Abstract
We here investigated whether the unique capacity of mesenchymal stem cells (MSCs) to re-establish tissue homeostasis depends on their potential to sense danger associated molecular pattern (DAMP) and to mount an adaptive response in the interest of tissue repair. Unexpectedly, after injection of MSCs which had been pretreated with the calcium-binding DAMP protein S100A8/A9 into murine full-thickness wounds, we observed a significant acceleration of healing even exceeding that of non-treated MSCs. This correlates with a fundamental reprogramming of the transcriptome in S100A8/A9 treated MSCs as deduced from RNA-seq analysis and its validation. A network of genes involved in proteolysis, macrophage phagocytosis, and inflammation control profoundly contribute to the clean-up of the wound site. In parallel, miR582-5p and genes boosting energy and encoding specific extracellular matrix proteins are reminiscent of scar-reduced tissue repair. This unprecedented finding holds substantial promise to refine current MSC-based therapies for difficult-to-treat wounds and fibrotic conditions.
Highlights
In aggregate, we here uncovered that mesenchymal stem cells (MSCs) when exposed to the danger signal molecule S100A8/A9 raise a beneficial adaptive response with accelerated wound healing
Growth differentiation factor GDF9 normally highly expressed in fibroproliferative conditions as in keloids and hypertrophic scars[65] is significantly reduced further underscoring the antifibrotic signature of the transcriptome of S100A8/A9 treated MSCs. These findings are important as we found a substantial increase in re-epithelialization in wounds injected with S100A8/A9 primed MSCs as opposed to PBS injected wounds or MSC injected wounds (Supplementary Fig. 2 and 3)
We here uncovered that MSCs when exposed to the danger signal molecule S100A8/A9 raise a beneficial adaptive response with accelerated wound healing
Summary
We here uncovered that MSCs when exposed to the danger signal molecule S100A8/A9 raise a beneficial adaptive response with accelerated wound healing. The underlying transcriptome signature is novel and, importantly, extends the previously coined MSC property of a “drug store”[74] to the clinically most relevant “adaptive drug store” which is advantageous over the delivery of defined recombinant factors in that MSCs can sense their environment and within short time adapt their transcriptome for the sake of tissue renewal and homeostasis. It is possible that other mechanisms of triggering activation of the MSCs enhance wound healing, and would support the idea of an “adaptive drug store”. This may hold for LPS, a wall constituent of gram-negative bacteria, which acts through the same TLR4 receptor. It will be interesting to see whether this, is the case, and if so whether an identical or a clearly distinct expression profile is induced by LPS as opposed to S100A8/A9
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