Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system
Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system
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DOI：
10.1002/glia.23724
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发表时间：
2019-10-21
期刊：
影响因子：
6.2
通讯作者：
Kuery, Patrick
中科院分区：
文献类型：
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作者：
Beyer, Felix;Jadasz, Janusz;Kuery, Patrick
除了专用的少突胶质前体细胞外，成人神经干细胞(ANSCs)还可以在成人中枢神经系统(CNS)中分化出新的少突胶质细胞。这一过程主要是在病理情况下提供髓鞘神经胶质细胞的替代，从而导致神经胶质细胞的异质性。我们以前的研究表明，p57Kip2基因编码了一种内在的神经胶质命运获取调节因子，我们在此研究了它的调节在多大程度上可以影响不同中枢神经系统环境中干细胞依赖的少突胶质细胞的形成。因此，我们将p57Kip2基因敲除的aNSCs移植到小鼠脑内的白质和灰质(WM和GM)区域、未损伤的脊髓以及脊髓损伤附近，并评估了体内的整合和分化。我们的实验表明，在健康条件下，p57Kip2的内在抑制以及WM的定位促进了向髓鞘少突胶质细胞的分化，但损害了星形胶质细胞的生成。此外，p57Kip2基因敲除对细胞存活和增加净少突胶质细胞生成有很大的好处。在半切脊髓附近，基因敲除导致了类似的少突胶质细胞特征的诱导；然而，新生成的少突胶质细胞似乎更多地受到恶劣环境的影响。这项研究有助于我们理解成人少突胶质发生和胶质细胞异质性的机制，并进一步揭示在损伤和疾病中考虑神经干细胞介导的细胞替代时的关键因素。
Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.