Vana Adam C, Flint Nicole C, Harwood Norah E, Le Tuan Q, Fruttiger Marcus, Armstrong Regina C
Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
J Neuropathol Exp Neurol. 2007 Nov;66(11):975-88. doi: 10.1097/NEN.0b013e3181587d46.
In multiple sclerosis, remyelination becomes limited after repeated or prolonged episodes of demyelination. To test the effect of platelet-derived growth factor-A (PDGF-A) in recovery from chronic demyelination we induced corpus callosum demyelination using cuprizone treatment in hPDGF-A transgenic (tg) mice with the human PDGF-A gene under control of an astrocyte-specific promoter. After chronic demyelination and removal of cuprizone from the diet, remyelination and oligodendrocyte density improved significantly in hPDGF-A tg mice compared with wild-type mice. In hPDGF-A tg mice, oligodendrocyte progenitor density and proliferation values were increased in the corpus callosum during acute demyelination but not during chronic demyelination or the subsequent recovery period, compared with hPDGF-A tg mice without cuprizone or to treatment-matched wild-type mice. Proliferation within the subventricular zone and subcallosal zone was elevated throughout cuprizone treatment but was not different between hPDGF-A tg and wild-type mice. Importantly, hPDGF-A tg mice had reduced apoptosis in the corpus callosum during the recovery period after chronic demyelination. Therefore, PDGF-A may support oligodendrocyte generation and survival to promote remyelination of chronic lesions. Furthermore, preventing oligodendrocyte apoptosis may be important not only during active demyelination but also for supporting the generation of new oligodendrocytes to remyelinate chronic lesions.
在多发性硬化症中，反复或长期脱髓鞘发作后，髓鞘再生变得有限。为了测试血小板衍生生长因子-A（PDGF-A）在慢性脱髓鞘恢复中的作用，我们在具有人PDGF-A基因且该基因在星形胶质细胞特异性启动子控制下的hPDGF-A转基因（tg）小鼠中，使用铜螯合剂诱导胼胝体脱髓鞘。在慢性脱髓鞘且从饮食中去除铜螯合剂后，与野生型小鼠相比，hPDGF-A tg小鼠的髓鞘再生和少突胶质细胞密度显著改善。与未使用铜螯合剂的hPDGF-A tg小鼠或治疗匹配的野生型小鼠相比，在急性脱髓鞘期间，hPDGF-A tg小鼠胼胝体内的少突胶质细胞祖细胞密度和增殖值增加，但在慢性脱髓鞘期间或随后的恢复期则没有增加。在整个铜螯合剂治疗期间，脑室下区和胼胝体下区的增殖升高，但hPDGF-A tg小鼠和野生型小鼠之间没有差异。重要的是，hPDGF-A tg小鼠在慢性脱髓鞘后的恢复期胼胝体内的细胞凋亡减少。因此，PDGF-A可能支持少突胶质细胞的生成和存活，以促进慢性病变的髓鞘再生。此外，不仅在活跃的脱髓鞘期间，而且对于支持新的少突胶质细胞生成以重新髓鞘化慢性病变，防止少突胶质细胞凋亡可能都很重要。
