissues without the skeletal protection and are thus easily damaged during physical trauma. Peripheral nerve injury triggers a massive wave of transdifferentiation and phenotypic plasticity to facilitate axonal regrowth. In both the neurons themselves and their critical glial cell support network, these cellular transitions rely on epigenetic regulatory processes that reorganize local genomic structure to enable activation of these regenerative gene programs, but understanding of this highly cell-specialized process has been limited by the lack of any available study with single cell resolution. Although peripheral nerve fibers show considerable potential for self-regeneration, nerve injury in human patients most often results in weak motor activity, sensory dysfunction, and persistent pain, with no available therapies that promote complete functional recovery. Better understanding of the how diverse cell-types mount this regeneration response, and the molecular mechanisms that drive the highly specialized role each cell has in this process might help harness its vast potential to promote long-lasting functional recovery after injury.

Peripheral nerve repair represents one of the greatest challenges in tissue bioengineering and regenerative medicine. Microsurgery remains the primary treatment for peripheral nerve injury, but outcomes remain poor, and there are no effective regenerative therapies that ensure complete functional recovery. Restoration of injured nerves requires a complex orchestra of cellular and molecular responses within both the lesioned neuron and the surrounding non-neuronal support network to rebuild functional axons and properly connect them with their targets. Recent work has shown that epigenetic mechanisms are responsible for shaping both pro neuro-regenerative and neuro-inflammatory pathways, either promoting or hindering regeneration depending on the nature of the injury and the cell types affected. My research will provide the field with single-cell resolution molecular profiles of this process to investigate how genetically-defined somatosensory neurons might harbor differences in intrinsic regeneration ability, and to identify emergent glial phenotypes relevant to the repair process. I will also use this data to create viral vector tools that target specific PNS cell-types. While this approach has just started to be used for cell-type-specific or even activity-dependent manipulation in the brain, we currently lack tools capable of doing this in the periphery. Furthermore, there are no available approaches to access cell populations that are epigenetically modified during biological state changes. Viral genetic tools that target specific PNS cell-types and cell states could transform basic neuroscience and targeted gene therapy. Finally, I will deploy these new tools to track, image, and manipulate PNS cells during axon repair to define their contributions to nerve regeneration outcomes and determine potential cell-types or molecular pathways that might improve functional recovery. Together, this study will initiate a new branch of inquiry focusing on cell-type specific epigenetic mechanisms of cellular plasticity in PNS regeneration, and potentially illuminate the barriers that restrict regenerative activity in the CNS.