S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes.

Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10- and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.

MRT-measurements of muscle volumes of the lower extremities of youths with spastic hemiplegia caused by cerebral palsy.

After long term of studies from our gait lab, the typical muscular dysbalances by all of our patients with cerebral palsy where pointed out. Now we wanted to examine using the MRT, weather the dysbalances of the hemiparetic musculoskeletal system also show up in discrepancies of the muscle volumes. The MRT slices of the lower extremities were segmented. From this cross sections the muscles volumes were derived. These where analyzed particularly with regard to asymmetries between spastic and healthy side. Hemiparetic patients showed reduced volumes of all muscles on the paretic leg in comparison to the healthy side. The muscles of the thigh of the paretic leg were reduced to 84% in the mean over all muscles and in comparison to the healthy leg. The volume of the muscles of the shank was reduced to 72%, significantly more than the muscles of the thigh. Concerning flexor and extensor muscles located at thigh and shank of the paretic leg there was found significantly the same relative deficit of the muscle volume. Examining the muscle volumes of subjects with different neurogene foot deformities, significant differences of the volume reduction of single muscles appeared within the lower leg.