Anti-inflammatory myeloid angiogenic cells (MIL4-MACs) attenuate angiotensin II‒induced heart failure in mice

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.