Abstract
Vascular endothelial inflammation and endothelial dysfunction are the main causes of endothelial injury in Kawasaki disease (KD). Human umbilical cord–derived mesenchymal stem cells (Huc-MSCs) have multiple functions in immune regulation. This study examined whether Huc-MSCs inhibited endothelial inflammation and improved endothelial function in KD through constructing cell and in vivo animal KD vasculitis models. The pyroptosis factor NOD-like receptor protein 3 (NLRP3) was involved in the inflammatory process in the acute phase of KD. After tail vein injection of Huc-MSCs, inflammatory cell infiltration and the expression of pyroptosis-related proteins in the LCWE-induced KD mouse vasculitis model were significantly reduced. In vitro, NLRP3-dependent pyroptosis successfully induced human umbilical vein endothelial cell (HUVEC) damage. Huc-MSCs effectively increased the abilities of impaired HUVECs to proliferate, migrate, invade, and form vessel-like tubes, while inhibiting their apoptosis, suggesting that Huc-MSCs can reduce inflammation and improve vascular endothelial function by inhibiting the NLRP3-dependent pyroptosis pathway in KD, providing a possibility and novel target for KD endothelial injury and dysfunction.
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Abbreviations
- ADSCs:
-
Adipose tissue–derived stem cells
- CAAs:
-
Coronary artery abnormalities
- CALs:
-
Coronary artery lesions
- CAWS:
-
Candida albicans Water-soluble fraction
- CCK-8:
-
Cell Counting Kit-8
- DAB:
-
Diaminobenzidine
- DMEM-F12:
-
Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12
- EC:
-
Endothelial cell
- FBS:
-
Fetal bovine serum
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- GSDMD:
-
Gasdermin D
- HC:
-
Healthy control
- Huc-MSCs:
-
Human umbilical cord–derived mesenchymal stem cells
- HUVECs:
-
Human umbilical vein endothelial cells
- IBD:
-
Inflammatory bowel disease
- IL:
-
Interleukin
- IVIG:
-
Intravenous immunoglobulin
- KD:
-
Kawasaki disease
- LCWE:
-
Lactobacillus casei Cell wall extract
- LDH:
-
Lactate dehydrogenase
- MI:
-
Myocardial infarction
- MSCs:
-
mesenchymal stem cells
- NLRP3:
-
NOD-like receptor protein 3
- PFA:
-
paraformaldehyde
- RA:
-
rheumatoid arthritis
- RT-qPCR:
-
real-time quantitative polymerase chain reaction
- scRNA-seq:
-
single-cell RNA sequencing
- SLE:
-
systemic lupus erythematosus
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
- UMAP:
-
uniform manifold approximation and projection
- VSMCs:
-
vascular smooth muscle cells
References
McCrindle, Brian W., Anne H. Rowley, Jane W. Newburger, Jane C. Burns, Anne F. Bolger, Michael Gewitz, Annette L. Baker, et al. 2017. Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. Circulation 135: e927–e999. https://doi.org/10.1161/CIR.0000000000000484.
Beaton, Andrea, Flavia B Kamalembo, James Dale, Joseph H Kado, Ganesan Karthikeyan, Dhruv S Kazi, Chris T Longenecker, et al. 2020. The American Heart Association’s call to action for reducing the global burden of rheumatic heart disease: A policy statement from the American Heart Association. Circulation 142. United States: e358–e368. https://doi.org/10.1161/CIR.0000000000000922.
Newburger, Jane W, Masato Takahashi, and Jane C Burns. 2016. Kawasaki disease. Journal of the American College of Cardiology 67. United States: 1738–1749. https://doi.org/10.1016/j.jacc.2015.12.073.
Denby, Kara J., Daniel E. Clark, and Larry W. Markham. 2017. Management of Kawasaki disease in adults. Heart (British Cardiac Society) 103: 1760–1769. https://doi.org/10.1136/heartjnl-2017-311774.
Gersony, Welton M. 2009. The adult after kawasaki disease the risks for late coronary events. Journal of the American College of Cardiology. United States. https://doi.org/10.1016/j.jacc.2009.06.057.
