Mesenchymal Stem Cells Alleviate Mouse Sepsis-Induced Cardiomyopathy by Inhibiting the NR1D2/LCN2 Pathway

Abstract

Sepsis is characterized as a systemic inflammatory response syndrome resulting from infection, leading to the development of multiple organ dysfunction syndrome. Sepsis induced cardiomyopathy (SICM) is a frequently encountered condition in clinical settings. Mesenchymal stem cells (MSCs) possess inherent immunomodulatory and anti-inflammatory attributes, rendering them a promising therapeutic approach to reestablish the equilibrium between anti-inflammatory and pro-inflammatory systems in septic patients. Consequently, MSCs are frequently employed in clinical investigations.In this study, the author established a mouse SICM model through cecal ligation and puncture (CLP) and administered MSCs via the tail vein. Following successful modeling, the myocardial function and histopathological changes were detected by echocardiography, HE staining, TUNEL staining, ELISA and other experiments. As a result, MSCs demonstrated the ability to enhance myocardial function, promote cardiac tissue repair, suppress inflammatory response, reduce levels of myocardial injury markers, and mitigate oxidative stress. Additionally, transcriptome and proteome analyses were conducted. Through differential expression analysis, functional enrichment analysis and multi omics association analysis, revealed that the transcriptional factors nuclear receptor subfamily 1 (NR1D2) and target gene lipocalin 2 (LCN2) played key roles in mediating the effects of MSCs on SICM. JASPAR website and ChIP-qPCR experiment were used to predict and confirm the targeting relationship between them. Subsequent cell co-culture experiments and a series of experiments confirmed that MSCs attenuated cardiomyocyte injury by downregulating the expression of NR1D2 and its downstream target gene LCN2. In conclusion, MSCs alleviate mice SICM via inhibiting NR1D2/LCN2 pathway.