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
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.