Gordon, John B., Andrew M. Kahn, and Jane C. Burns. 2009. When children with Kawasaki disease grow up: Myocardial and vascular complications in adulthood. Journal of the American College of Cardiology 54: 1911–1920. https://doi.org/10.1016/j.jacc.2009.04.102.
Chen, Shaojie, Ying Dong, Marcio Galindo Kiuchi, Jiazhi Wang, Ruotian Li, Zhiyu Ling, Tingquan Zhou, et al. 2016. Coronary artery complication in Kawasaki disease and the importance of early intervention: A systematic review and meta-analysis. JAMA Pediatrics 170. United States: 1156–1163. https://doi.org/10.1001/jamapediatrics.2016.2055.
Rife, Eileen, and Abraham Gedalia. 2020. Kawasaki disease: An update. Current Rheumatology Reports 22. Current Rheumatology Reports. https://doi.org/10.1007/s11926-020-00941-4.
Kumrah, Rajni, Pandiarajan Vignesh, Amit Rawat, and Surjit Singh. 2020. Immunogenetics of Kawasaki disease. Clinical Reviews in Allergy & Immunology 59. United States: 122–139. https://doi.org/10.1007/s12016-020-08783-9.
Shi, Jianjin, Yue Zhao, Kun Wang, Xuyan Shi, Yue Wang, Huanwei Huang, Yinghua Zhuang, Tao Cai, Fengchao Wang, and Feng Shao. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526. England: 660–665. https://doi.org/10.1038/nature15514.
Sekerdag, Emine, Ihsan Solaroglu, and Yasemin Gursoy-Ozdemir. 2018. Cell death mechanisms in stroke and novel molecular and cellular treatment options. Current Neuropharmacology 16: 1396–1415. https://doi.org/10.2174/1570159X16666180302115544.
Takahashi, Masafumi. 2022. NLRP3 inflammasome as a key driver of vascular disease. Cardiovascular Research 118. England: 372–385. https://doi.org/10.1093/cvr/cvab010.
Ji, Nan, Zhongwen Qi, Yueyao Wang, Xiaoya Yang, Zhipeng Yan, Meng Li, Qihui Ge, and Junping Zhang. 2021. Pyroptosis: A new regulating mechanism in cardiovascular disease. Journal of Inflammation Research 14: 2647–2666. https://doi.org/10.2147/JIR.S308177.
Hara, Toshiro, Kenichiro Yamamura, and Yasunari Sakai. 2021. The up-to-date pathophysiology of Kawasaki disease. Clinical & Translational Immunology 10: e1284. https://doi.org/10.1002/cti2.1284.
Jia, Chang, Jian Zhang, Huanwen Chen, Yingzhi Zhuge, Huiqiao Chen, Fanyu Qian, Kailiang Zhou, et al. 2019. Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation. Cell Death and Disease 10: 778. https://doi.org/10.1038/s41419-019-2021-3.
Porritt, Rebecca A., David Zemmour, Masanori Abe, Youngho Lee, Meena Narayanan, Thacyana T. Carvalho, Angela C. Gomez, et al. 2021. NLRP3 inflammasome mediates immune-stromal interactions in vasculitis. Circulation Research 129: e183–e200. https://doi.org/10.1161/CIRCRESAHA.121.319153.
Shi, Yufang, Yu Wang, Qing Li, Keli Liu, Jianquan Hou, Changshun Shao, and Ying Wang. 2018. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nature reviews. Nephrology 14. England: 493–507. https://doi.org/10.1038/s41581-018-0023-5.
Galipeau, Jacques, and Luc Sensébé. 2018. Mesenchymal stromal cells: Clinical challenges and therapeutic opportunities. Cell Stem Cell 22: 824–833. https://doi.org/10.1016/j.stem.2018.05.004.
