美国埃默里大学医学院Steven A. Sloan课题组近日取得一项新成果。他们绘制了人类星形胶质细胞的发育轨迹，并揭示了胶质母细胞瘤（GBM）的分化过程。相关论文于2025年1月8日发表在《自然—细胞生物学》杂志上。

研究人员表示，胶质母细胞瘤由异质和弹性细胞群构成，这些细胞群反映了神经发育的细胞类型。虽然GBM与早期和不成熟的细胞状态相呼应，但由于缺乏神经胶质细胞和神经元系的高分辨率轨迹图，确定这些肿瘤中哪些特定的发育程序受损一直难以实现。

研究人员探究了人类星形胶质细胞的成熟过程，以揭示GBM所反映的离散发育阶段和属性。研究人员利用培养了近两年的皮质器官组织，生成了人类星形胶质细胞成熟的转录组和表观基因组图谱。通过这种方法，研究人员记录了一个多阶段的发育过程。

本研究中人类星形胶质细胞的成熟时间过程，包括一个分子上独特的中间阶段，它是成熟静止期上游的一个谱系检查点。这一中间阶段是IDH野生型肿瘤性星形胶质细胞，与静止星形胶质细胞发育发生分离的偏差阶段。有趣的是，IDH1突变的肿瘤星形胶质细胞是这种发育扰动的例外，其不成熟特性受到d-2-羟基戊二酸代谢物的抑制。

研究认为，这种缺陷是IDH1突变相关表观遗传失调的结果，研究发现成熟基因中DNA羟甲基化（5hmC）偏好可能是其产生的机制。总之，该研究揭示了GBM星形胶质细胞系中一种独特的细胞状态畸变，并为实验和治疗提供了潜在的靶点。

附：英文原文

Title: Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma

Author: Sojka, Caitlin, Wang, Hsiao-Lin V., Bhatia, Tarun N., Li, Yangping, Chopra, Pankaj, Sing, Anson, Voss, Anna, King, Alexia, Wang, Feng, Joseph, Kevin, Ravi, Vidhya M., Olson, Jeffrey, Hoang, Kimberly, Nduom, Edjah, Corces, Victor G., Yao, Bing, Sloan, Steven A.

Issue&Volume: 2025-01-08

Abstract: Glioblastoma (GBM) is defined by heterogeneous and resilient cell populations that closely reflect neurodevelopmental cell types. Although it is clear that GBM echoes early and immature cell states, identifying the specific developmental programmes disrupted in these tumours has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly 2years. Through this approach, we chronicled a multiphase developmental process. Our time course of human astrocyte maturation includes a molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wild-type neoplastic astrocyte-lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumour astrocyte-lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D-2-hydroxyglutarate oncometabolite exposure. We propose that this defiance is a consequence of IDH1-mutant-associated epigenetic dysregulation, and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a distinct cellular state aberration in GBM astrocyte-lineage cells and presents developmental targets for experimental and therapeutic exploration.

DOI: 10.1038/s41556-024-01583-9

Source: https://www.nature.com/articles/s41556-024-01583-9