MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism

Abstract

Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials (immunomodulatory, anti-bacterial, anti-inflammatory, anti-oxidant defenses and metabolic adaptation…) and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation.

Keywords: cell therapy; immunomodulation; inflammation; macrophage; mesenchymal stromal cells (MSCs); metabolic reprogramming; regenerative medicine.

Figure 1

MSCs and inflammatory response: dual effect on induction and resolution of the inflammation. In the initial phase of the inflammatory process, MSCs actively participate to neutrophil attraction (IL8, MIF secretion) for anti-bacterial effect and clearance of tissue debris. This initial phase is required to further promote tissue recovery and repair. MSCs also have decisive effects on the switch from this inflammatory phase to its resolution necessary to initiate tissue reconstruction. MSCs thus favor granulocyte recruitments through cytokines (CCL2, CCL3, CCL12), induce M2 polarization (PGE2, IDO, TSG6) as well as Th1/Th17 balance.

Figure 2

Description of the metabolic immuno-mesenchymal axis. Macrophages can be activated to polarize into M1 phenotype driving the inflammatory response upon cell damage or tissue failure. This phenotype is associated with a glycolytic metabolism and the production of multiple inflammatory and oxidative signals detected by MSCs through different way of communication. MSCs react by functional adaptations of their metabolic and immune functions but will basically induce macrophage switch into a M2 phenotype associated with their metabolic reprograming and develop immunosuppressive and regenerative activities.