Transplantation of Ex Vivo Amplified Mononuclear Cells From Peripheral Blood Improves Rat Pulmonary Hypertension via CD14 ‐ and CD163 ‐Positive M2 Macrophages

Background and Objective The progression of pulmonary arterial hypertension (PAH) is associated with pulmonary artery (PA) remodelling by M2 macrophages through excessive tissue repair, although some M2 macrophages have a vascular protective role. A quality and quantity culture method (MNC‐QQc) increases the number of M2 macrophages in mononuclear cells (MNCs) from peripheral blood. Several studies demonstrate that MNC‐QQc has vascular protective effects in ischemic lesions. This study aimed to investigate whether MNC‐QQc transplantation ameliorates PAH development in a rat model. Methods MNC‐QQc extracted from GFP positive donor rats were administered into recipient rats with PAH via the cervical vein. Pulmonary haemodynamics and PA remodelling were assessed. Immunohistochemistry and flow cytometry analysis were performed to identify the donor‐derived MNC‐QQc cell types in the lungs. The effects of MNC‐QQc on the functions of vascular constituent cells were evaluated, and gene expression related to the pathological abnormalities in PA was assessed using microarray analysis. Results MNC‐QQc transplantation reversed the PAH‐induced pulmonary haemodynamics and PA remodelling. GFP‐positive MNC‐QQc cells, predominantly CD14‐positive M2 macrophages, were found around the recipient's PAs. The therapeutic effect was reduced in MNC‐QQc without M2 cells. MNC‐QQc also enhanced angiogenesis in pulmonary endothelial cells. Microarray analysis of the lung tissue showed that MNC‐QQc decreased the expression of Tachykinin Receptor 1, associated with PAH progression, with this reduction linked to CD14‐ and CD163‐positive M2 macrophages. Conclusions These findings suggest that MNC‐QQc, particularly through CD14‐ and CD163‐positive M2 macrophages, could be a novel treatment for PAH.