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Pulmonary arterial hypertension (PAH) is a refractory disease characterized by progressive pulmonary vascular remodelling, increased pulmonary vascular resistance, and ultimately right heart failure. Significant advances have been made in the treatment of PAH with the development of pulmonary vasodilators targeting the endothelin, NO–cGMP, and prostacyclin pathways. However, these therapies primarily address vasoconstriction and do not reverse the underlying structural vascular remodelling [1]. Recently, sotatercept has emerged as a novel therapy that modulates the imbalance in the TGF-β pathway and has been shown to ameliorate PAH [2]. Despite these therapeutic developments, disease progression continues in some patients with PAH, necessitating invasive interventions such as lung transplantation. Therefore, establishing therapeutic strategies capable of reversing pulmonary arterial remodelling in patients with PAH who are resistant to existing therapies remains an urgent priority. In a recent publication in Respirology, Suzuki and colleagues report an intriguing study exploring the therapeutic potential of a novel cell therapy involving the transplantation of peripheral blood mononuclear cells cultured under ex vivo quality and quantity control (QQc) conditions (MNC-QQc) [3]. Their work identifies a new mechanism involving CD14- and CD163-positive M2 macrophages and suggests a promising new direction for PAH treatment. The study by Suzuki et al. focuses on phenotypic changes in peripheral blood mononuclear cells (PBMNCs) when placed in a specific ex vivo culture environment (QQc). Previous studies of macrophages in PAH have suggested that while M1 macrophages promote inflammation, M2 macrophages may be associated with excessive tissue repair and fibrosis, potentially contributing to pulmonary arterial remodelling [4]. However, Suzuki and colleagues emphasize that the M2 macrophage population is heterogeneous and that certain subsets possess vascular-protective and regenerative properties. Using the MNC-QQc method, they successfully increased the proportion of CD163-positive M2 macrophages, a key cellular component of the transplanted cell population. In experiments using a rat PAH model (Sugen 5416/hypoxia), systemic administration of these cultured cells significantly improved abnormal pulmonary hemodynamics and pulmonary arterial remodelling. A major strength of this study lies in the identification of the specific cell population responsible for the therapeutic effects. GFP-positive transplanted MNC-QQc cells were shown to accumulate around remodelled pulmonary arteries in recipient rats. Most importantly, depletion of M2 macrophages prior to transplantation markedly attenuated the therapeutic effects of MNC-QQc. This finding confirms that CD14- and CD163-positive M2 macrophages are the principal mediators of vascular reverse remodelling in this model. Interestingly, therapeutic improvement was still observed even when endothelial progenitor cells (EPCs) were depleted. In contrast to previous studies of cell therapy using EPCs [5], this finding suggests that M2 macrophages play a more dominant role than EPCs in mediating the therapeutic effects of MNC-QQc in PAH. Furthermore, the study demonstrated that MNC-QQc promotes angiogenesis in pulmonary microvascular endothelial cells. This paracrine effect likely contributes to stabilization of the fragile pulmonary microvasculature. In addition, microarray analysis identified significant suppression of TACR-1 expression in the lung tissues of rats treated with MNC-QQc. Suppression of TACR-1 signalling by M2 macrophages suggests a potential new therapeutic target pathway. Exploring the crosstalk between these regenerative macrophages and other cells in the pulmonary vascular niche will be essential for further understanding the ‘healing’ process in pulmonary arteries. The study by Suzuki et al. is particularly attractive because autologous peripheral blood can serve as the source for cell therapy. The QQc method enables the rapid generation of regenerative cell populations from a simple blood draw, suggesting the potential for a scalable therapeutic strategy. However, several challenges remain before clinical translation can be achieved. While rat PAH models are relatively homogeneous, human PAH represents a heterogeneous group of conditions involving diverse pathogenic mechanisms. Further investigation, including clinical trials, will be required to determine whether this approach is effective in the advanced remodelling states observed in human PAH. Additionally, the long-term survival of the transplanted cells remains unclear. It will also be important to carefully evaluate the long-term role of M2 macrophages in the human lung and whether they might contribute to excessive fibrosis over time. Nevertheless, this study by Suzuki and colleagues represents an important step forward in the exploration of regenerative medicine for PAH. The authors have identified MNC-QQc as a promising therapeutic candidate. As pulmonary vascular medicine increasingly shifts toward more personalized biological approaches, this work provides an important framework for harnessing regenerative capacity to combat this devastating disease. The transition of MNC-QQc therapy from ‘bench to bedside’ may offer new hope for patients with pulmonary arterial hypertension, and its future development deserves close attention. The author has nothing to report. The author declares no conflicts of interest.