Effect of human placental mesenchymal stem cells transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with acute lung injury_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XU Mingjun ^1,2 , LI Xiaoguo ^1,2 ^△ , MA Chen ^1,2 , LÜ Yuzhen ^1,2 , MA Xiaona ² ,  MA Xiaowei ³

1. Clinical Medical College of Ningxia Medical University, Yinchuan Ningxia, 750003, P.R.China;
2. Institute for Ningxia Human Stem Cell Research, Yinchuan Ningxia, 750004, P.R.China;
3. Intensive Care Unit, Cardiocerebral Vascular Disease Hospital of General Hospital of Ningxia Medical University, Yinchuan Ningxia, 750012, P.R.China;

Corresponding author：

MA Xiaowei, Email: mxwei-99@163.com

Keywords：

Placental mesenchymal stem cells; acute lung injury; vascular endothelial permeability; mouse

DOI：

10.7507/1002-1892.201909070

Video：

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Objective To investigate the effects of human placental mesenchymal stem cells (hPMSCs) transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI).Methods The hPMSCs were isolated from the human placental tissue by enzyme digestion and passaged. The cell phenotype of the 3rd generation hPMSCs was detected by flow cytometry. Twenty-four 6-week-old healthy male C57BL/6 mice were randomly divided into 3 groups (n=8). The mice were instilled with LPS in the airway to prepare an ALI model in the ALI model group and the hPMSCs treatment group, and with saline in the control group. At 12 hours after LPS infusion, the mice were injected with 3rd generation hPMSCs via the tail vein in hPMSCs treatment group and with saline in the ALI model group and the control group. At 24 hours after injection, the lung tissues of all mice were taken. The pathological changes were observed by HE staining. The wet/dry mass ratio (W/D) of lung tissue was measured. The Evans blue leak test was used to detect the pulmonary vascular endothelial permea bility in mice. The expression of lung tissue permeability-related protein (VE-cadherin) was detected by Western blot.Results Flow cytometry examination showed that the isolated cells had typical MSCs phenotypic characteristics. Mice in each group survived. The alveolar structure of the ALI model group significantly collapsed, a large number of inflammatory cells infiltrated, and local alveolar hemorrhage occurred; while the alveolar structure collapse of the hPMSCs treatment group significantly improved, inflammatory cells infiltration significantly reduced, and a few red blood cells were in the interstitial lung. W/D and exudation volume of Evans blue stain were significantly higher in the ALI model group than in the control group and the hPMSCs treatment group (P<0.05), in the hPMSCs treatment group than in the control group (P<0.05). The relative protein expression of VE-cadherin was significantly lower in the ALI model group than in the control group and the hPMSCs treatment group (P<0.05), and in the hPMSCs treatment group than in the control group (P<0.05).Conclusion Intravenous injection of hPMSCs can effectively reduce the increased pulmonary vascular endothelial permeability mediated by LPS, relieve the degree of lung tissue damage, and play a therapeutic role in ALI mice.

Citation： XU Mingjun, LI Xiaoguo, MA Chen, LÜ Yuzhen, MA Xiaona, MA Xiaowei. Effect of human placental mesenchymal stem cells transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with acute lung injury. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(3): 387-392. doi: 10.7507/1002-1892.201909070 Copy

