Saluja I, Granneman J G, Skoff R P
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Glia. 2001 Mar 1;33(3):191-204.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily that have been described as master genes that switch cells from an undifferentiated phenotype to a differentiated phenotype. In the present investigation, we examined the possibility that ligands for PPARs are potent activators of oligodendrocyte (OL) differentiation and/or proliferation. Primary glial cultures and enriched OL cultures of neonatal mouse cerebra were treated with three different PPAR agonists: a PPAR gamma-selective agonist, a PPAR delta-selective agonist, and a pan agonist selective for both PPAR gamma and delta. Treatment with PPAR gamma agonist does not have an effect on the differentiation of OLs; however, PPAR delta agonist and the pan agonist treatment accelerates the differentiation of OLs within 24 h of application in mixed glial cultures. The number of OLs with processes and huge membrane sheets increases two- to threefold in both groups. The increase in the size of the sheets is also mirrored by changes in the intensity and distribution of myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs. As compared to controls, the PPAR delta agonist-treated groups contain more OLs that have MBP and PLP mRNA extending into distal processes. These results indicate that PPAR delta plays a significant role in the maturation of OLs and regulates the size of OL sheets. BrdU immunostaining reveals that these agonists do not significantly stimulate proliferation of OLs expressing glycolipids. The studies in enriched OL cultures reproduce the effects of the PPAR agonists seen in the mixed glial cultures, indicating that the effect of the PPAR agonists is directly on the OLs and not via astrocytes. In the enriched cultures, the total number of OLs increases significantly in the PPAR delta agonist-treated groups, but BrdU immunostaining does not show an increased proliferation of cells. These findings suggest that PPAR delta increases the survival of cells and/or prevents cell death in enriched cultures. Although PPAR delta is expressed in various cell types, its role as a factor in the transcriptional regulation of OL differentiation has not been explored. We show for the first time that a ligand that serves as an agonist for PPAR delta activates the program of OL differentiation in primary and enriched OL cultures.
过氧化物酶体增殖物激活受体（PPARs）是核激素受体超家族的配体激活转录因子，被描述为可将细胞从未分化表型转变为分化表型的主控基因。在本研究中，我们探讨了PPARs的配体是否为少突胶质细胞（OL）分化和/或增殖的有效激活剂。用三种不同的PPAR激动剂处理新生小鼠大脑的原代胶质细胞培养物和富集的OL培养物：一种PPARγ选择性激动剂、一种PPARδ选择性激动剂以及一种对PPARγ和δ均有选择性的泛激动剂。用PPARγ激动剂处理对OL的分化没有影响；然而，在混合胶质细胞培养物中，用PPARδ激动剂和泛激动剂处理在应用后24小时内加速了OL的分化。两组中具有突起和巨大膜片的OL数量增加了两到三倍。膜片大小的增加也反映在髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）mRNA的强度和分布变化上。与对照组相比，用PPARδ激动剂处理的组中含有更多具有延伸至远端突起的MBP和PLP mRNA的OL。这些结果表明，PPARδ在OL的成熟中起重要作用，并调节OL膜片的大小。BrdU免疫染色显示，这些激动剂不会显著刺激表达糖脂的OL的增殖。在富集的OL培养物中的研究重现了在混合胶质细胞培养物中观察到的PPAR激动剂的作用，表明PPAR激动剂的作用直接作用于OL，而不是通过星形胶质细胞。在富集培养物中，用PPARδ激动剂处理的组中OL的总数显著增加，但BrdU免疫染色未显示细胞增殖增加。这些发现表明，PPARδ增加了富集培养物中细胞的存活率和/或防止细胞死亡。尽管PPARδ在多种细胞类型中表达，但其作为OL分化转录调节因子的作用尚未得到探索。我们首次表明，作为PPARδ激动剂的配体在原代和富集的OL培养物中激活了OL分化程序。