Sun, Xiaoya, Haojie Hao, Qingwang Han, Xiaoyan Song, Jiejie Liu, Liang Dong, Weidong Han, and Mu. Yiming. 2017. Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated inflammation in type 2 diabetes rats. Stem Cell Research & Therapy 8: 241. https://doi.org/10.1186/s13287-017-0668-1.
Liu, Linan, Henry P. Farhoodi, Menglu Han, Guangyang Liu, Yu. Jingxia, Lily Nguyen, Brenda Nguyen, Agnes Nguyen, Wenbin Liao, and Weian Zhao. 2020. Preclinical evaluation of a single intravenous infusion of hUC-MSC (BX-U001) in rheumatoid arthritis. Cell Transplantation 29: 963689720965896. https://doi.org/10.1177/0963689720965896.
Uchimura, Ryoichi, Takahiro Ueda, Ryuji Fukazawa, Jun Hayakawa, Ryuji Ohashi, Noriko Nagi-Miura, Naohito Ohno, Makoto Migita, and Yasuhiko Itoh. 2020. Adipose tissue-derived stem cells suppress coronary arteritis of Kawasaki disease in vivo. Pediatrics International: official journal of the Japan Pediatric Society 62. Australia: 14–21. https://doi.org/10.1111/ped.14062.
Correction to: Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. 2019. Circulation 140. United States: e181–e184. https://doi.org/10.1161/CIR.0000000000000703.
Jaggi, Preeti, Asuncion Mejias, Xu. Zhaohui, Han Yin, Melissa Moore-Clingenpeel, Bennett Smith, Jane C. Burns, et al. 2018. Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki disease. PLoS ONE 13: e0197858. https://doi.org/10.1371/journal.pone.0197858.
Wright, Victoria J., Jethro A. Herberg, Myrsini Kaforou, Chisato Shimizu, Hariklia Eleftherohorinou, Hannah Shailes, Anouk M. Barendregt, et al. 2018. Diagnosis of Kawasaki disease using a minimal whole-blood gene expression signature. JAMA Pediatrics 172: e182293. https://doi.org/10.1001/jamapediatrics.2018.2293.
Hoang, Long Truong, Chisato Shimizu, Ling Ling, Ahmad Nazri Mohamed. Naim, Chiea Chuen Khor, Adriana H. Tremoulet, Victoria Wright, Michael Levin, Martin L. Hibberd, and Jane C. Burns. 2014. Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease. Genome Medicine 6: 541. https://doi.org/10.1186/s13073-014-0102-6.
Lehman, T J, S M Walker, V Mahnovski, and D McCurdy. 1985. Coronary arteritis in mice following the systemic injection of group B Lactobacillus casei cell walls in aqueous suspension. Arthritis and Rheumatism 28. United States: 652–659. https://doi.org/10.1002/art.1780280609.
Murata, H. 1979. Experimental candida-induced arteritis in mice. Relation to arteritis in the mucocutaneous lymph node syndrome. Microbiology and Immunology 23. Australia: 825–831. https://doi.org/10.1111/j.1348-0421.1979.tb02815.x.
Rivas, Noval, and Magali, and Moshe Arditi. 2020. Kawasaki disease: Pathophysiology and insights from mouse models. Nature reviews. Rheumatology 16: 391–405. https://doi.org/10.1038/s41584-020-0426-0.
Lee, Youngho, Danica J. Schulte, Kenichi Shimada, Shuang Chen, Timothy R. Crother, Norika Chiba, Michael C. Fishbein, Thomas J A. Lehman, and Moshe Arditi. 2012. Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease. Circulation 125: 1542–1550. https://doi.org/10.1161/CIRCULATIONAHA.111.072769.
Chen, Tao, Ting Xu, Mingye Cheng, Hao Fang, Xianjuan Shen, Zhiyuan Tang, and Jianmei Zhao. 2021. Human umbilical cord mesenchymal stem cells regulate CD54 and CD105 in vascular endothelial cells and suppress inflammation in Kawasaki disease. Experimental Cell Research 409. United States: 112941. https://doi.org/10.1016/j.yexcr.2021.112941.
