By training as a veterinarian, veterinary pathologist, comparative neuropathologist and neuroscientist, I conduct studies examining cellular events taking place in the functional regeneration ofthe adult central nervous system (CNS). In my research, I use unique rat models devoid of myelin, an insulator along the nerve processes (axons) which is necessary for proper function in axons. Loss of myelin, particularly well known in Multiple Sclerosis, brain and spinal cord injury, results in permanent and devastating neurologic deficits in human patients. My studies involve the examination of rodent and human cells' ability to form and maintain myelin in the brain and spinal cord of adult dysmyelinated (myelin lacking) rats.
Once axons are severed (as in a spinal cord injury), their re-growth is inhibited in a normal CNS. Currently, there are no treatments for acute or chronic spinal cord injury. This unsatisfactory status persists despite considerable efforts being devoted to understanding the cellular and molecular mechanisms involved in the inhibition of axonal regeneration. Progress in this field has been hampered by the lack of animal models where regeneration of CNS nerve processes can be observed and studied.
Normal animals have myelin sheaths around axons in the CNS and this causes two fundamental problems with using normally myelinated CNS to study its regeneration in vivo: FIRSTLY – damaged myelin initiates a very severe phagocyte-rich inflammatory response resulting in more myelin damage which stimulates more phagocytosis, myelin damage; a vicious cycle that within a few months causes the destruction of a large area of the CNS surrounding the initial injury. Importantly, any materials or cells implanted into an acute CNS lesion resulting from myelin damage will be intensely affected by the severe phagocytic response against damaged myelin and will likely be destroyed. SECONDLY – myelin potently inhibits regeneration of transacted axons.
We demonstrated that adult CNS axons regenerate at a rate of >2mm a day in a crush model of filum terminale on both dysmyelinated, Long Evans Shaker (LES) and in normally myelinated control rats (Kwiecien & Avram, J Neurotrauma, 2008). The unprecedented regeneration of CNS axons was regulated by ependymal cells of the central canal in the filum terminale. We took this knowledge to demonstrate and study axonal regeneration in the dorsal column crush model in the mid-thoracic spinal cord of adult LES rats. Although the lack of myelin allows for axonal regeneration in the injured spinal cord of LES rats, they do not cross the site of the lesion that fills with fluid after the injury. Presumably, to regenerate across the site of injury, they need a solid substrate. We implanted the site of the crush with rat neural cells and observed robust and long distance axonal regeneration in ascending pathways. Adult LES rats have been used to demonstrate the formation of new CNS tissue in an acute spinal cord lesion implanted with neural cells. New tissue forming at the interface of the lesion cavity and the surviving CNS tissue was complete with numerous axons, glial cells and Schwann cells. Robust and long distance axonal regeneration in implanted spinal cord is currently being studied in adult LES rats.
Cells may not be ideal to serve as a bridge in the spinal cord injury. Although rat neural cells appear to work very well to conduct axonal regeneration across the lesion, procuring, culturing and testing cells for medical purposes requires (from FDA and EU regulations) that each batch of cells is tested for safety and efficacy and the process of their production be validated. The requirements are onerous and the process of testing and validation long and very expensive and unlikely to remove risks of infectious or malignant nature. To address this conundrum, we have used the spinal crush model for testing of synthetic materials designed for implantation into the CNS.