2D-cultured MSCs Suppress Pro-Inflammatory Phenotypes of Human M1 Macrophages, while 3D-cultured MSCs Enhance Anti-Inflammatory Phenotypes of Human M2c Macrophages
In chronic diabetic wound beds, myeloid cells dysregulate recruitment and circulation, due to hyperglycemia environment and lack of blood supply. The dysfunction of macrophages causes pro-longed inflammation. As a result, epithelial cell proliferation and tissue remodeling are halted. One challenge to treating chronic wounds is decreasing inflammation to promote tissue remodeling. While synthesized biomaterial grafts have the risk of causing foreign body reactions, cell therapies have been brought to interests, including immuno-modulatory mesenchymal stromal cells. Macrophages involved in wound healing are divided into two major subclasses: pro-inflammatory M1s, which produce TNF-α and kill pathogens, and anti-inflammatory M2s, which produce IL-10, clean debris, and promote phagocytosis and angiogenesis. Enlighteningly, previous studies have shown that 3D-cultured human mesenchymal stromal cells (MSCs) have the potential to alter murine macrophage phenotypes through PGE2 signaling. In this study, the influences of 2D- and 3D-cultured human MSCs on primary human macrophages and their subclasses were investigated. The results suggested that different culturing methods resulted in different immunomodulatory phenotypes—2D-cultured MSCs suppressed the M1 phenotype, while 3D-cultured MSCs enhanced the M2 phenotype. 3D-cultured MSCs promoted not only the gene expression of IL-10 and CD206, but also the phagocytic ability of M2 macrophages. Moreover, extracellular PGE2 signals produced by 3D-cultured MSCs were determined to be necessary to induce upregulation of M2 phenotypes.