Macrophages at the nexus of mesenchymal stromal cell potency: The emerging role of chemokine cooperativity

Abstract

Pharmacological depletion of macrophages in vivo with liposomal clodronate renders mice unresponsive to adoptive transfer of mesenchymal stromal cells (MSCs) for affecting outcomes of acute inflammatory pathology. This experimental observation identifies host macrophages as necessary in mediating the salutary anti-inflammatory properties of MSCs as a cellular pharmaceutical. This theory is supported by the observation that transfusion of MSCs leads to the prompt phagocytosis of nearly half of lung entrapped MSCs by lung resident macrophages, triggering an interleukin (IL)-10 suppressive efferocytotic response. In addition, non-phagocytosed MSCs with COX2 competency shape the immune milieu by inducing tissue macrophages to express IL-10. Additional experimental evidence identifies MSC-borne IL-6, IDO and TSG-6 as directly involved in macrophage polarization. Along similar lines of functional convergence, implantation of CCL2⁺ MSCs in the extravascular space where interaction with lung resident perivascular macrophages is not operative, also leads to IL-10 polarization of CCR2⁺ macrophages within acute injured tissue far removed from MSC depot. Intriguingly, MSC-derived CCL2 on its own is not sufficient to polarize macrophages and requires heterodimerization with MSC-borne CXCL12 to trigger macrophage IL-10 polarization via CCR2, but not CXCR4. Such chemokine cooperativity opens a new venue for analysis of MSC potency especially considering the rich chemokine secretome of MSC exposed to inflammatory stimulus. As an aggregate, these data highlight a necessary MSC and host macrophage functional dyad that may inform potency attribute analysis of MSCs-including the chemokine interactome-that may be directly linked to in vivo clinical anti-inflammatory and regenerative response.

Keywords: CCL2; CCR2; IL-10; chemokine; efferocytosis; macrophage; mesenchymal stem/stromal cell; monocyte.

FIGURE 1

Hypothetical and verified chemokine heterocomplexes from mesenchymal stromal cell (MSC) secretome. Human and mouse chemokines identified in MSC secretome (blue) and following PBMC co‐culture (red) which have been found in silico to predictably form heterocomplexes are linked by blue lines. CXCL4 is not expressed by MSCs but shown here with predicted partners found in MSC secretome. The CCL2/CXCL12 dyad was validated experimentally in mouse MSC system and shown linked in red