A Novel S100A8/A9 Induced Fingerprint of Mesenchymal Stem Cells associated with Enhanced Wound Healing

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.

Novel trends in application of stem cells in skin wound healing

“…Similarly, human ADSCs co-cultured with endothelial cells on collagen peptide bioscaffold accelerated wound closure on irradiated mice model (Mashiko et al, 2018). Unexpectedly, MSCs pretreated with S100A8/A9 (protein complex belonging to danger associated molecular patterns recognized by immune system) accelerated murine wound healing to the greater extent, than MSCs alone (Basu et al, 2018).…”

Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing

“…Although S100A8/A9 (MRP8/14), a DAMP and an endogenous TLR4 ligand, primed AT-MSCs also lead to accelerate wound healing, the adaptive response of MSCs to S100A8/A9 is quite different when compared to that to LPS priming (Basu et al, 2018). Changes in the transcriptome of LPS primed MSCs enhance mainly the numbers and the activity of neutrophils, and thereafter in the second instance macrophages are activated following engulfment of apoptotic neutrophils with enhanced release of TGF-β1 (Munir et al, 2020).…”

“…By contrast, in S100A8/A9 primed MSCs mainly a transcriptome responsible for "the big clean up" of tissue debris at the wound site was observed with increased expression of MSCs genes which upon release of the encoded proteins enhance the phagocytotic capacity of macrophages. In addition, genes enhancing niche protection and energy homeostasis most likely play a major role in accelerating wound healing after injection of S100A8/A9 primed MSCs (Basu et al, 2018). It would be interesting to tease out how MSCs are able to mount distinct adaptive responses in their transcriptome through TLR4 in a ligand-specific manner.…”

“…Accumulating evidence suggests that MSCs are endowed with the capacity for environmental sensing during granulation tissue formation and are able to mount adaptive responses, a superior property compared to conventional chemical-based or recombinant growth factor-based therapies (Basu et al, 2018;Vander Beken et al, 2019;Jiang et al, 2020b;Munir et al, 2020). This adaptive property allows for refinement of MSC-based therapies in near future.…”

Mesenchymale Stromazellen auf dem Weg zur klinischen Anwendung: Update 2018

“…Das veränderte Zytokin-und Chemokinmilieu fördert zudem die dermale Regeneration [47]. Ganz aktuelle Daten deuten an, dass lokale Danger-Signale MSC derart programmieren können, dass ihre therapeutische Wirkung auf die Wundheilung noch gesteigert wird [48].…”