Wu, Xianxian, Haiying Zhang, Wei Qi, Ying Zhang, Jiamin Li, Zhange Li, Yuan Lin, et al. 2018. Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death & Disease 9: 171. https://doi.org/10.1038/s41419-017-0257-3.
Cheng, Tao, Shuai Ding, Shanshan Liu, Yan Li, and Lingyun Sun. 2021. Human umbilical cord-derived mesenchymal stem cell therapy ameliorates lupus through increasing CD4+ T cell senescence via MiR-199a-5p/Sirt1/p53 axis. Theranostics 11: 893–905. https://doi.org/10.7150/thno.48080.
Xie, Min, Cuifang Li, Zhou She, Wu. Feifeng, Jueyi Mao, Marady Hun, Senlin Luo, Wuqing Wan, Jidong Tian, and Chuan Wen. 2022. Human umbilical cord mesenchymal stem cells derived extracellular vesicles regulate acquired immune response of lupus mouse in vitro. Scientific Reports 12: 13101. https://doi.org/10.1038/s41598-022-17331-8.
Deng, DanQi, Peilian Zhang, Yun Guo, and Teck Onn Lim. 2017. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Annals of the Rheumatic Diseases 76. England: 1436–1439. https://doi.org/10.1136/annrheumdis-2017-211073.
Ma, Dan, Ke Xu, Gailian Zhang, Yang Liu, Jinfang Gao, Min Tian, Chun Wei, Juan Li, and Liyun Zhang. 2019. Immunomodulatory effect of human umbilical cord mesenchymal stem cells on T lymphocytes in rheumatoid arthritis. International Immunopharmacology 74. Netherlands: 105687. https://doi.org/10.1016/j.intimp.2019.105687.
Chou, Hsiu-Chu., Chien-Hsiang. Chang, Chien-Han. Chen, Willie Lin, and Chung-Ming. Chen. 2021. Consecutive daily administration of intratracheal surfactant and human umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced lung injury in neonatal rats. Stem Cell Research & Therapy 12: 258. https://doi.org/10.1186/s13287-021-02335-4.
Zhang, Shuang, Weiwei Zhang, Yanping Li, Liping Ren, Haotian Deng, Xiaowei Yin, Xu Gao, Shuang Pan, and Yumei Niu. 2020. Cotransplantation of human umbilical cord mesenchymal stem cells and endothelial cells for angiogenesis and pulp regeneration in vivo. Life Sciences 255. Netherlands: 117763. https://doi.org/10.1016/j.lfs.2020.117763.
Liu, Jinwen, Zhixin Yan, Fuji Yang, Yan Huang, Yao Yu, Liping Zhou, Zixuan Sun, Dawei Cui, and Yongmin Yan. 2021. Exosomes derived from human umbilical cord mesenchymal stem cells accelerate cutaneous wound healing by enhancing angiogenesis through delivering angiopoietin-2. Stem Cell Reviews and Reports 17. United States: 305–317. https://doi.org/10.1007/s12015-020-09992-7.
Zhu, Yanfang P, Isaac Shamie, Jamie C Lee, Cameron J Nowell, Weiqi Peng, Shiela Angulo, Linh Nn Le, et al. 2021. Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C. The Journal of Clinical Investigation 131. https://doi.org/10.1172/JCI147076.
Bukulmez, Hulya. 2021. Current understanding of multisystem inflammatory syndrome (MIS-C) following COVID-19 and its distinction from Kawasaki disease. Current Rheumatology Reports 23: 58. https://doi.org/10.1007/s11926-021-01028-4.
Qiu, Yu., Yulin Zhang, Yifei Li, Yimin Hua, and Yue Zhang. 2022. Molecular mechanisms of endothelial dysfunction in Kawasaki-disease-associated vasculitis. Frontiers in Cardiovascular Medicine 9: 981010. https://doi.org/10.3389/fcvm.2022.981010.
Eiro, Noemi, Maria Fraile, Alberto González-Jubete, Luis O González, and Francisco J Vizoso. 2022. Mesenchymal (stem) stromal cells based as new therapeutic alternative in inflammatory bowel disease: Basic mechanisms, experimental and clinical evidence, and challenges. International Journal of Molecular Sciences 23. https://doi.org/10.3390/ijms23168905.
