A glial progenitor cell pool persists throughout the adult central nervous system. This population is responsible for remyelination after white matter stroke, traumatic brain injury and the lesions of relapsing- remitting multiple sclerosis. However, remyelination is often inhibited in cases such as chronic multiple sclerosis, and spinal cord injury. There could be two reasons for inhibition of myelination, either undue maintenance of the progenitor, or the differentiation of resident glial progenitors into reactive astrocytes. We seek to determine the molecular mechanism that inhibits glial progenitor cells from remyelinating. On the basis of a genomics screen of adult human glial progenitor cells, we found that these cells express high levels of a constitutively activate receptor tyrosine phosphatase, RPTP?/? (PTPRZ1). PTPRZ1 can act to dephosphorylate ?-catenin, and by so doing modulates canonical wnt signaling. Pleiotrophin serves as an endogenous inhibitor for RPTP?/?, and we have found that pleiotrophin is abundantly expressed by both glial progenitors and endothelial cells, suggesting both autocrine and paracrine regulatory control of RPTP?/? - dependent signaling. In preliminary experiments, we have found that pleiotrophin increases activated ?-catenin, and similarly, that RPTP?/? /PTPRZ1 shRNAi knockdown increases wnt-signaled TCF-dependent transcription by fetal human glial progenitor cells. Furthermore, we found that RPTP?/? /PTPRZ1 knockdown potentiated both the self-renewal and expansion competence of glial progenitors, consistent with the greater availability of ?-catenin afforded by RPTP2/6 suppression. In this application, we propose to use RPTP?/? knock-down in association with microarray analysis to define the transcriptional response of fetal human glial progenitor cells to RPTP?/? inhibition. By so doing, we expect to identify the downstream targets of RPTP?/? in these cells;these in turn would comprise likely targets for modulating the differentiated fate of resident human glial progenitor cells. In addition, we also intend to assess if pleiotrophin-mediated RPTP?/? inhibition may be used as a strategy by which to promote the reactive expansion of glial progenitor cells, and if so, whether pleiotrophin inhibition might be used to suppress reactive astrocytosis and thus enhance myelination for clinical therapies of remyelination. As such, these basic studies of signal control in glial progenitor cells may provide us great insight, in a physiologically-relevant human cell system, into a broad category of neurological diseases that share reactive gliosis and aborted remyelination as key impediments to recovery.
Glial progenitor cells persists throughout adulthood, and this population is responsible for remyelination after injuries such as white matter stroke, traumatic brain injury and in acute multiple sclerosis lesions. However, remyelination is often inhibited in cases such as chronic multiple sclerosis, and spinal cord injury. Therefore, this proposal aims to characterize a novel candidate, pleiotrophin, and its likely contribution to inhibiting glial progenitor differentiation in vitro and in vivo.