Biology session

Recently, bone-marrow derived mesenchymal stem- or stromal cells (BM-MSC) have been subjects to several researches due to their ability to support hematopoiesis, promote tissue maintenance and regeneration and inhibit inflammatory and immune processes. MSCs are promising targets in the treatment of certain inflammatory and/or autoimmune diseases, such as acute graft versus host disease or Chron-disease. Little is known, however, about the interaction between BM-MSCs and macrophages (MP), therefore, in our work we aimed to clarify the functional consequences resulting from the relationship between these cell types, especially the changes resulting from possible alterations in the phagocytic activity and cytokine production. Since MSCs derived from the more easier accessible adipose tissue (AD-MSC) are also capable of exerting a highly similar immunomodulatory effect in the body as BM-MSCs, we aimed to investigate the similarities and/or differences between the effects of these two cell types on MPs as well.

We used MSC cultures established from the bone marrow and adipose tissue of 10-12 weeks old mice. MPs were isolated from the peritoneal cavity of mice of the same age. We measured the intensity of yeast- or apoptotic cell (steroid-treated thymocyte) phagocytosis of MPs incubated in cultures with or without MSCs for 48 hours, while the levels of TNFa (an inflammatory cytokine), IL-10 (an anti-inflammatory cytokine) and PGE2 in the culture supernates were determined. The same experiments were repeated using bacterial endotoxin (LPS) stimulated MPs. We found that both BM- and AD-MSCs were capable of enhancing the phagocytic activity of MPs, concurrently significantly altering the ratio of secreted cytokines in the culture supernates: while levels of TNFa was not affected in general, elevated levels of IL-10 could be observed, thus suggesting that MPs tend to show an anti-inflammatory (M2 or „alternative”) phenotype instead of a „classical” pro-inflammatory (M1) phenotype in the presence of MSCs. Polarization of MPs towards an M1 phenotype upon in vitro LPS activation was also hindered by the stromal cells. This effect was strongly mitigated in the presence of indomethacin, a specific prostaglandin synthesis inhibitor, moreover, the concentration of PGE2 in the culture supernates increased in parallel with IL-10 levels indicating that PGE2 can be an important mediator in the MSC-MP interaction.

Our results therefore show that MSCs, regardless of their tissue of origin (bone marrow or adipose tissue), are capable of facilitating the polarization of MPs towards the „alternative” (M2) phenotype while inhibiting the development of the „classical” – or pro-inflammatory – (M1) phenotype. This can play a pivotal role in the in vivo observed strong anti-inflammatory effect of MSCs.