Jacek M. Kwiecien

, PhD, DVM

Assistant Professor (Part-Time)
Pathology and Molecular Medicine

McMaster University
Central Animal Facility
1U22D Health Sciences Centre
905-525-9140 ext. 22827
kwiecien@mcmaster.ca

Administrative Assistant: Lisa Bulger

Education and Professional Standing

• PhD Veterinary Pathology, University of Guelph, 1995
• MSc Veterinary Pathology, University of Guelph, 1991
• DVM, University of Agriculture (Poland), 1983

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Interests

Research and Clinical Focus

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.

Affiliations with Research Centres

While the mutant dysmyelinated rats are bred and raised at McMaster University, and neurosurgeries are performed at McMaster as well, some tissues are analyzed in excellent laboratories around the continent specializing in studies on CNS regeneration.

My research collaborators include investigators from: Department of Surgery, Division of Otolaryngology, McMaster University; University of Toronto; University of British Columbia; University of California; Aventis Pharmaceuticals; CNRS-CERMAV Grenoble, France; University of Trento, Italy; University of Minho, Portugal

Research Goals

• Mechanisms of axonal regeneration following spinal cord injury
• Materials for neurosurgical treatment of spinal cord injury
• Pharmacologic treatment of myelin-lacking axons to improve/restore their function
• Remyelination by transplanted exogenous cells, including human cells

Noteworthy Accomplishments

Development of animal models of:

• Remyelination by exogenous transplanted cells
• Axonal regeneration in the adult CNS
• Testing of cellular and synthetic materials for biocompatibility with the CNS and efficacy to conduct axonal regeneration.

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Team Members

Surgery Residents

Jonathan MacLean. Bosco, Lui, Justin Khetani, Rajveer Hundal

Selected Publications

• Kwiecien JM, Avram R. Long distance axonal regeneration in the filum terminale of adult rats is regulated by ependymal cells. Journal of Neurotrauma 2008, 25: 196-204.
• McPhail LT, Borisoff JF, Tsang B, Hwi LP-R, Kwiecien JM, Ramer MS. Protracted myelin clearance hinders central primary afferent regeneration following dorsal rhizotomy and delayed neurotrophin-3 treatment. Neuroscience Letters 2007, 411: 206-211
• Scott ALM, Ramer LM, Soril LJJ,Kwiecien JM, Ramer MS. Targeting myelin to optimize plasticity of spared spinal axons. Molecular Neurobiology 2006, 33: 91-111.
• Eftekhapour E, Karimi-Abdolrezaee S, Sinha K, Velumian AA, Kwiecien JM, Fehlings MH. Structural and functional, alterations in spinal cord axons in adult Long Evans Shaker (LES) dysmyelinated rats. Experimental Neurology 2005, 193: 334-349.
• McPhail LT, Stirling DP, Tetzlaff W, Kwiecien JM, Ramer MS. The contribution of activated phagocytes and myelin degeneration to axonal retraction/dieback following spinal cord injury" European Journal of Neuroscience 2004, 20: 1984-1994.
• Phokeo V, Kwiecien JM, Ball AK. Characterization of the optic nerve and retinal ganglion cell layer in the dysmyelinated adult Long Evans Shaker rat: possible axonal sprouting. Journal of Comparative Neurology 2002, 451: 213-224.
• Kwiecien JM, Blanco M, Fox JG, Delaney KH, Fletch AL. Neuropathology of bouncer Long Evans, a novel dysmyelinated rat. Comparative Medicine 2000; 50: 503-510.
• O’Connor LT, Goetz BD, Kwiecien JM, Delaney KH, Fletch AL, Duncan ID. Insertion of a retrotransposon into the myelin basic protein gene causes CNS dysmyelination in the Long Evans shaker (LES) rat. Journal of Neuroscience 1999; 19: 3404-24-13.
• Kwiecien JM, O’Connor LT, Goetz BD, Delaney KH, Fletch AL, Duncan ID. Morphological and morphometric studies of the dysmyelinating mutant, the Long Evans shaker rat. Journal of Neurocytology 1998; 27: 581-591.
• Delaney KH, Kwiecien JM, Wegiel J, Wisniewski HM, Fletch AL. Familial dysmyelination in a Long Evans rat mutant. Laboratory Animal Science 1995; 45: 547-553.