1. Integrated spatial multiomics reveals fibroblast fate during tissue repair.
- Author
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Foster DS, Januszyk M, Yost KE, Chinta MS, Gulati GS, Nguyen AT, Burcham AR, Salhotra A, Ransom RC, Henn D, Chen K, Mascharak S, Tolentino K, Titan AL, Jones RE, da Silva O, Leavitt WT, Marshall CD, des Jardins-Park HE, Hu MS, Wan DC, Wernig G, Wagh D, Coller J, Norton JA, Gurtner GC, Newman AM, Chang HY, and Longaker MT
- Subjects
- Animals, Cell Differentiation, Cell Movement, Cell Proliferation, Extracellular Matrix metabolism, Female, Mechanotransduction, Cellular physiology, Mice, Mice, Inbred C57BL, Skin metabolism, Cicatrix pathology, Fibroblasts metabolism, Fibrosis pathology, Skin injuries, Wound Healing physiology
- 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., Competing Interests: Competing interest statement: H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor of 10× Genomics, Arsenal Biosciences, and Spring Discovery. The entities had no role in the design, execution, or interpretation of this research. They had no role in the funding of this research. The paper reports basic research and has no financial implications for the listed companies. Two authors have co-published perspective or review articles with one reviewer over the last 4 y., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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