Jenko, Barbara, Sonja Praprotnik, Matija Tomšic, and Vita Dolžan. 2016. NLRP3 and CARD8 polymorphisms influence higher disease activity in rheumatoid arthritis. Journal of Medical Biochemistry 35: 319–323. https://doi.org/10.1515/jomb-2016-0008.
da Cruz, Heidi Lacerda Alves, Catarina Addobbati Jordão Cavalcanti, Jaqueline de Azêvedo Silva, Camilla Albertina Dantas de Lima, Thiago Sotero Fragoso, Alexandre Domingues Barbosa, Andréa Tavares Dantas, et al. 2020. Differential expression of the inflammasome complex genes in systemic lupus erythematosus. Immunogenetics 72. United States: 217–224. https://doi.org/10.1007/s00251-020-01158-6.
Zhao, Shengchun, Hongwei Chen, Guolin Wu, and Chen Zhao. 2017. The association of NLRP3 and TNFRSF1A polymorphisms with risk of ankylosing spondylitis and treatment efficacy of etanercept. Journal of Clinical Laboratory Analysis 31. https://doi.org/10.1002/jcla.22138.
Li, Zhe, Jialong Guo, and Liqi Bi. 2020. Role of the NLRP3 inflammasome in autoimmune diseases. Biomedicine & Pharmacotherapy = Biomedecine & pharmacotherapie 130. France: 110542. https://doi.org/10.1016/j.biopha.2020.110542.
Jia, Chang, Yingzhi Zhuge, Shuchi Zhang, Chao Ni, Linlin Wang, Wu. Rongzhou, Chao Niu, et al. 2021. IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway. Cell Death & Disease 12: 575. https://doi.org/10.1038/s41419-021-03852-z.
Li, Hao, Yanling Guan, Bo Liang, Peng Ding, Xin Hou, Wei Wei, and Yang Ma. 2022. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. European Journal of Pharmacology 928. Netherlands: 175091. https://doi.org/10.1016/j.ejphar.2022.175091.
Xie, Qixin, Rui Liu, Jia Jiang, Jing Peng, Chunyan Yang, Wen Zhang, Sheng Wang, and Jing Song. 2020. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Research & Therapy 11: 519. https://doi.org/10.1186/s13287-020-02011-z.
Funding
This work was supported by the National Natural Science Foundation of China (82270528), the Jiangsu Provincial Commission of Health and Family Planning (ZDA2020010), the 5th of the “226 Project” Scientific Research Project in 2020, the Scientific Research Surface A Class Project of Nantong City Health Committee (MA2021003), the Maternal and Child Health Project of Jiangsu Provincial Health Commission (F202154), the People's Livelihood Science and Technology Projetct of Nantong Science and Technology Bureau (MS22022116), the Multicenter Clinical Collaborative Research Project of the Affiliated Hospital of Nantong University (LCYJ-A06), and the Graduate Practice Innovation Program of Jiangsu Province (SJCX23_1802).
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T.X., T.C., X.J.S., Z.Y.T., and J.M.Z. designed experiments. T.X. drafted the manuscript. T.X., T.C., X.J.S., Z.Y.T., and J.M.Z. edited the manuscript. T.X., T.C., H.F., and K.W. performed the animal experiments. T.X. and T.C. performed the experiments in vitro. T.X., T.C., Z.Y.T., and J.M.Z. take responsibility for the accuracy of the analysis of the whole experiment.
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Xu, T., Chen, T., Fang, H. et al. Human Umbilical Cord Mesenchymal Stem Cells Repair Endothelial Injury and Dysfunction by Regulating NLRP3 to Inhibit Endothelial Cell Pyroptosis in Kawasaki Disease. Inflammation 47, 483–502 (2024). https://doi.org/10.1007/s10753-023-01921-3
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DOI: https://doi.org/10.1007/s10753-023-01921-3