Integrated spatial multiomics reveals fibroblast fate during tissue repair

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.

Skin‐ny deeping: Uncovering immune cell behavior and function through imaging techniques*

“…169 Another time-course study of wound healing showed that different fibroblast populations were spatially distinct and exhibited key functional differences in mechanotransduction and proliferation during the course of wound healing. 170 Similarly, metabolically heterogenous epidermal stem cell populations were also spatially segregated during re-epithelization of the wound. 171 Together, these spatial transcriptomics studies show that different cell subsets play different functions in wound healing.…”

“…Critically, the presence of fibroblasts is important to support the epidermal growth in decellularized human dermis and the lin ‐ CD90 + CD39 + subset were found to better support formation of a multi‐layered epithelium 169 . Another time‐course study of wound healing showed that different fibroblast populations were spatially distinct and exhibited key functional differences in mechanotransduction and proliferation during the course of wound healing 170 . Similarly, metabolically heterogenous epidermal stem cell populations were also spatially segregated during re‐epithelization of the wound 171 .…”

Single‐cell transcriptomics in human skin research: available technologies, technical considerations and disease applications

“…92 For instance, spatial transcriptomics has been combined with ATAC-seq and scRNA-seq, providing information about the space and time of gene expression in mouse fibroblasts during the wound healing process. 8 Other technologies facilitating the incorporation of multiple-omic approaches, include single-cell triple-omics sequencing (scTrio-seq), 93 which combines genetic, epigenetic and transcriptomic profiling, as well as genome and transcriptome sequencing (G&T-seq). 94 These technologies provide high-throughput omic readouts that could be applied to molecular medicine and dermatology research.…”

SpatialCorr: Identifying Gene Sets with Spatially Varying Correlation Structure

“…Unlike single-cell RNA-seq (scRNA-seq) approaches in which a tissue sample is dissociated to produce a suspension of single cells thereby losing information about each cell’s location within the tissue, ST experiments retain spatial information and are therefore essential for comprehensively addressing questions associated with cell state and function when cell position and neighbors are crucial. By allowing investigators to address questions related to how adjacent cells communicate, how functional specialization is influenced by spatial location within a tissue, and how proximity among varying cell types affects downstream phenotypes, the ST technology has already enabled key insights into embryonic development (Srivatsan et al, 2021), nephrology (Ferreira et al, 2021), wound healing (Foster et al, 2021), brain function (Maynard et al, 2021), and cancer (Hunter et al, 2021; Ji et al, 2020; Moncada et al, 2020).…”