Integrated spatial multiomics reveals fibroblast fate during tissue repair.

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Publication Year:
2021
Authors:
Deshka S Foster, Michael Januszyk, Kathryn E Yost, Malini S Chinta, Gunsagar S Gulati, Alan T Nguyen, Austin R Burcham, Ankit Salhotra, R Chase Ransom, Dominic Henn, Kellen Chen, Shamik Mascharak, Karen Tolentino, Ashley L Titan, R Ellen Jones, Oscar da Silva, W Tripp Leavitt, Clement D Marshall, Heather E des Jardins-Park, Michael S Hu, Derrick C Wan, Gerlinde Wernig, Dhananjay Wagh, John Coller, Jeffrey A Norton, Geoffrey C Gurtner, Aaron M Newman, Howard Y Chang, Michael T Longaker
PubMed ID:
34620713
Funding Grants:
Public Summary:
In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive, in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to skin injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to reveal potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.
Scientific Abstract:
In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive, in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to skin injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to reveal potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.