Jacek M. Kwiecien, McMaster University
Assistant Professor
Pathology & Molecular Medicine
Hamilton, Ontario
kwiecien@mcmaster.ca
Office:
(905) 525-9140 ext. 22872
Expert In
Bio/Research
By training a veterinarian, veterinary pathologist, comparative neuropathologist and neuroscientist, I conduct studies examining cellular events taking place in the functional regeneration in the adult central nervous system (CNS). For my research I use unique rat models devoid of myelin, an insu...
Click to Expand >>
Click to Expand >>
Bio/Research
By training a veterinarian, veterinary pathologist, comparative neuropathologist and neuroscientist, I conduct studies examining cellular events taking place in the functional regeneration in the adult central nervous system (CNS). For 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 the spinal cord injury, their re-growth is inhibited in a normal CNS such as in a typical unfortunate human patient. Currently, there are no treatments of acute or chronic spinal cord injury. This unsatisfactory status persists despite the fact that considerable efforts have been devoted to understanding of cellular and molecular mechanisms involved in inhibition of axonal regeneration. Progress in this field has been hampered by 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 myelin constitutes formidable inhibition for axons attempting to regenerate. Dysmyelinated rats have abundant axonal plasticity in the spinal cord throughout their adult life, therefore, axonal regeneration can be studied in this animal model.
Recent experiments revealed that axons without myelin re-grow in a robust fashion after transection.
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 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 2 weeks after the surgery. This study is currently continued and its objective is to determine whether regenerating axons can reach their original targets, approximately 6 cm rostral to the lesion, in the brain stem.
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 validated. The requirements are onerous and the process of testing and validation long and very expensive and will likely not 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 central nervous system. We have not identified a suitable material to treat an acute spinal cord injury by neurosurgical implantation but we did made two important discoveries. (1) Damage to CNS myelin results in very severe, phagocyte-rich inflammation that results in more myelin damage and a vicious cycle leading to progression of destruction of CNS tissue around the original site of injury of a number of weeks. Lack of myelin in the CNS of LES rats allows for avoidance of this problem. LES rats’ components of the inflammatory response are normal. Therefore this animal model is the only one known to be suitable to test experimental implants into the CNS. Normally myelinated animals are not suitable for this purpose since severe inflammation directed against damaged myelin will destroy the implant whether compatible or not. (2) In order for the regenerating axons to use a synthetic material as a bridge across the site of injury, they have to be able to enter it. A number of laboratories specializing in tissue engineering work with us on this issue.
Click to Shrink <<
Once axons are severed as in the spinal cord injury, their re-growth is inhibited in a normal CNS such as in a typical unfortunate human patient. Currently, there are no treatments of acute or chronic spinal cord injury. This unsatisfactory status persists despite the fact that considerable efforts have been devoted to understanding of cellular and molecular mechanisms involved in inhibition of axonal regeneration. Progress in this field has been hampered by 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 myelin constitutes formidable inhibition for axons attempting to regenerate. Dysmyelinated rats have abundant axonal plasticity in the spinal cord throughout their adult life, therefore, axonal regeneration can be studied in this animal model.
Recent experiments revealed that axons without myelin re-grow in a robust fashion after transection.
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 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 2 weeks after the surgery. This study is currently continued and its objective is to determine whether regenerating axons can reach their original targets, approximately 6 cm rostral to the lesion, in the brain stem.
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 validated. The requirements are onerous and the process of testing and validation long and very expensive and will likely not 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 central nervous system. We have not identified a suitable material to treat an acute spinal cord injury by neurosurgical implantation but we did made two important discoveries. (1) Damage to CNS myelin results in very severe, phagocyte-rich inflammation that results in more myelin damage and a vicious cycle leading to progression of destruction of CNS tissue around the original site of injury of a number of weeks. Lack of myelin in the CNS of LES rats allows for avoidance of this problem. LES rats’ components of the inflammatory response are normal. Therefore this animal model is the only one known to be suitable to test experimental implants into the CNS. Normally myelinated animals are not suitable for this purpose since severe inflammation directed against damaged myelin will destroy the implant whether compatible or not. (2) In order for the regenerating axons to use a synthetic material as a bridge across the site of injury, they have to be able to enter it. A number of laboratories specializing in tissue engineering work with us on this issue.
Click to Shrink <<