Exogenous and fibroblast growth factor 2/epidermal growth factor-regulated endogenous cytokines regulate neural precursor cell growth and differentiation
Exogenous and fibroblast growth factor 2/epidermal growth factor-regulated endogenous cytokines regulate neural precursor cell growth and differentiation
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DOI：
10.1634/stemcells.2005-0138
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发表时间：
2006-03-01
期刊：
影响因子：
5.2
通讯作者：
Hugnot, Jean-Philippe
中科院分区：
文献类型：
--
作者：
Deleyrolle, Loic;Marchal-Victorion, Sophie;Hugnot, Jean-Philippe
神经球是由神经干细胞和神经祖细胞组成的克隆性细胞聚集体。对它们的增殖和分化调节的全面描述是它们用于生物治疗的必要先决条件。细胞因子是调节细胞前体命运的重要分子。使用基因阵列策略，我们进行了内源性细胞因子的描述性和功能性分析;脊髓来源的NS在其生长或分化为神经元和神经胶质细胞的过程中表达的受体。发现NS表达约100个受体亚基和细胞因子/分泌的发育因子。几个血管生成因子和受体，可以介导神经前体细胞-内皮细胞的关系进行了检测。其中，内皮素受体B高表达，内皮素被发现增加NS生长。相比之下，NS表达睫状神经营养因子（CNTF）、骨形态发生蛋白（BMP）、干扰素（IFN）-γ或肿瘤坏死因子（TNF）-α的受体，当在生长期加入时，其导致显著的生长减少，随后是分化时少突胶质细胞形成的减少或丧失。此外，NS合成参与其生长和分化的成纤维细胞生长因子2/表皮生长因子（FGF 2/EGF）调节的内源性细胞因子。值得注意的是，BMP-7和CNTF在扩增过程中表达，但在分化时，BMP-7显著转变为BMP-4和-6，CNTF急剧增加。重新引入生长因子逆转BMP表达谱，表明生长因子-BMP交叉调节。通过从CNTF基因敲除小鼠中衍生NS来研究内源性CNTF的作用。这些NS具有与细胞凋亡减少相关的增加的生长速率，并产生具有减少的胶质纤维酸性蛋白（GFAP）含量的星形胶质细胞。这些结果证明了内源性和外源性细胞因子在神经前体细胞生长和分化中的联合作用。
Neurospheres (NSs) are clonal cellular aggregates composed of neural stem cells and progenitors. A comprehensive description of their proliferation and differentiation regulation is an essential prerequisite for their use in biotherapies. Cytokines are essential molecules regulating cell precursor fate. Using a gene-array strategy, we conducted a descriptive and functional analysis of endogenous cytokines; and receptors expressed by spinal cord-derived NSs during their growth or their differentiation into neuronal and glial cells. NSs were found to express approximately 100 receptor subunits and cytokine/secreted developmental factors. Several angiogenic factors and receptors that could mediate neural precursor cell-endothelial cell relationships were detected. Among them, receptor B for endothelins was highly expressed, and endothelins were found to increase NS growth. In contrast, NSs express receptors for ciliary neurotrophic factor (CNTF), bone morphogenetic protein (BMP), interferon (IFN)-gamma, or tumor necrosis factor (TNF)-alpha, which, when added in the growth phase, led to a dramatic growth reduction followed by a reduction or a loss of oligodendrocyte formation on differentiation. In addition, NSs synthesize fibroblast growth factor 2/epidermal growth factor (FGF2/EGF)-regulated endogenous cytokines that participate in their growth and differentiation. Notably, BMP-7 and CNTF were expressed during expansion, but upon differentiation there was a remarkable switch from BMP-7 to BMP-4 and -6 and a sharp increase of CNTF. Reintroduction of growth factors reverses the BMP expression profile, indicating growth factor-BMP cross-regulations. The role of endogenous CNTF was investigated by deriving NSs from CNTF knockout mice. These NSs have an increased growth rate associated with reduction of apoptosis and generate astrocytes with a reduced glial fibulary acidic protein (GFAP) content. These results demonstrate the combined role of endogenous and exogenous cytokines in neural precursor cell growth and differentiation.