It is typically assumed that a portion of functional deficits following spinal cord injury (SCI) are due to loss of myelin around surviving axons. Indeed, studies of injured human spinal cords and our own preliminary data from contused rat spinal cords suggest that demyelination is present chronically. However, a relationship between recovery and myelination has never been directly tested. This proposal will use a clinically relevant model of rat spinal contusion injury to test the hypothesis that improved myelination of the injury site leads to better functional recovery. We will attempt to increase myelination of spared axons in the lesion and then evaluate the consequences on motor and sensory function. Specifically, two approaches will be used to stimulate myelination. First, the ability of endogenous cells to enhance myelination after SCI will be tested by intrathecal infusion to the injured spinal cord of growth factors known to increase survival and proliferation of oligodendrocyte lineage cells (Aim 1). Our preliminary data suggest that the number of myelinating cells will be increased in the lesion site with this technique. However, because massive oligodendrocyte death occurs acutely after SCI, infusion of growth factors alone may be insufficient to completely restore myelination after SCI. Therefore, in the second aim, oligodendrocyte progenitors (OPCs) will be transplanted directly into the lesion. OPCs are highly migratory and proliferative and differentiate into myelinating oligodendrocytes following transplantation into the adult central nervous system. Thus, this study will reveal the therapeutic potential of increasing the number of oligodendrocyte lineage cells after SCI. These two approaches will be combined in the third aim; growth factors will be infused to spinal cords that received OPC transplants thereby maximizing the function of transplanted and endogenous OPCs within the injured spinal cord. Collectively, these studies will evaluate if myelination can be enhanced after SCI by increasing the number of oligodendrocyte lineage cells. Furthermore, using sensitive locomotor and sensory tests, the ability of increased myelination to be translated into improved function will be carefully analyzed. Since many studies, from basic science to clinical trials, assume that myelination needs to be improved after SCI in order to increase function, these experiments will provide important groundwork for those and other studies seeking to identify myelin-based therapies for spinal cord injured patients.
|Almad, Akshata; Lash, A Todd; Wei, Ping et al. (2011) The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice. Exp Neurol 232:309-17|
|Schonberg, David L; McTigue, Dana M (2009) Iron is essential for oligodendrocyte genesis following intraspinal macrophage activation. Exp Neurol 218:64-74|
|Tripathi, Richa B; McTigue, Dana M (2008) Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats. J Comp Neurol 510:129-44|
|McTigue, Dana M; Tripathi, Richa; Wei, Ping et al. (2007) The PPAR gamma agonist Pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury. Exp Neurol 205:396-406|
|Schonberg, David L; Popovich, Phillip G; McTigue, Dana M (2007) Oligodendrocyte generation is differentially influenced by toll-like receptor (TLR) 2 and TLR4-mediated intraspinal macrophage activation. J Neuropathol Exp Neurol 66:1124-35|
|Tripathi, Richa; McTigue, Dana M (2007) Prominent oligodendrocyte genesis along the border of spinal contusion lesions. Glia 55:698-711|
|McTigue, Dana M; Tripathi, Richa; Wei, Ping (2006) NG2 colocalizes with axons and is expressed by a mixed cell population in spinal cord lesions. J Neuropathol Exp Neurol 65:406-20|