Extracellular vesicles derived from bone marrow mesenchymal stem cells improve lung tissue injury in mice with severe acute pancreatitis_West China Medical Journal

Authors：

SUOLANG Yuzhen ^1,2 , HU Qian ³ , YANG Yue ³ , Kang Hongxin ³ ,  ZHANG Shu ¹ ,  WAN Meihua ³

1. Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Emergency, Tibet Autonomous Region People’s Hospital, Lhasa, Tibet 850000, P. R. China;
3. West China Center of Excellence for pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Shu, Email: 5042708@qq.com; WAN Meihua, Email: wanmh@scu.edu.cn

Keywords：

Mesenchymal stem cells; severe acute pancreatitis; pulmonary microvascular endothelial cells; tight junction; acute lung injury

DOI：

10.7507/1002-0179.202403090

Video：

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Objective To investigate the effect and potential mechanism of bone marrow mesenchymal stem cells (BMSCs) – derived extracellular vesicles (EVs) on lung tissue injury in mice with severe acute pancreatitis (SAP). Methods 24 SPF grade male C57BL/6 mice and primary mouse lung microvascular endothelial cells(PMVEC) were selected. Divide the mice into sham group (sham group), SAP group, and BMSC group, with 8 mice in each group. Divide mouse primary PMVEC into model group (NaTC group), BMSC-EV group, and control group (control group). Extraction and characterization of healthy mouse BMSCs and their derived extracellular vesicles (BMSC-EVs). A mouse model of severe acute pancreatitis (SAP) was established, and BMSC-EVs were injected into SAP mice by tail vein or intervened in PMVECs in vitro, to observe the pathological damage of pancreatic and lung tissues, the changes of serum amylase, lipase, and inflammatory factors [tumor necrosis factor α (TNFα), interleukin-6 (IL-6)], and the inflammatory factors of lung tissues and PMVECs, and the endothelial cell barrier related proteins [E-cadherin, ZO-1, intercellular cell adhesion molecule-1(ICAM-1)] expression, and tight junctions between PMVECs to explore the effects of BMSC-EVs on pancreatic and lung tissues in SAP mice and PMVECs in vitro. Results BMSCs have the potential for osteogenic, chondrogenic, and lipogenic differentiation, and the EVs derived from them have a typical cup-shaped structure with a diameter of 60-100 nm. BMSC-EVs expressed the extracellular vesicle-positive proteins TSG101 and CD63 and did not express the negative protein Calnexin. Compared with sham mice, SAP mice underwent significant pathological damage to the pancreas (P<0.05), and their serum amylase, lipase, inflammatory factor IL-6, and TNFα levels were significantly up-regulated (P<0.05); whereas, BMSC-EVs markedly ameliorated the pancreatic tissue damage in SAP mice (P<0.01), down-regulated the levels of peripheral serum amylase, lipase, IL-6 and TNFα (P<0.05), and up-regulated the level of anti-inflammatory factor IL-10 (P<0.05). In addition to this, SAP mice showed significant lung histopathological damage (P<0.05), higher neutrophils and macrophages infiltration (P<0.05), higher levels of the inflammatory factors TGFβ and IL-6 (P<0.05), as well as reduced barrier protein E-cadherin, ZO-1 expression and elevated expression of the intercellular adhesion protein ICAM-1 (P<0.05), BMSC-EVs significantly ameliorated lung histopathological injury, inflammatory cells infiltration, inflammatory factor levels, and expression of barrier proteins, and suppressed ICAM-1 expression (P < 0.05). In the in vitro PMVECs experiments, it was found that intercellular tight junctions were broken in the NaTC group, and the levels of inflammatory factors TNFα and IL-6 (P<0.05) were significantly up-regulated, the protein expression of E-cadherin and ZO-1 (P<0.05) was significantly down-regulated, and the expression of ICAM-1 (P<0.05) was significantly up-regulated. BMSC-EVs significantly improved intercellular tight junctions in the NaTC group and inhibited the secretion of TNFα and IL-6 (P<0.05), up-regulated the expression of the barrier proteins E-cadherin and ZO-1, and down-regulated the expression of ICAM-1 (P<0.05). Conclusion Bone marrow mesenchymal stem cell-derived extracellular vesicles ameliorate lung tissue injury in SAP mice by restoring the lung endothelial cell barrier and inhibiting inflammatory cell infiltration.

