Mesenchymal stem/stromal cell therapy for pulmonary arterial hypertension: Comprehensive review of preclinical studies.

Pulmonary arterial hypertension (PAH) is a disease characterized by progressive pulmonary vascular remodeling, resulting in right-sided heart failure and premature death. Current available therapies for PAH have limited efficacy, and new therapeutic strategies need to be developed. Mesenchymal stem/stromal cells (MSCs) may offer a novel therapeutic approach to PAH. Since the first report in 2006, a number of preclinical studies have demonstrated a potential therapeutic effect of this approach, with attenuated hemodynamic and histological progression of PAH, in animal models of PAH. However, there remain several issues that should be addressed for this approach to be clinically successful. With the aim to highlight such issues, this review clarifies existing knowledge on MSC therapy for PAH in preclinical studies, including types of PAH animal models used for MSC therapy, MSC sources, and administration protocol (route, cell dose, and timing of administration). This review thereafter summarizes thoroughly and discusses the mechanism underpinning MSC therapy for PAH. For clinical success of MSC therapy, insufficient evidence of safety (e.g. critical risk of pulmonary embolism) and therapeutic efficacy of MSCs on established PAH with severe vascular remodeling, as well as further optimization of the MSC administration protocol, are considered as remaining issues to be addressed. In terms of the efficacy, it is controversial whether angiogenic cytokines, which are considered as one of the therapeutic mechanisms of MSC, have beneficial effect for human PAH. To address these issues, further preclinical data using more clinically-relevant animal models of PAH, such as SU5416 model, should be accumulated, whereas most preclinical studies have been conducted using monocrotaline-induced PAH model. While MSC therapy has a great potential to become a novel therapy in PAH, continuing careful preclinical research is warranted for clinical success in PAH.