Fig 1: Graphical summary. Differentially regulated (DE) genes involved in specific wound healing phases (see red-rimmed boxes, e.g. control of inflammation, clearance of the wound bed, others) are depicted. The distinct wound healing phases are composed of several cellular functions (for example clearance the wound bed relies on proteases and their inhibitors, the alternate complement system and macrophage phagocytosis and activation). DE genes in MSCs treated with S100A8/A9 versus non-treated MSCs are depicted in blue (up-regulated) or red (downregulated). Differentially regulated genes are selected according to their known functions. Brackets aside indicate that genes and functions are related to a specific wound phase. Differentially up-regulated miRNAs are depicted in green and the corresponding target genes DE genes in MSCs treated with S100A8/A9 versus non-treated MSCs are depicted in blue (up-regulated) or red (downregulated). in light green. S100A8/A9 treated MSCs fundamentally switch their transcriptome to fast healing mode. Accordingly, the dramatic change in the transcriptome enforces a well-controlled influx of inflammatory cells which are predicted to be involved in the suppression of an unrestrained immune response and, importantly, in cleaning up the wound site (IL-32, MSTR1, C3a). In fact, activation and phagocytotic properties of macrophages are enhanced by the alternate complement system and activation of PI3 kinase upon binding of MSTR1 to its ligand. The debridement of the wound site is complemented by controlled activation of proteases and their inhibitors. At the same time, synthesis and deposition of a fetal repair like extracellular matrix (ECM) (e.g. SPARC encoded by SPOCK2) is promoted, while genes encoding distinct extracellular matrix proteins involved in scar formation are suppressed. This unique ECM signature is further implemented by the control of factors impacting on the proteoglycan rich ECM. ECM synthesis, in addition to angiogenesis, re-epithelialization and overall niche protection are highly energy consuming processes. Therefore energy homeostasis and the availability of sufficient ATP is a necessary request which according to the transcriptome is fully available. In consequence, accelerated tissue repair of wounds injected with S100A8/A9 treated MSCs is even better when compared to the already accelerated healing of wounds treated with control MSCs and, thus, holds substantial promise to be translated to clinical routine. The switch of the transcriptome of MSCs by danger molecules like S100A8/A9 may also be beneficial for the treatment of fibrotic conditions including hypertrophic scar formation. Teff, effector Tcells; Treg, regulatory T cells.