星形胶质细胞之间的接触和生长因子信号传导的正反馈回路对星形胶质细胞成熟的调节

Astrocyte-to-astrocyte Contact and a Positive Feedback Loop of Growth Factor Signaling Regulate Astrocyte Maturation

星形胶质细胞对于中枢神经系统的发育和功能至关重要。在大脑发育过程中,未成熟的星形胶质细胞会发生形态、分子、细胞和功能的变化以至成熟。尽管已经广泛研究了调节中枢神经系统中其他主要细胞类型(如神经元和少突胶质细胞)成熟过程的机制,但对于控制星形胶质细胞成熟的细胞和分子机制知之甚少。本研究确定了星形胶质细胞成熟的分子标志物,并建立了研究星形胶质细胞成熟机制的离体检验方法。离体条件下,成熟的星形胶质细胞表现出与在体星形胶质细胞相似的分子变化及类似的多种分子亚型。使用该系统,我们发现星形胶质细胞之间的接触强烈促进星形胶质细胞的成熟。此外,来自小胶质细胞、少突胶质细胞前体细胞或内皮细胞的分泌信号影响星形胶质细胞的一小部分基因,但不会持续改变星形胶质细胞的成熟。为了确定星形胶质细胞成熟的分子机制,我们用影响肿瘤相关基因功能的分子处理了成熟中的星形胶质细胞。我们发现肝素结合表皮生长因子样生长因子(HBEGF)和表皮生长因子受体(EGFR)信号通路的正反馈回路调节星形胶质细胞的成熟。此外,HBEGF、EGFR和肿瘤蛋白53(TP53)影响一些基因的表达,这些基因对纤毛发育,昼夜节律和突触功能至关重要。这些结果揭示了星形胶质细胞成熟的细胞和分子机制,对理解胶质母细胞瘤具有重要意义。

Astrocytes are critical for the development and function of the central nervous system.In developing brains,immature astrocytes undergo morphological,molecular,cellular,and functional changes as they mature.Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied,little is known about the cellular and molecular mechanisms that control astrocyte maturation.Here,we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation.Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo.Using this system,we found that astrocyte-to-astrocyte contact strongly promotes astrocyte maturation.In addition,secreted signals from microglia,oligodendrocyte precursor cells,or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation.To identify molecular mechanisms underlying astrocyte maturation,we treated maturing astrocytes with molecules that affect the function of tumor-associated genes.We found that a positive feedback loop of heparin-binding epidermal growth factor-like growth factor(HBEGF)and epidermal growth factor receptor(EGFR)signaling regulates astrocytes maturation.Furthermore,HBEGF,EGFR,and tumor protein 53(TP53)affect the expression of genes important for cilium development,the circadian clock,and synapse function.These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.