Differentiation of mesenchymal stem/stromal cells into CD45⁺ macrophage-like cells: expanding insights into MSC plasticity

Mesenchymal stem/stromal cells (MSCs) are notable for their differentiation potential and immunomodulatory properties. They share several features with macrophages as well as fibrocytes. This study aimed to investigate the relationship between MSCs, fibrocytes, and macrophages, focusing on the hypothesis of a possible direct lineage. Particularly, the focus lies on a freshly isolated murine MSC population known as PαS cells, which were transplanted into irradiated recipients, resulting in cells expressing a macrophage-like phenotype with CD45, CD68, and CSF1R (also known as CD115) expression. Further analysis showed that PαS cells cultured in macrophage differentiation media acquired characteristics of M2 macrophages (CD45, CD68, and CD206) through interaction with CSF1R. These results were confirmed in several mouse strains and human MSCs. Single-cell RNA sequencing revealed macrophage-like populations among the PαS cells, demonstrating the phenotypic plasticity of non-cultured MSCs, giving into MSC potential roles in immune regulation and tissue repair.