Dokument: Die Rolle epikardialer stromaler Zellen in der Heilungsphase nach Myokardinfarkt

Titel:

Die Rolle epikardialer stromaler Zellen in der Heilungsphase nach Myokardinfarkt

Weiterer Titel:

The role of epicardial stromal cells in the healing phase after myocardial infarction

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=64992

URN (NBN):

urn:nbn:de:hbz:061-20240226-130123-1

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Zalfen, Ria [Autor]

Dateien:

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Dateien vom 18.02.2024 / geändert 18.02.2024

Beitragende:

Prof. Dr. med. Schrader, Jürgen [Gutachter]
Prof. Dr. rer. nat. Scheller, Jürgen [Gutachter]

Stichwörter:

Molekulare Kardiologie, Molekulare Biologie, Pharmazie

Dewey Dezimal-Klassifikation:

600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit

Beschreibungen:

Nach einem Myokardinfarkt wird das Epikard aktiviert und es bildet sich eine Multizellschicht aus proliferierenden, epikardialen stromalen Zellen (EpiSCs), in denen Teile des embryonalen Genprogramms reaktiviert werden. Diese EpiSCs besitzen aufgrund ihrer multipotenten Zelleigenschaften das Potenzial, zur Herzheilung nach Infarkt beizutragen. Eine Voraussetzung zur Entwicklung therapeutischer Strategien, um EpiSCs für die Förderung der Herzheilung zu nutzen, ist es ein tieferes Verständnis der zellulären Eigenschaften der EpiSCs nach Infarkt zu erarbeiten.
In der vorliegenden Arbeit wurden EpiSCs in einem Infarkt-Mausmodell hinsichtlich ihrer zellulären Heterogenität und ihres Potenzials zur Herzheilung untersucht. Basierend auf vorangegangenen Studien unserer Arbeitsgruppe wurde die Lokalisation von identifizierten EpiSC-Zellclustern 5 Tage nach Infarkt mittels RNA-in situ-Hybridisierung definiert. Hier konnte ein möglicher Zusammenhang zwischen der Lokalisation und dem transkriptionellen Charakter der EpiSC-Zellcluster gezeigt werden. Eine detaillierte Analyse der EpiSCs an zwei Zeitpunkten nach Infarkt (5 und 21 Tage) mittels Einzelzell-RNA-Sequenzierung (scRNAseq) zeigte unter anderem einen Rückgang von proliferierenden EpiSCs 21 Tage nach Infarkt. Aufbauend auf Hinweisen, dass Sphingolipid-1-Phosphat (S1P) und Thymosin-beta 4 (Tβ4) erfolgsversprechende Moleküle bei der Herzheilung sein könnten, wurde deren Wirkung auf EpiSCs näher analysiert. Nach pharmakologischer Anreicherung von S1P in vivo konnten in histologischen Analysen Kardiomyozyten-Vorläufer identifiziert werden. Eine Lipidomics-Analyse der Sphingolipide in EpiSCs nach Infarkt zeigte eine signifikante Erhöhung von Ceramid C16:0 im Vergleich zu Fibroblasten und belegt erstmals eine mögliche Rolle von S1P in EpiSCs. Um die Bedeutung von Tβ4 in Infarkt-aktivierten EpiSCs zu untersuchen, wurde ein AAV9-Vektorsystem zur herz-spezifischen Tβ4-Überexpression entwickelt und dies führte zu einem Trend einer Erhöhung von WT-1+-Zellen. ScRNAseq-Analysen 5 und 14 Tage nach Infarkt ergaben, dass die Expression einer Vielzahl von Genen nach Tβ4-Überexpression verändert war, darunter eine gesteigerte Expression von Kollagen vor allem 14 Tage nach Infarkt.
Zusammen bilden die erhobenen Daten die Grundlage, das Infarktgeschehen auf Zellebene besser zu verstehen und zukünftig neue Therapiemöglichkeiten zur Förderung der Herzheilung zu entwickeln.

Myocardial infarction leads to the activation of the epicardium, forming a multi-cell layer of proliferating epicardial stromal cells (EpiSCs) by reactivating their embryonic gene program. Due to their multipotent cell characteristics, EpiSCs have the potential to improve cardiac healing after infarction. For developing new therapeutic strategies by pharmacologically targeting EpiSCs, a deeper understanding of the cellular characteristics of EpiSCs is required.
The present study aimed at analyzing EpiSCs regarding their cellular heterogeneity and their potential for infarct healing in a mouse infarction model. Based on recent findings of our group, the localization of single-cell RNA sequencing (scRNAseq)-identified cell clusters 5 days post infarction was defined by using RNA-in situ-hybridization. Individual transcriptionally defined cell clusters could be attributed to a specific localization within the epicardial cell layer. ScRNAseq of EpiSCs 5 and 21 days after infarction characterized the temporal changes in gene expression within the EpiSC clusters. This includes a significant reduction of proliferating cells at 21 days post infarction.
The second focus of the present work concerned the role of two molecules on EpiSCs in infarct healing: Sphingosine-1-phosphate (S1P) and thymosin-beta 4 (Tβ4). Pharmacological enrichment of S1P resulted in the formation of cardiomyocyte precursor cells in infarcted hearts as identified by histochemistry. Using MS-based lipidomic analysis, the sphingolipid composition in stromal cells after infarction was analyzed. A significant higher level of ceramide C16:0 in EpiSCs in comparison to fibroblasts was observed, suggesting a functional relevance of S1P in EpiSCs. To analyze the cardioprotective effects of Tβ4 and its impact on EpiSCs, an AAV9 vector system for heart-specific Tβ4 overexpression was generated. This Tβ4 overexpression led to the trend of an increase in WT-1+-cells within the epicardial layer. ScRNAseq analysis of EpiSCs 5 and 14 days after infarction characterized multiple temporal changes in EpiSC gene expression in response to Tβ4 overexpression. This included an increased expression of collagen, especially 14 days after infarction.
In summary, the data obtained improved our understanding of the molecular and cellular processes in infarct-activated EpiSCs and thus may be helpful to develop future strategies to better target EpiSCs in the healing process.

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Dokument: Die Rolle epikardialer stromaler Zellen in der Heilungsphase nach Myokardinfarkt