William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
J Cardiol. 2019 Oct;74(4):304-312. doi: 10.1016/j.jjcc.2019.04.006. Epub 2019 May 18.
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.
肺动脉高压（PAH）是一种以进行性肺血管重构为特征的疾病，导致右心衰竭和过早死亡。目前可用的 PAH 治疗方法疗效有限，需要开发新的治疗策略。间充质干细胞（MSCs）可能为 PAH 提供一种新的治疗方法。自 2006 年首次报道以来，许多临床前研究已经证明了这种方法的潜在治疗效果，在 PAH 动物模型中，PAH 的血流动力学和组织学进展得到了减弱。然而，这种方法要在临床上取得成功，仍有几个问题需要解决。为了突出这些问题，本综述阐明了间充质干细胞治疗 PAH 的临床前研究中的现有知识，包括用于 MSC 治疗的 PAH 动物模型的类型、MSC 来源和管理方案（途径、细胞剂量和给药时间）。本综述随后全面总结并讨论了间充质干细胞治疗 PAH 的机制。为了使 MSC 治疗取得临床成功，还需要解决一些问题，例如安全性证据不足（例如肺栓塞的严重风险）、MSC 对严重血管重构的已建立 PAH 的治疗效果，以及进一步优化 MSC 给药方案。就疗效而言，作为 MSC 治疗机制之一的血管生成细胞因子是否对人类 PAH 有益，这是有争议的。为了解决这些问题，应该使用更具临床相关性的 PAH 动物模型（如 SU5416 模型）积累更多的临床前数据，而大多数临床前研究都是使用单克隆抗体诱导的 PAH 模型进行的。虽然 MSC 治疗有很大的潜力成为 PAH 的一种新疗法，但为了在 PAH 中取得临床成功，继续进行仔细的临床前研究是有必要的。
