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A discrete ‘early-responder’ stromal-cell subtype orchestrates immunocyte recruitment to injured tissue

2023; Nature Portfolio; Volume: 24; Issue: 12 Linguagem: Inglês

10.1038/s41590-023-01669-w

1529-2916

Omar Yaghi, Bola S. Hanna, P. Kent Langston, Daniel A. Michelson, Teshika Jayewickreme, Miguel Marin-Rodero, Christophe Benoist, Diane Mathis,

Adipose Tissue and Metabolism

Following acute injury, stromal cells promote tissue regeneration by a diversity of mechanisms. Time-resolved single-cell RNA sequencing of muscle mesenchymal stromal cells (MmSCs) responding to acute injury identified an 'early-responder' subtype that spiked on day 1 and expressed a notable array of transcripts encoding immunomodulators. IL-1β, TNF-α and oncostatin M each strongly and rapidly induced MmSCs transcribing this immunomodulatory program. Macrophages amplified the program but were not strictly required for its induction. Transfer of the inflammatory MmSC subtype, tagged with a unique surface marker, into healthy hindlimb muscle induced inflammation primarily driven by neutrophils and macrophages. Among the abundant inflammatory transcripts produced by this subtype, Cxcl5 was stroma-specific and highly upregulated with injury. Depletion of this chemokine early after injury revealed a substantial impact on recruitment of neutrophils, a prolongation of inflammation to later times and an effect on tissue regeneration. Mesenchymal stromal cell subtypes expressing a comparable inflammatory program were found in a mouse model of muscular dystrophy and in several other tissues and pathologies in both mice and humans. These 'early-responder' mesenchymal stromal cells, already in place, permit rapid and coordinated mobilization and amplification of critical cell collaborators in response to injury. Mathis and colleagues identify a subset of muscle mesenchymal stromal cells that coordinates tissue immune responses and drives regenerative mechanisms following muscle injury.