1.	Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA, 2021, 325(4): 382-390.
2.	De Campos T, Deree J, Coimbra R. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt), 2007, 8(1): 107-120.
3.	Owusu L, Xu C, Chen H, et al. Gamma-enolase predicts lung damage in severe acute pancreatitis-induced acute lung injury. J Mol Histol, 2018, 49(4): 347-356.
4.	Hu Q, Zhang S, Yang Y, et al. Extracellular vesicle ITGAM and ITGB2 mediate severe acute pancreatitis-related acute lung injury. ACS Nano, 2023, 17(8): 7562-7575.
5.	Hu Q, Zhang S, Yang Y, et al. Extracellular vesicles in the pathogenesis and treatment of acute lung injury. Mil Med Res, 2022, 9(1): 61.
6.	Li Q, Chen X, Li J. Marrow-derived mesenchymal stem cells regulate the inflammatory response and repair alveolar type Ⅱ epithelial cells in acute lung injury of rats. J Int Med Res, 2020, 48(4): 300060520909027.
7.	Villar J, Fernández RL, Ambrós A, et al. A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy. Crit Care Med, 2015, 43(2): 346-353.
8.	Lee JH, Park J, Lee JW. Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury. Transfusion, 2019, 59(S1): 876-883.
9.	Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell, 2020, 11(10): 707-722.
10.	Zhao M, Liu S, Wang C, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano, 2021, 15(1): 1519-1538.
11.	Hu Q, Su H, Li J, et al. Clinical applications of exosome membrane proteins. Precis Clin Med, 2020, 3(1): 54-66.
12.	Zheng L, Gong H, Zhang J, et al. Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol, 2023, 11: 1322514.
13.	Hu Q, Yao J, Wu X, et al. Emodin attenuates severe acute pancreatitis-associated acute lung injury by suppressing pancreatic exosome-mediated alveolar macrophage activation. Acta Pharm Sin B, 2022, 12(10): 3986-4003.
14.	Yang Y, Hu Q, Kang H, et al. Urolithin A protects severe acute pancreatitis‐associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes. MedComm(2020), 2023, 4(6): e459.
15.	Perides G, van Acker GJ, Laukkarinen JM, et al. Experimental acute biliary pancreatitis induced by retrograde infusion of bile acids into the mouse pancreatic duct. Nat Protoc, 2010, 5(2): 335-341.
16.	康鸿鑫, 赵先林, 李娟, 等. 基于“温邪上受, 首先犯肺”探讨胰源性外泌体介导重症急性胰腺炎先发急性肺损伤的机制. 中国中西医结合消化杂志, 2020, 28(3): 180-183.
17.	Tomita K, Saito Y, Suzuki T, et al. Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury. Naunyn Schmiedebergs Arch Pharmacol, 2020, 393(12): 2365-2374.
18.	Wang P, Luo R, Zhang M, et al. A cross-talk between epithelium and endothelium mediates human alveolar-capillary injury during SARS-CoV-2 infection. Cell Death Dis, 2020, 11(12): 1042.
19.	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.
20.	白吉佳, 石国翠, 马申懋, 等. TNF-α下调大鼠肺微血管内皮细胞紧密连接蛋白 ZO-1、Claudin-5 的表达. 重庆医科大学学报, 2024, 49(2): 125-131.
21.	Ge P, Luo Y, Okoye C S, et al. Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: a troublesome trio for acute pancreatitis. Biomed Pharmacother, 2020, 132: 110770.

1. Mederos MA, Reber HA, Girgis MD. Acute pancreatitis: a review. JAMA, 2021, 325(4): 382-390.
2. De Campos T, Deree J, Coimbra R. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt), 2007, 8(1): 107-120.
3. Owusu L, Xu C, Chen H, et al. Gamma-enolase predicts lung damage in severe acute pancreatitis-induced acute lung injury. J Mol Histol, 2018, 49(4): 347-356.
4. Hu Q, Zhang S, Yang Y, et al. Extracellular vesicle ITGAM and ITGB2 mediate severe acute pancreatitis-related acute lung injury. ACS Nano, 2023, 17(8): 7562-7575.
5. Hu Q, Zhang S, Yang Y, et al. Extracellular vesicles in the pathogenesis and treatment of acute lung injury. Mil Med Res, 2022, 9(1): 61.
6. Li Q, Chen X, Li J. Marrow-derived mesenchymal stem cells regulate the inflammatory response and repair alveolar type Ⅱ epithelial cells in acute lung injury of rats. J Int Med Res, 2020, 48(4): 300060520909027.
7. Villar J, Fernández RL, Ambrós A, et al. A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy. Crit Care Med, 2015, 43(2): 346-353.
8. Lee JH, Park J, Lee JW. Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury. Transfusion, 2019, 59(S1): 876-883.
9. Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell, 2020, 11(10): 707-722.
10. Zhao M, Liu S, Wang C, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano, 2021, 15(1): 1519-1538.
11. Hu Q, Su H, Li J, et al. Clinical applications of exosome membrane proteins. Precis Clin Med, 2020, 3(1): 54-66.
12. Zheng L, Gong H, Zhang J, et al. Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol, 2023, 11: 1322514.
13. Hu Q, Yao J, Wu X, et al. Emodin attenuates severe acute pancreatitis-associated acute lung injury by suppressing pancreatic exosome-mediated alveolar macrophage activation. Acta Pharm Sin B, 2022, 12(10): 3986-4003.
14. Yang Y, Hu Q, Kang H, et al. Urolithin A protects severe acute pancreatitis‐associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes. MedComm(2020), 2023, 4(6): e459.
15. Perides G, van Acker GJ, Laukkarinen JM, et al. Experimental acute biliary pancreatitis induced by retrograde infusion of bile acids into the mouse pancreatic duct. Nat Protoc, 2010, 5(2): 335-341.
16. 康鸿鑫, 赵先林, 李娟, 等. 基于“温邪上受, 首先犯肺”探讨胰源性外泌体介导重症急性胰腺炎先发急性肺损伤的机制. 中国中西医结合消化杂志, 2020, 28(3): 180-183.
17. Tomita K, Saito Y, Suzuki T, et al. Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury. Naunyn Schmiedebergs Arch Pharmacol, 2020, 393(12): 2365-2374.
18. Wang P, Luo R, Zhang M, et al. A cross-talk between epithelium and endothelium mediates human alveolar-capillary injury during SARS-CoV-2 infection. Cell Death Dis, 2020, 11(12): 1042.
19. 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.
20. 白吉佳, 石国翠, 马申懋, 等. TNF-α下调大鼠肺微血管内皮细胞紧密连接蛋白 ZO-1、Claudin-5 的表达. 重庆医科大学学报, 2024, 49(2): 125-131.
21. Ge P, Luo Y, Okoye C S, et al. Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: a troublesome trio for acute pancreatitis. Biomed Pharmacother, 2020, 132: 110770.

West China Medical Journal

Latest ArticlesExtracellular vesicles derived from bone marrow mesenchymal stem cells improve lung tissue injury in mice with severe acute pancreatitis

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