The role of CXCR4 in endothelial-to-mesenchymal transition and cardiac fibrosis

by Xin Wang
Doctoral thesis
Date of Examination:2025-06-25
Date of issue:2025-06-24
Advisor:Prof. Dr. Elisabeth Zeisberg
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-11293

 

 

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Abstract

English

Cardiac fibrosis contributes critically to the deterioration of heart function in numerous cardiovascular disorders by disrupting normal tissue structure and compliance,which characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Emerging evidence suggests that endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells lose their phenotype and acquire mesenchymal characteristics, plays a pivotal role in the fibrotic remodeling of the heart. The chemokine receptor CXCR4, known for its role in cell migration and tissue repair, has been implicated in fibrotic diseases; however, its specific function in EndMT and cardiac fibrosis remains inadequately understood. This study investigates the regulatory role of CXCR4 in EndMT and its pathological contribution to cardiac fibrosis. In vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that treatment with transforming growth factor β1 (TGFβ1) induced EndMT, as evidenced by decreased endothelial markers and increased mesenchymal markers. Concomitantly, CXCR4 expression was upregulated. Genetic knockdown of CXCR4 using CRISPR/Cas13d and pharmacological inhibition with the CXCR4 antagonist AMD3100 significantly attenuated EndMT, indicating a functional role for CXCR4 in this process. Conversely, overexpression of CXCR4 enhanced EndMT marker expression, supporting its pro-fibrotic potential. In vivo, an Angiotensin II (AngII)-induced mouse model of cardiac fibrosis was employed. CXCR4 was found to be highly expressed in fibrotic heart tissue. Targeted knockdown of CXCR4 via AAV-mediated delivery of CRISPR constructs, as well as systemic administration of AMD3100, resulted in reduced collagen deposition, decreased expression of EndMT and fibrosis markers, and preserved cardiac structure. These findings suggest that CXCR4 mediates EndMT and contributes to the pathogenesis of cardiac fibrosis. In summary, this work identifies CXCR4 as a critical mediator of TGFβ1-induced EndMT and fibrotic remodeling in the heart. Modulating CXCR4 signaling—either through gene silencing or pharmacological blockade—effectively suppresses EndMT and mitigates cardiac fibrosis in experimental models. These insights provide a compelling rationale for targeting CXCR4 as a potential therapeutic strategy in the treatment of cardiac fibrosis.
Keywords: Cardiac fibrosis; EndMT; CXCR4; AMD3100; CRISPR/Cas13d; Gene therapy