High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways

Jamie L Marshall; Teia Noel; Qingbo S Wang; Haiqi Chen; Evan Murray; Ayshwarya Subramanian; Katherine A Vernon; Silvana Bazua-Valenti; Katie Liguori; Keith Keller; Robert R Stickels; Breanna McBean; Rowan M Heneghan; Astrid Weins; Evan Z Macosko; Fei Chen; Anna Greka

doi:10.1016/j.isci.2022.104097

High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways

iScience. 2022 Mar 16;25(4):104097. doi: 10.1016/j.isci.2022.104097. eCollection 2022 Apr 15.

Authors

Jamie L Marshall¹, Teia Noel¹, Qingbo S Wang^{2

3

4

5}, Haiqi Chen^{6

7

8}, Evan Murray⁹, Ayshwarya Subramanian^{1

10}, Katherine A Vernon^{1

11}, Silvana Bazua-Valenti^{1

11}, Katie Liguori¹, Keith Keller^{1

12}, Robert R Stickels^{7

13

14}, Breanna McBean¹⁵, Rowan M Heneghan¹, Astrid Weins^{11

12}, Evan Z Macosko^{9

16}, Fei Chen^{6

17}, Anna Greka^{1

11}

Affiliations

¹ Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
⁶ Program in Cell Circuits and Epigenetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02115, USA.
¹⁴ Division of Medical Science, Harvard University, Boston, MA 02115, USA.
¹⁵ Broad Summer Research Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁶ Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Abstract

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 LYVE1+ 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.

Keywords: Cell biology; Pathophysiology; Transcriptomics.

Abstract

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