C5: Role of ABCB5+ MSCs in niche homoeostasis and repair after trauma

PI: K. Scharffetter-Kochanek

Mesenchymal stem cells (MSCs) are essential for tissue regeneration and repair. Most likely, though not fully understood, MSCs are able to sense their environment, to adaptively respond and to influence local and systemic inflammation occurring in severe tissue trauma. In the last CRC period, we found that priming of MSCs with trauma released DAMPs or PAMPs like the calcium-binding S100A8/A9, the bacterial cell wall component LPS, or the master growth factor TGFβ1 result in fundamental changes of the transcriptional profile of MSCs which are distinct and depend on the priming agent. Interestingly, in case of injection of S100A8/A9 or LPS primed MSCs into full thickness wounds, improved wound healing was observed by an unexpected acceleration of 60% when compared to PBS injected or MSC injected control wounds. Also combined chest- and skin trauma resulted in the release of distinct soluble factors and a profound increase in healing of skin wounds. We are now highly interested to dissect the underlying mechanisms of the adaptive MSC response to S100A8/A9 as opposed to LPS, to study whether MSC priming also enhances healing of other organs like bone fracture and peripheral nerve injury (A01, C01, C06), to better understand a potential hierarchy of adaptive responses when MSCs are exposed to different DAMP and PAMP factors which are concomitantly released in traumatic conditions, and to dissect the mechanism of endogenous MSC priming after chest trauma. In the model of combined chest and skin trauma, priming by trauma induced danger molecules with mobilization of MSCs from the bone marrow and subsequent homing to skin wounds will be studied as opposed to priming of the endogenous MSC niche at the site of skin wounds. Likewise, we will assess whether distinct metabolic states of primed MSCs impact on the inflammatory cells within the wound. Experimental data thereof will help to develop refined MSC-based therapeutic strategies.

Projektleiterin

Prof. Dr. med. Karin Scharffetter-Kochanek
Universitätsklinikum Ulm
Klinik für Dermatologie und Allergologie
Albert-Einstein-Allee 23
89081 Ulm
Tel.: +49 731 500 57501
Fax: +49 731 500 57502
karin.scharffetter-kochanek(at)uniklinik-ulm.de

Human neutrophils (Neu), if stimulated by infectious agents or PMA release neutrophil extracellular traps (NETs, red) as a defence mechanism against pathogens. However, unrestrained activation of Neutrophils with uncontrolled NET formation can contribute to severe damage of tissues and organs, in particular as NETs bind different proteases. We are interested in the potential of MSCs to down regulate NET formation in sterile inflammation and thus protect from tissue damage. Of note, stimulated Neutrophils cocultured with Mesenchymal Stem Cells (MSC) reveal reduced NET formation. Nuclei are stained with DAPI (blue).