Marshall Jamie L, Noel Teia, Wang Qingbo S, Chen Haiqi, Murray Evan, Subramanian Ayshwarya, Vernon Katherine A, Bazua-Valenti Silvana, Liguori Katie, Keller Keith, Stickels Robert R, McBean Breanna, Heneghan Rowan M, Weins Astrid, Macosko Evan Z, Chen Fei, Greka Anna
Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
iScience. 2022 Mar 16;25(4):104097. doi: 10.1016/j.isci.2022.104097. eCollection 2022 Apr 15.
High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse and human kidneys, in healthy and distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in tissue from nine distinct human kidneys, which revealed a cell neighborhood centered around a population of macrophages. Second, in a mouse model of diabetic kidney disease, we detected changes in the cellular organization of the spatially restricted kidney filter and blood-flow-regulating apparatus. Third, in a mouse model of a toxic proteinopathy, we identified previously unknown, disease-specific cell neighborhoods centered around macrophages. In a spatially restricted subpopulation of epithelial cells, we discovered perturbations in 77 genes associated with the unfolded protein response. Our studies illustrate and experimentally validate the utility of Slide-seqV2 for the discovery of disease-specific cell neighborhoods.
高分辨率空间转录组学能够直接从完整的组织切片中绘制RNA表达图谱；然而，其在阐明疾病过程和治疗可操作途径方面的效用仍未得到探索。我们将Slide-seqV2应用于健康和不同疾病模式下的小鼠和人类肾脏。首先，我们确定了Slide-seqV2在来自九个不同人类肾脏的组织中的可行性，这揭示了一个以巨噬细胞群体为中心的细胞邻域。其次，在糖尿病肾病小鼠模型中，我们检测到空间受限的肾脏滤过器和血流调节装置的细胞组织变化。第三，在一种毒性蛋白病小鼠模型中，我们确定了以前未知的、以巨噬细胞为中心的疾病特异性细胞邻域。在一个空间受限的上皮细胞亚群中，我们发现了77个与未折叠蛋白反应相关的基因的扰动。我们的研究说明了并通过实验验证了Slide-seqV2在发现疾病特异性细胞邻域方面的效用。