1.	Sklar MC, Patel BK, Beitler JR, et al. Optimal ventilator strategies in acute respiratory distress syndrome. Semin Respir Crit Care Med, 2019, 40(1): 81-93.
2.	Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers, 2019, 5(1): 18.
3.	Fan E, Brodie D, Slutsky AS, et al. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA, 2018, 319(7): 698-710.
4.	Bai C, Chen S, Gao Y, et al. Multi-lineage potential research of bone marrow mesenchymal stem cells from Bama miniature pig. J Exp Zool B Mol Dev Evol, 2015, 324(8): 671-685.
5.	Liu G, Lv H, An Y, et al. Tracking of transplanted human umbilical cord-derived mesenchymal stem cells labeled with fluorescent probe in a mouse model of acute lung injury. Int J Mol Med, 2018, 41(5): 2527-2534.
6.	Ok JS, Song SB, Hwang ES. Enhancement of replication and differentiation potential of human bone marrow stem cells by nicotinamide treatment. Int J Stem Cells, 2018, 11(1): 13-25.
7.	Lee HK, Lim SH, Chung IS, et al. Preclinical efficacy and mechanisms of mesenchymal stem cells in animal models of autoimmune diseases. Immune Netw, 2014, 14(2): 81-88.
8.	卢遥, 邓力, 李秀群, 等. 胎盘间充质干细胞与骨髓间充质干细胞分离培养和生物学特性研究. 中国修复重建外科杂志, 2007, 21(9): 989-993.
9.	Jeon YJ, Kim J, Cho JH, et al. Comparative analysis of human mesenchymal stem cells derived from bone marrow, placenta, and adipose tissue as sources of cell therapy. J Cell Biochem, 2016, 117(5): 1112-1125.
10.	Wang L, Yang Y, Zhu Y, et al. Characterization of placenta-derived mesenchymal stem cells cultured in autologous human cord blood serum. Mol Med Rep, 2012, 6(4): 760-766.
11.	Xiang B, Chen L, Wang X, et al. Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of LPS-induced acute lung injury. Int J Mol Sci, 2017, 18(4): 689.
12.	Li X, Yu Y, Gorshkov B, et al. Hsp70 suppresses mitochondrial reactive oxygen species and preserves pulmonary microvascular barrier integrity following exposure to bacterial toxins. Front Immunol, 2018, 9: 1309.
13.	Acosta-Herrera M, Lorenzo-Diaz F, Pino-Yanes M, et al. Correction: Lung transcriptomics during protective ventilatory support in sepsis-induced acute lung injury. PLoS One, 2015, 10(12): e0145696.
14.	Liu H, Yu X, Yu S, et al. Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Int Immunopharmacol, 2015, 29(2): 937-946.
15.	Wong JJM, Leong JY, Lee JH, et al. Insights into the immuno-pathogenesis of acute respiratory distress syndrome. Ann Transl Med, 2019, 7(19): 504.
16.	Lou J, Hu Y, Wu MD, et al. Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury. Acta Pharmacol Sin, 2019, 40(6): 769-780.
17.	Guillamat-Prats R, Puig F, Camprubí-Rimblas M, et al. Intratracheal instillation of alveolar type Ⅱ cells enhances recovery from acute lung injury in rats. J Heart Lung Transplant, 2018, 37(6): 782-791.
18.	Ma X, Liu X, Feng J, et al. Fraxin alleviates LPS-Induced ARDS by downregulating inflammatory responses and oxidative damages and reducing pulmonary vascular permeability. Inflammation, 2019, 42(5): 1901-1912.
19.	Potter DR, Miyazawa BY, Gibb SL, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. J Trauma Acute Care Surg, 2018, 84(2): 245-256.
20.	Wang F, Lu F, Huang H, et al. Ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis-associated acute lung injury. Ultrastruct Pathol, 2016, 40(1): 33-42.
21.	Mu S, Liu Y, Jiang J, et al. Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury. Respir Res, 2018, 19(1): 220.
22.	Hu S, Li J, Xu X, et al. The hepatocyte growth factor-expressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo. Stem Cell Res Ther, 2016, 7(1): 66.
23.	Zhang Z, Wu Z, Xu Y, et al. Vascular endothelial growth factor increased the permeability of respiratory barrier in acute respiratory distress syndrome model in mice. Biomed Pharmacother, 2019, 109: 2434-2440.
24.	Oskolkova O, Sarich N, Tian Y, et al. Incorporation of iloprost in phospholipase-resistant phospholipid scaffold enhances its barrier protective effects on pulmonary endothelium. Sci Rep, 2018, 8(1): 879.
25.	Chen L, Li W, Qi D, et al. Honokiol protects pulmonary microvascular endothelial barrier against lipopolysaccharide-induced ARDS partially via the Sirt3/AMPK signaling axis. Life Sci, 2018, 210: 86-95.

