Integrated spatial multiomics reveals fibroblast fate during tissue repair

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. HuDerrick C. Wan, Gerlinde Wernig, Dhananjay Wagh, John Coller, Jeffrey A. Norton, Geoffrey C. Gurtner, Aaron M. Newman, Howard Y. Chang, Michael T. Longaker

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere2110025118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number41
DOIs
StatePublished - Oct 12 2021
Externally publishedYes

Keywords

  • Chromatin accessibility
  • Fibrosis
  • Multiomics
  • Spatial epigenomics
  • Spatial transcriptomics

ASJC Scopus subject areas

  • General

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