Neutrophils direct preexisting matrix in to initiate repair of damaged organs

Internal organs heal injuries with new connective tissue. However the cellular and molecular events, and the sources of this tissue, remain obscure. Here we tagged extracellular matrix around the mesothelium lining various mouse tissues: peritoneum, liver, and cecum, and applied various injury models. We discovered that preexisting matrix is transferred across organs into wounds. Using proteomics, genetic lineage-tracing and by selectively injuring juxtaposed organs, we demonstrate that the matrix tissue of origin likely dictates the final healing outcome: whether scarring or regeneration. Through single-cell RNA sequencing and genetic and chemical screens, we demonstrate that preexisting matrix is transferred by neutrophils in a heat shock factor, integrin AM/B2, kindlin3, cascade and pharmacologic inhibition of this axis prevented matrix transfer and peritoneal adhesions. Matrix transfer is thus an early event of wound repair that creates a therapeutic space to dampen scaring across a range of human conditions. Overall design: Transcriptomic examination of liver cells exposed to irreversible electroporation in adult C57BL/6 mice.