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Human Umbilical Cord Mesenchymal Stem Cells Repair Endothelial Injury and Dysfunction by Regulating NLRP3 to Inhibit Endothelial Cell Pyroptosis in Kawasaki Disease

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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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We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. The authors confirm that the data supporting the findings of this study are available within the article.

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

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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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  1. Ting Xu and Tao Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong Jiangsu Province, 226001, China

    Ting Xu, Tao Chen, Hao Fang, Xiwei Shen & Jianmei Zhao

  2. Research Institute of Comparative Medicine, Nantong University, Nantong Jiangsu Province, 226001, China

    Ting Xu, Hao Fang & Xiwei Shen

  3. Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Nantong Jiangsu Province, 226001, China

    Xianjuan Shen

  4. Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

    Zhiyuan Tang

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Contributions

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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Correspondence to Zhiyuan Tang or Jianmei Zhao.

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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 (2023). https://doi.org/10.1007/s10753-023-01921-3

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