Schmuck Eric G, Hacker Timothy A, Schreier David A, Chesler Naomi C, Wang Zhijie
Department of Medicine, University of Wisconsin , Madison, Wisconsin.
Department of Biomedical Engineering, University of Wisconsin , Madison, Wisconsin.
Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1005-H1013. doi: 10.1152/ajpheart.00091.2018. Epub 2019 Mar 1.
Right ventricular failure (RVF) is a common cause of death in patients suffering from pulmonary arterial hypertension (PAH). The current treatment for PAH only moderately improves symptoms, and RVF ultimately occurs. Therefore, it is necessary to develop new treatment strategies to protect against right ventricle (RV) maladaptation despite PAH progression. In this study, we hypothesize that local mesenchymal stem cell (MSC) delivery via a novel bioscaffold can improve RV function despite persistent PAH. To test our hypothesis, we induced PAH in adult rats with SU5416 and chronic hypoxia exposure; treated with rat MSCs delivered by intravenous injection, intramyocardial injection, or epicardial placement of a bioscaffold; and then examined treatment effectiveness by in vivo pressure-volume measurement, echocardiography, histology, and immunohistochemistry. Our results showed that compared with other treatment groups, only the MSC-seeded bioscaffold group resulted in RV functional improvement, including restored stroke volume, cardiac output, and improved stroke work. Diastolic function indicated by end-diastolic pressure-volume relationship was improved by the local MSC treatments or bioscaffold alone. Cardiomyocyte hypertrophy and RV fibrosis were both reduced, and von Willebrand factor expression was restored by the MSC-seeded bioscaffold treatment. Overall, our study suggests a potential new regenerative therapy to rescue the pressure-overload failing RV with persistent pulmonary vascular disease, which may improve quality of life and/or survival of PAH patients. NEW & NOTEWORTHY We explored the effects of mesenchymal stem cell-seeded bioscaffold on right ventricles (RVs) of rats with established pulmonary arterial hypertension (PAH). Some beneficial effects were observed despite persistent PAH, suggesting that this may be a new therapy for RV to improve quality of life and/or survival of PAH patients.
右心室衰竭（RVF）是肺动脉高压（PAH）患者常见的死亡原因。目前针对PAH的治疗仅能适度改善症状，最终仍会发生RVF。因此，有必要制定新的治疗策略，以防止右心室（RV）在PAH进展的情况下出现适应不良。在本研究中，我们假设通过新型生物支架进行局部间充质干细胞（MSC）递送，尽管PAH持续存在，仍可改善RV功能。为了验证我们的假设，我们通过SU5416诱导成年大鼠患PAH并使其长期暴露于低氧环境；分别通过静脉注射、心肌内注射或生物支架的心外膜放置给予大鼠MSC进行治疗；然后通过体内压力-容积测量、超声心动图、组织学和免疫组织化学检查治疗效果。我们的结果表明，与其他治疗组相比，只有接种MSC的生物支架组导致RV功能改善，包括恢复每搏输出量、心输出量和改善每搏功。局部MSC治疗或单独使用生物支架可改善由舒张末期压力-容积关系所表明的舒张功能。心肌细胞肥大和RV纤维化均减轻，接种MSC的生物支架治疗可使血管性血友病因子表达恢复。总体而言，我们的研究提示了一种潜在的新的再生疗法，可挽救伴有持续性肺血管疾病的压力超负荷衰竭RV，这可能改善PAH患者的生活质量和/或生存率。新发现与值得注意之处我们探讨了接种间充质干细胞的生物支架对已患肺动脉高压（PAH）大鼠右心室（RV）的影响。尽管PAH持续存在，但仍观察到一些有益效果，这表明这可能是一种改善RV功能、提高PAH患者生活质量和/或生存率的新疗法。
