MicroRNA-associated regulatory mechanisms in human mesenchymal stem cells and endothelial cells

Egea Alonso, Virginia (2024): MicroRNA-associated regulatory mechanisms in human mesenchymal stem cells and endothelial cells. Habilitationsschrift, LMU München: Medizinische Fakultät

Abstract

At the sites of inflammation mesenchymal stem cells (MSCs) are found aiding in tissue repair and immunomodulation. MSCs are in the focus of international research efforts aiming to understand their characteristics and potential for cell- and secretome-based therapeutic applications in the context of various diseases. MSCs migrate from different origin tissues to sites of injury or inflammation in a complex process that involves chemokine-mediated migration and the release of bioactive factors that modulate the behavior of surrounding cells. MicroRNAs (miRNAs) are a class of non-coding RNAs which are pivotal in post-transcriptional regulation of gene expression. Fluctuations in miRNA expression result in changes of protein expression, thereby influencing numerous biological processes and contributing to a variety of human diseases. Additionally, miRNAs can be transferred between cells, thereby regulating gene expression remotely from their cell of origin. It is therefore not surprising that miRNAs modulate major MSC functions such as differentiation, migration and paracrine immunomodulation. The central aim of the habilitation project was ultimately to investigate the role of miRNAs in the process of chemokine-driven migration of MSCs towards sites of inflammation, as well as their paracrine impact on target cells in tumor or atheromatous tissues. Interestingly, although members of the let-7 miRNA family typically function as tumor suppressors by restraining growth and invasion in cancer cells, let-7f appears to exhibit a contrasting role in MSCs. In our studies, we explored how this unique characteristic could potentially prove advantageous in the development of therapeutic approaches. Through four distinct yet complementary studies, we were able to underscore the importance of the miRNA let-7f in MSC biology. Our findings consistently demonstrated that overexpression of let-7f enhances the migratory capacity of MSCs. Let-7f upregulates cell surface receptors such as CXCR4 and FPR2, which in turn improves MSCs migratory response to stimuli like SDF-1 and LL-37. Finally, at the tumor site, MSC-derived exosomes containg let-7f are able to reach and enter the cancer cells exhibiting an anti-tumoral effect. These results were confirmed by in vitro and in vivo results in both glioma and breast cancer tumor models. The aforementioned properties were also evaluated ex vivo using an arterial perfusion model of atherosclerosis in a non-tumoral context. During our studies we also identified a remarkable non-canonical example of miRNA functionality in endothelial cells demonstrating that miR-126-5p inhibits the function of caspase 3 through direct biophysical interaction. This ultimately modulates crucial aspects of cardiovascular biology including the integrity of endothelial cells. These findings were achieved during my postdoctoral tenure in the Department of Clinical Chemistry and Biochemistry, under the direction of Prof. Dr. rer. nat. Marianne Jochum, and at the Institute for Cardiovascular Research (IPEK), led by Prof. Dr. Christian Weber, with mentorship from Prof. Christian Ries at LMU Munich.

• Dokumententyp: Habilitationsschriften
• Keywords: Mesenchymal stem cells, MSCs, MSC-Derived Exosomes, Trojan Horse approach, microRNAs, miRNAs, Non-Canonical miRNA Functionality, Cancer therapy, Cardiovascular Biology
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 2024