Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination.
To design therapies for demyelinating diseases such as multiple sclerosis, it will be important to understand the mechanisms that control oligodendrocyte progenitor cell (OPC) numbers in the adult central nervous system (CNS). During development, OPC numbers are limited by the supply of platelet-derived growth factor-A (PDGF-A). Here, we examine the role of PDGF-A in regulating OPC numbers in normal and demyelinated adult CNS using transgenic mice that overexpress PDGF-A in astrocytes under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-PDGF-A mice). In adult GFAP-PDGF-A mice, there was a marked increase in OPC density, particularly in white matter tracts, indicating that the PDGF-A supply controls OPC numbers in the adult CNS as well as during development. To discover whether increasing PDGF expression increases the number of OPCs following demyelination and whether this enhances the efficiency of remyelination, we induced demyelination in GFAP-PDGF-A transgenic mice by intraspinal injection of lysolecithin or dietary administration of cuprizone. In both demyelinating models, OPC density within lesions was significantly increased compared to wild-type mice. However, morphological analysis of lysolecithin lesions did not reveal any difference in the time course or extent of remyelination between GFAP-PDGF-A and wild-type mice. We conclude that the availability of OPCs is not rate limiting for remyelination of focal demyelinated lesions in the mouse. Nevertheless, our experiments show that it is possible to increase OPC population density in demyelinated areas by artificially increasing the supply of PDGF.
Woodruff
Rachel H
RH
Wolfson Institute for Biomedical Research and Department of Biology, University College London, London WC1E 6BT, UK.
Fruttiger
Marcus
M
Richardson
William D
WD
Franklin
Robin J M
RJ
D000818:Animals; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D008244:Lysophosphatidylcholines; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000235:genetics; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D005904:Glial Fibrillary Acidic Protein; D008244:Lysophosphatidylcholines; D010982:Platelet-Derived Growth Factor; D003471:Cuprizone