20 provided much of our knowledge about the signaling

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20provided much of our knowledge about the signaling pathways and mechanismsinvolved during remyelination.Oligodendrocyte progenitors (OPs). It has been well described that OPs persistin adult rodent white matter in a mitotically competent state and are the primarysubstrate by which endogenous remyelination occurs (Blakemore et al., 1995;Gensert and Goldman, 1997). OPs have also been isolated from adult humanwhite matter using FACS based identification of reporter expression driven off ofOP-specific promoters (Roy et al., 1999). When cultured, the human OPs (hOPs)proliferated and differentiated into mature mixed glial populations with apredominantly oligodendroglial phenotype. It has been suggested that successfulendogenous remyelination in the CNS is often perturbed due to axon loss,inflammation, myelin debris, the glial scar and lack of the appropriate cuesrequired to direct remyelination (Back et al., 2005; Kotter et al., 2006; Fuller etal., 2007; Giger et al., 2008; Fancy et al., 2009). However, this has beenchallenged as being an animal model-specific phenomenon as spontaneousremyelination has been described in human MS patients (Kipp et al., 2012). Thisdiscrepancy has been suggested to result from a failure to assess remyelinationof intact axons as accounting for this discrepancy showed near normalmyelination patterns in spared rodent axons following spinal contusion (Lasieneet al., 2008).
21OP engraftment.In an effort to enhance endogenous remyelination, OP celltransplantation studies in animals have begun to identify the necessaryconsiderations for implementation in the clinical setting. Many groups havedemonstrated that following transplantation of OPs isolatedin vivo, there isevidence of graft survival and successful integration within the host CNS.However, obtaining OPs with approaches that isolate them from whole tissuedoes not yield the number of OPs necessary for clinical consideration (Ben-Hurand Goldman, 2008). Therefore, several groups have begun to use embryonicstem (ES) cells as a source for OPs as they can be limitlessly expandedex vivoprior to their differentiation into OPs (Ben-Hur and Goldman, 2008). Brustle et al.(1999) was the first to report remyelination following ES cell-derived OPengraftment. Using a rat model of Pelizaeus-Merzbacher disease (PMD) where(similar to human patients) PMD rats carry a mutation in the X-linked PLP generesulting in myelin deficiency (Hodes et al., 1993), isolated ES cells weredifferentiatedin vitrointo OPs, expanded to scale for transplantation and injectedinto the spinal cord of PMD rat pups (Brustle et al., 1999). Two weeks post-injection, ultrastructural analysis of demyelinated white matter within the dorsalcolumn of OP-injected PMD rats exhibited abundant myelin sheaths ascompared to control PMD rats. Han et al. (2004) isolated A2B5+glial restrictedprecursor (GRP) cells from E13.5 rat embryos transgenically expressing alkalinephosphatase using flow activated cell sorting (FACS). Sorted GRPs were thenexpanded and engrafted into the cervical spinal cord following unilateralhemisection of the lateral funiculus. Tracking the GRP grafts with human alkaline

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