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

PI: K. Scharffetter-Kochanek

The aim of this proposal is to characterise the role of distinct multipotent mesenchymal progenitor-/stem cell populations (MSCs) of the skin with particular focus on the newly identified dermal ABCB5+ MSC subset on niche homoeostasis and tissue repair following full thickness skin trauma in acute wounds, iron overload wounds after severe haemorrhagic soft tissue trauma alone or in combination with an additional severe chest trauma, a strong inducer of posttraumatic systemic inflammation. Specifically, we will address the interaction of skin ABCB5+ MSCs and conventional skin adipose tissue derived MSCs (AT-MSCs) with stimulated pro-inflammatory M1 macrophages and activated neutrophils as occurring in acute and iron overload wounds in combination with contusive chest trauma and identify 1.) afferent mechanisms sensing wound site and systemic inflammation and 2.) efferent responses via paracrine factors and mitochondria transfer by which MSCs may redirect their niche homoeostasis and tissue repair/regeneration in human skin wounds. Vice versa, the effect of a pro-inflammatory macrophage and neutrophil dominated inflammation on MSC subsets will be evaluated in terms of their stress resistance, apoptosis, DNA damage-induced senescence under conditions of IGF-1 depletion / resistance as occurring in acute, iron overload cutaneous wounds and posttraumatic systemic inflammation. This project strongly supports the aims of the here suggested collaborative research centre in that it will delineate the effect of danger signals and the adaptive response of MSCs to the posttraumatic inflammation. This approach will advance our knowledge for the meaningful application of MSC-based therapies for acute tissue injury, iron-overload (severe soft tissue haemorrhage) and chest trauma with the goal to control unrestrained inflammation and promote scar-reduced wound healing. Importantly, the here suggested experiments will advance our understanding of the endogenous MSC niche in uninjured and wounded skin. This knowledge holds substantial promise to manipulate endogenous MSCs in favour of improved tissue regeneration under various traumatic conditions.

Video

Projektleiter

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).