Effects of human umbilical cord mesenchymal stem cells(MSCs)-derived exosomes on pulmonary vascular remodeling in hypoxic pulmonary hypertension
The present study aimed to investigate the effect of human umbilical cord mesenchymal stem cells(MSCs)-derived exosomes(MSCs-Exo)on mice with hypoxic pulmonary hypertension(HPH).MSCs were isolated and cultured from human umbilical cords under aseptic conditions,and exosomes were extracted from the supernatants and identified.Healthy SPF C57BL/6 mice were randomly divided into three groups:normoxic group,hypoxic group,and hypoxic+MSCs-Exo group.Mice in the hypoxic group and the hypoxic+MSCs-Exo group were maintained for 28 d at an equivalent altitude of 5 000 m in a hypobaric chamber to establish HPH mouse model.The mice in the hypoxic+MSCs-Exo group were injected with MSCs-Exo via tail vein before hypoxia and on days 1,3,5 and 9 of hypoxia,and the mice in the other two groups were injected with PBS.At the end of the experiment,echocardiography was performed to detect pulmonary arterial acceleration time/pulmonary arterial ejection time ratio(PAAT/PET),right ventricular free wall thickness,and right ventricular hypertrophy index RV/(LV+S).HE staining was performed to observe the lung tissue morphology.EVG staining was performed to observe elastic fiber hyperplasia.Immunohistochemistry was performed to detect α smooth muscle actin(α-SMA)expression in lung tissue.Immunofluorescence staining was used to detect macrophage infiltration in lung tissue.qPCR was performed to detect IL-1β and IL-33 in lung tissue,and cytometric bead array was performed to detect IL-10 secretion.Western blotting was used to detect the M1 macrophage marker iNOS,M2 macrophage marker Arg-1 and IL-33/ST2 pathway proteins in lung tissues.The results showed that hypoxia increased pulmonary artery pressure and pulmonary vascular remodeling,increased macro-phage infiltration,IL-1β and IL-33 expression(P＜0.05)and upregulated the IL-33/ST2 pathway(P＜0.05).Compared with the hypoxic group,MSCs-Exo treatment increased PAAT/PET(P＜0.05),decreased right ventricular free wall thickness(P＜0.05),right ventricular hypertrophy index RV/(LV+S)(P＜0.05),α-SMA expression in small pulmonary vessels(P＜0.05),and inflammatory factors including IL-1β and IL-33 expression in lung tissue,however increased IL-10 secretion(P＜0.05).In addition,MSCs-Exo treatment upregulated Arg-1 and downregulated iNOS and IL-33/ST2(P＜0.05).The results suggest that MSC-Exo may alleviate HPH through their immunomodulatory effects.
hypoxic pulmonary hypertensionpulmonary vascular remodellingmesenchymal stem cells and exosomesimmuno-modulation
刘红、张雨薇、张晴晴、王玉香、格日力、马兰
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青海大学高原医学研究中心
高原医学教育部重点实验室
青海省高原医学应用基础重点实验室(青海-犹他高原医学联合重点实验室)
青海大学医学部公共卫生系,西宁 810001
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低氧性肺动脉高压 肺血管重塑 间充质干细胞及外泌体 免疫调节
National Natural Science Foundation of ChinaNational Natural Science Foundation of Chinaproject of QinghaiProvincial Science and Technology Department,China
NETL
NSTL
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