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

iScience (Apr 2022)

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

Affiliations

Jamie L. Marshall: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Teia Noel: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Qingbo S. Wang: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Haiqi Chen: Program in Cell Circuits and Epigenetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Evan Murray: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ayshwarya Subramanian: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Katherine A. Vernon: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Silvana Bazua-Valenti: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Katie Liguori: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Keith Keller: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Robert R. Stickels: Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02115, USA; Division of Medical Science, Harvard University, Boston, MA 02115, USA
Breanna McBean: Broad Summer Research Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Rowan M. Heneghan: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Astrid Weins: Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Evan Z. Macosko: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
Fei Chen: Program in Cell Circuits and Epigenetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
Anna Greka: Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA; Corresponding author

Journal volume & issue: Vol. 25, no. 4
p. 104097

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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