TY - JOUR
T1 - High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways
AU - Marshall, Jamie L.
AU - Noel, Teia
AU - Wang, Qingbo S.
AU - Chen, Haiqi
AU - Murray, Evan
AU - Subramanian, Ayshwarya
AU - Vernon, Katherine A.
AU - Bazua-Valenti, Silvana
AU - Liguori, Katie
AU - Keller, Keith
AU - Stickels, Robert R.
AU - McBean, Breanna
AU - Heneghan, Rowan M.
AU - Weins, Astrid
AU - Macosko, Evan Z.
AU - Chen, Fei
AU - Greka, Anna
N1 - Funding Information:
We thank Rajesh Thakker at the University of Oxford for providing the UMOD-KI mice used in this study, Sophia Liu for discussions and advice on immune cells, Pawan Kumar for generation of beads used in the arrays, Jilong Li for developing the computational pipeline used to map sequencing data to spatial locations, Dylan Cable for advice on RCTD, Aleks Goeva for advice and code for mapping cell types with NMF-reg, Terri Woo for performing PAS staining on kidney tissue, Michael Howard for mouse husbandry and treatments, and Jillian Shaw, Juanchi Pablo, and Aviv Regev for comments on the manuscript. The authors thank all members of the Greka and Chen labs for comments and suggestions. We thank the following funding agencies for supporting this work: BroadIgnite (JLM), CZI Seed Networks grant number CZI2019-02447 (AG, FC), NIH grants DK095045 and DK099465 (AG).
Funding Information:
We thank Rajesh Thakker at the University of Oxford for providing the UMOD-KI mice used in this study, Sophia Liu for discussions and advice on immune cells, Pawan Kumar for generation of beads used in the arrays, Jilong Li for developing the computational pipeline used to map sequencing data to spatial locations, Dylan Cable for advice on RCTD, Aleks Goeva for advice and code for mapping cell types with NMF-reg, Terri Woo for performing PAS staining on kidney tissue, Michael Howard for mouse husbandry and treatments, and Jillian Shaw, Juanchi Pablo, and Aviv Regev for comments on the manuscript. The authors thank all members of the Greka and Chen labs for comments and suggestions. We thank the following funding agencies for supporting this work: BroadIgnite (JLM), CZI Seed Networks grant number CZI2019-02447 (AG, FC), NIH grants DK095045 and DK099465 (AG). JLM conceived of and designed the study, collected mouse tissue, performed all slide-seqV2 and HCR experiments, supervised data analysis, drafted figures, and wrote the manuscript. TN performed data analysis for slide-seqV2 data, drafted figures, and wrote the manuscript. QSW supervised and performed data analysis for slide-seqV2 data, provided high-level direction for data analysis, and wrote the manuscript. HC developed computational methods for both HCR and slide-seqV2, performed HCR image analysis, and wrote the manuscript. EM generated all slide-seqV2 arrays. KAV assisted with procurement of human samples, AS performed computational analysis of human and BTBR w/w mouse single-cell data used for mapping cell types on slide-seqV2 data, and KAV and AS contributed to findings on LYVE1+ and Trem2+ macrophages from single-cell analysis of human and mouse kidneys. KL designed immune cell interaction schematics. RRS performed experiments using the original slide-seq version 1 protocol. BM performed analysis of NMF-reg cell mappings and cell-type interactions. RMH collected images of PAS stained tissue. KK and AW assisted with procurement of human samples. EZM provided Slide-seqV2 arrays for this study. FC provided Slide-seqV2 arrays for this study, assisted with study design and implementation, and provided input on results. AG supervised the study and wrote the manuscript. All authors reviewed and provided input on the manuscript. AG serves as a founding advisor to Goldfinch Biopharma and to a new Atlas Ventures funded company, with respective agreements reviewed and managed by Mass General Brigham (MGB) and the Broad Institute of MIT and Harvard in accordance with their conflict of interest policies. RRS, FC, and EZM are inventors on a pending patent application related to the development of Slide-seq. EZM is an advisor to Curio Biosciences, Inc. FC is a paid consultant for Atlas Bio. KAV is currently an employee and shareholder of Q32 Bio, Inc. JLM is currently an employee and shareholder of Solid Biosciences, Inc.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.
AB - 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.
KW - Cell biology
KW - Pathophysiology
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85127101579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127101579&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104097
DO - 10.1016/j.isci.2022.104097
M3 - Article
C2 - 35372810
AN - SCOPUS:85127101579
VL - 25
JO - iScience
JF - iScience
SN - 2589-0042
IS - 4
M1 - 104097
ER -