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Effects of human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes on pulmonary vascular remodeling in hypoxic pulmonary hypertension

LIU Hong^1,2,3, ZHANG Yu-Wei^1,4, ZHANG Qing-Qing^1,2,3, WANG Yu-Xiang^1,2,3, GE Ri-Li^1,2,3, MA Lan^1,2,3,*

¹Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China；²Key Laboratory of High Altitude Medicine of Ministry of Education, Xining 810001, China；³Qinghai Key Laboratory of High Altitude Medicine Application Foundation (Qinghai-Utah Joint Key laboratory of High Altitude Medicine), Xining 810001, China；⁴Department of Public Health, Faculty of Medicine, Qinghai University, Xining 810001, China

Abstract

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 macrophage 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.

Key words: hypoxic pulmonary hypertension; pulmonary vascular remodelling; mesenchymal stem cells and exosomes; immunomodulation

Received: 　　Accepted:

Corresponding author: 马兰　　E-mail: judyml-325@163.com

DOI: 10.13294/j.aps.2024.0006

Citing This Article：

LIU Hong, ZHANG Yu-Wei, ZHANG Qing-Qing, WANG Yu-Xiang, GE Ri-Li, MA Lan. Effects of human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes on pulmonary vascular remodeling in hypoxic pulmonary hypertension. Acta Physiol Sin 2024; 76 (1): 33-44 (in Chinese with English abstract).