Akifumi Matsuyama

For cell therapy to treat heart failure, therapeutic cells should possess the abilities to promote vascularization, remodel tissues, and reduce inflammation. Previously we clarified that CD14+-derived myeloid angiogenic cells (MACs) possessed an angiogenic ability. In this paper, we induced strong high anti-inflammatory and tissue-remodeling properties in CD14+ cells by adding both M-CSF and interleukin-4 to the endothelial medium. This culture condition produced a higher number of adherent cells than MACs and exhibited greater angiogenic capability; we named these cells 'MIL4-MACs'. Through analysis of cytokine production, gene expression, and membrane markers, MIL4-MACs were characterized as anti-inflammatory cells, with lower expression of HLA-Class Ⅱ and higher expression of PD-L1 and PD-L2 compared to MACs. Mixed lymphocyte reaction analysis showed that T cells did not attack MIL4-MACs. Moreover, MIL4-MACs expressed active-matrix metalloproteinase-9 on their surface and had high collagen-degrading activity. Administration of MIL4-MACs improved angiotensin Ⅱ‒induced severe cardiac failure and attenuated cardiac fibrosis in mice. These data indicate that the anti-inflammatory, angiogenic, and remodeling properties of MIL4-MACs may represent a novel candidate for cell therapy in heart failure.