1. Sklar MC, Patel BK, Beitler JR, et al. Optimal ventilator strategies in acute respiratory distress syndrome. Semin Respir Crit Care Med, 2019, 40(1): 81-93.
2. Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers, 2019, 5(1): 18.
3. Fan E, Brodie D, Slutsky AS, et al. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA, 2018, 319(7): 698-710.
4. Bai C, Chen S, Gao Y, et al. Multi-lineage potential research of bone marrow mesenchymal stem cells from Bama miniature pig. J Exp Zool B Mol Dev Evol, 2015, 324(8): 671-685.
5. Liu G, Lv H, An Y, et al. Tracking of transplanted human umbilical cord-derived mesenchymal stem cells labeled with fluorescent probe in a mouse model of acute lung injury. Int J Mol Med, 2018, 41(5): 2527-2534.
6. Ok JS, Song SB, Hwang ES. Enhancement of replication and differentiation potential of human bone marrow stem cells by nicotinamide treatment. Int J Stem Cells, 2018, 11(1): 13-25.
7. Lee HK, Lim SH, Chung IS, et al. Preclinical efficacy and mechanisms of mesenchymal stem cells in animal models of autoimmune diseases. Immune Netw, 2014, 14(2): 81-88.
8. 卢遥, 邓力, 李秀群, 等. 胎盘间充质干细胞与骨髓间充质干细胞分离培养和生物学特性研究. 中国修复重建外科杂志, 2007, 21(9): 989-993.
9. Jeon YJ, Kim J, Cho JH, et al. Comparative analysis of human mesenchymal stem cells derived from bone marrow, placenta, and adipose tissue as sources of cell therapy. J Cell Biochem, 2016, 117(5): 1112-1125.
10. Wang L, Yang Y, Zhu Y, et al. Characterization of placenta-derived mesenchymal stem cells cultured in autologous human cord blood serum. Mol Med Rep, 2012, 6(4): 760-766.
11. Xiang B, Chen L, Wang X, et al. Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of LPS-induced acute lung injury. Int J Mol Sci, 2017, 18(4): 689.
12. Li X, Yu Y, Gorshkov B, et al. Hsp70 suppresses mitochondrial reactive oxygen species and preserves pulmonary microvascular barrier integrity following exposure to bacterial toxins. Front Immunol, 2018, 9: 1309.
13. Acosta-Herrera M, Lorenzo-Diaz F, Pino-Yanes M, et al. Correction: Lung transcriptomics during protective ventilatory support in sepsis-induced acute lung injury. PLoS One, 2015, 10(12): e0145696.
14. Liu H, Yu X, Yu S, et al. Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Int Immunopharmacol, 2015, 29(2): 937-946.
15. Wong JJM, Leong JY, Lee JH, et al. Insights into the immuno-pathogenesis of acute respiratory distress syndrome. Ann Transl Med, 2019, 7(19): 504.
16. Lou J, Hu Y, Wu MD, et al. Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury. Acta Pharmacol Sin, 2019, 40(6): 769-780.
17. Guillamat-Prats R, Puig F, Camprubí-Rimblas M, et al. Intratracheal instillation of alveolar type Ⅱ cells enhances recovery from acute lung injury in rats. J Heart Lung Transplant, 2018, 37(6): 782-791.
18. Ma X, Liu X, Feng J, et al. Fraxin alleviates LPS-Induced ARDS by downregulating inflammatory responses and oxidative damages and reducing pulmonary vascular permeability. Inflammation, 2019, 42(5): 1901-1912.
19. Potter DR, Miyazawa BY, Gibb SL, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. J Trauma Acute Care Surg, 2018, 84(2): 245-256.
20. Wang F, Lu F, Huang H, et al. Ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis-associated acute lung injury. Ultrastruct Pathol, 2016, 40(1): 33-42.
21. Mu S, Liu Y, Jiang J, et al. Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury. Respir Res, 2018, 19(1): 220.
22. Hu S, Li J, Xu X, et al. The hepatocyte growth factor-expressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo. Stem Cell Res Ther, 2016, 7(1): 66.
23. Zhang Z, Wu Z, Xu Y, et al. Vascular endothelial growth factor increased the permeability of respiratory barrier in acute respiratory distress syndrome model in mice. Biomed Pharmacother, 2019, 109: 2434-2440.
24. Oskolkova O, Sarich N, Tian Y, et al. Incorporation of iloprost in phospholipase-resistant phospholipid scaffold enhances its barrier protective effects on pulmonary endothelium. Sci Rep, 2018, 8(1): 879.
25. Chen L, Li W, Qi D, et al. Honokiol protects pulmonary microvascular endothelial barrier against lipopolysaccharide-induced ARDS partially via the Sirt3/AMPK signaling axis. Life Sci, 2018, 210: 86-95.

Chinese Journal of Reparative and Reconstructive Surgery

Effect of human placental mesenchymal stem cells transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with acute lung injury

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