视网膜铺片中神经节细胞的分子和空间分析确定了对青光眼具有抵抗力的血管周围神经元。

Molecular and spatial analysis of ganglion cells on retinal flatmounts identifies perivascular neurons resilient to glaucoma.

作者信息

Nimkar Kushal, Tsai Nicole Y, Zhao Mengya, Yi Yujuan, Lum Matthew R, Garrett Tavita R, Wang Yixiao, Toma Kenichi, Caval-Holme Franklin, Reddy Nikhil, Ehrlich Aliza T, Kriegstein Arnold R, Do Michael Tri H, Hu Yang, Sivyer Benjamin, Shekhar Karthik, Duan Xin

机构信息

Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.

Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.

出版信息

Neuron. 2025 Aug 19. doi: 10.1016/j.neuron.2025.07.025.

DOI:10.1016/j.neuron.2025.07.025

PMID:40840447

Abstract

Recent transcriptomic studies have categorized mouse retinal ganglion cells (RGCs) into 45 types; however, little is known about their spatial distributions on the two-dimensional retinal surface and how their local microenvironments impact their functions. Here, we optimized a workflow combining imaging-based spatial transcriptomics (multiplexed-error robust fluorescent in situ hybridization [MERFISH]) and immunostaining on retinal flatmounts. We computationally registered the somata distributions of all RGCs and found that 34/45 molecularly defined types exhibited non-uniform distributions. We analyzed local neighborhoods for each cell and identified seven RGC types enriched in the perivascular niche, including direction-selective RGC (DSGC) and intrinsically photosensitive RGC (ipRGC) types. We further examined an experimental glaucoma model and found that surviving RGCs are enriched in the perivascular niche. Perivascular DSGCs and M1 ipRGCs were especially resilient, suggesting that proximity to vasculatures confers mTOR-independent, cell-extrinsic neuroprotection. Together, our work provides a comprehensive spatial atlas of RGC types and links their microenvironment to differential vulnerability in neurodegeneration.

摘要

最近的转录组学研究已将小鼠视网膜神经节细胞（RGC）分为45种类型；然而，对于它们在二维视网膜表面的空间分布以及局部微环境如何影响其功能，我们却知之甚少。在这里，我们优化了一种工作流程，该流程将基于成像的空间转录组学（多重误差稳健荧光原位杂交[MERFISH]）与视网膜平铺标本上的免疫染色相结合。我们通过计算记录了所有RGC的胞体分布，发现45种分子定义类型中的34种呈现出非均匀分布。我们分析了每个细胞的局部邻域，并确定了七种在血管周围微环境中富集的RGC类型，包括方向选择性RGC（DSGC）和内在光敏RGC（ipRGC）类型。我们进一步研究了一个实验性青光眼模型，发现存活的RGC在血管周围微环境中富集。血管周围的DSGC和M1 ipRGC尤其具有弹性，这表明靠近血管赋予了不依赖mTOR的细胞外神经保护作用。总之，我们的工作提供了一个RGC类型的全面空间图谱，并将它们的微环境与神经退行性变中的不同易损性联系起来。