Mouse Bone Marrow-Derived Mesenchymal Stromal Cells Turn Activated Macrophages into a Regulatory-Like Profile

Abstract

In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-α, IL-6, IL-12p70 and interferon-γ while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE2 we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-α and IL-6 by activated M. MSC also inhibited the up-regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Iab and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens.

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

“…Recent works showed slower phagosome maturation for M1 than M2a Ms [36] serving as an explanation for the delayed particle uptake by M1 compared to M2a macrophages. Increased zymosan and apoptotic thymocyte phagocytosis by mouse Ms in the presence of MSCs was described by Maggini et al [30].…”

“…However, the effect of MSCs on M functions has not clearly been explored yet. So far, the majority of studies have used adherent cells from peritoneal exudates or spleen isolates [30,31]. Using the standard method for M isolation from the mouse peritoneum based on plastic adherence [22], these cultures contain at least 5-10% of non-M cells [25,32] [13,17,35].…”

Therapeutic Potential of Gingival Fibroblasts for Cutaneous Radiation Syndrome: Comparison to Bone Marrow-Mesenchymal Stem Cell Grafts

“…Recruited macrophages induce granulation tissue and myofibroblast differentiation during the early stage of the repair and are crucial for the stabilization of vascular structures and the transition of granulation tissue to scar tissue during intermediate stages of repair [28]. MSCs are involved in reprogramming macrophages to an M2 phenotype, through their IL-10 production; they thus enhance wound healing [38]. An important point demonstrated by Horton et al is that the bone marrow-derived MSC infusion that slows or stops the progression of radiation-induced cutaneous fibrosis is associated with the presence of CD163 + macrophages [39].…”

La biologie des cellules souchesmésenchymateuses d’origine humaine

“…Par génie génétique, ces auteurs ont spécifiquement détruit les cellules transplantées selon leur phé-notype pour définir l'implication respective de chacune des populations. L'implication de l'activité paracrine des CSM est beaucoup plus facile à démontrer par interférence ARN, ce qui a permis d'identifier de nombreuses molécules telles que les facteurs angiogéniques ou antifibrotiques ou des molécules capables de moduler l'état immunitaire et inflammatoire [6,36]. Il paraît hautement improbable qu'une seule de ces molécules soit responsable de l'ensemble de ces effets.…”