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Wasl 对于维持胶质母细胞瘤起始阶段小胶质细胞的核心活动至关重要。

Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages.

机构信息

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Laboratoire GBCM, EA7528, Conservatoire National des Arts et Métiers, HESAM Université, Paris, France.

出版信息

Glia. 2022 Jun;70(6):1027-1051. doi: 10.1002/glia.24154. Epub 2022 Feb 22.

DOI:10.1002/glia.24154
PMID:35194846
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9306864/
Abstract

Microglia actively promotes the growth of high-grade gliomas. Within the glioma microenvironment an amoeboid microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumor promoting activities is unclear. Using the advantages of the larval zebrafish model, we identified the underlying mechanism and show that microglial morphology and functions are already impaired during glioma initiation stages. The presence of pre-neoplastic HRasV12 expressing cells induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factor wasla in microglia. Importantly, a microglia specific rescue of wasla expression restores microglial morphology and functions. This results in increased phagocytosis of pre-neoplastic cells and slows down tumor progression. In conclusion, we identified a mechanism that de-activates core microglial functions within the emerging glioma microenvironment. Restoration of this mechanism might provide a way to impair glioma growth.

摘要

小胶质细胞积极促进高级别神经胶质瘤的生长。在神经胶质瘤微环境中，观察到阿米巴样小胶质细胞形态，但潜在的原因及其对小胶质细胞功能和肿瘤促进活性的相关影响尚不清楚。利用幼鱼斑马鱼模型的优势，我们确定了潜在的机制，并表明小胶质细胞形态和功能在神经胶质瘤起始阶段已经受损。存在前神经瘤性 HRasV12 表达细胞诱导小胶质细胞的阿米巴样形态，增加小胶质细胞数量并降低其运动性和吞噬活性。RNA 测序分析显示小胶质细胞中肌动蛋白成核促进因子 wasla 的表达水平降低。重要的是，小胶质细胞特异性挽救 wasla 的表达可恢复小胶质细胞的形态和功能。这导致对前神经瘤细胞的吞噬作用增加，并减缓肿瘤进展。总之，我们确定了一种在新出现的神经胶质瘤微环境中使核心小胶质细胞功能失活的机制。恢复这种机制可能为削弱神经胶质瘤生长提供一种方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/5a65c66c6431/GLIA-70-1027-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/4507812cf094/GLIA-70-1027-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/a44b9c96b21c/GLIA-70-1027-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/1d85cf03217d/GLIA-70-1027-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/a465cccec345/GLIA-70-1027-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/91830b4f5f3f/GLIA-70-1027-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/5a65c66c6431/GLIA-70-1027-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/4507812cf094/GLIA-70-1027-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/a44b9c96b21c/GLIA-70-1027-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/1d85cf03217d/GLIA-70-1027-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/a465cccec345/GLIA-70-1027-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/91830b4f5f3f/GLIA-70-1027-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa68/9306864/5a65c66c6431/GLIA-70-1027-g002.jpg

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