Myocardial infarction (MI) is based on the lack of blood supply in the heart muscle with the possible consequence of irreversible structural changes, known as cardiac remodeling. These ischemia-related adaption mechanisms include the dedifferentiation of cardiomyocytes (CMs). Despite intensive research, the dynamic pattern of dedifferentiated CMs, their cell fate and molecular characteristics during cardiac remodeling are still insufficiently described. I assumed in my doctoral thesis that the Runt-related transcription factor 1 (Runx1) is the central inductor and regulator of CM dedifferentiation and therefore used Runx1 as the primary target gene for further characterization of this process in the context of experimental myocardial infarction. First, I was able to demonstrate that Runx1 deficient adult mouse cardiomyocytes (mACMs) originated from a heart-specific Runx1 knock-out strain lacked the ability to sprout, elongate and decline sarcomeric proteins as typical signs of dedifferentiation. In contrast, OSM signaling, which constituted a central modulator pathway for the induction of CM dedifferentiation, was not impaired, indicating an OSM-initiated but Runx1-triggered dedifferentiation. In the second part of my study, I established a reproducible Runx1 tracing approach. There, I used different transgenic reporter mouse strains and applied them to models of MI in order to characterize ischemic and dedifferentiated Runx1+ CMs more in depth. Here, a strong induction of Runx1 expression was noted adjacent to the infarcted region. The number of Runx1+ ACMs, which also demonstrated a dedifferentiated phenotype at this time, increased within the first 7 days post MI and declined thereafter. Furthermore, living once Runx1 expressing ACMs were found throughout the entire remodeling process, what indicated that Runx1 is directly associated with the survival of ischemic CMs. Last, profiling of Runx1-traced CMs by a unique live-cell sorting approach in combination with next-generation sequencing revealed an active pro-angiogenic, proliferative and immunomodulative character with the ability of those cells to contribute to regenerative processes of the infarcted heart. Overall, I could show that the time-limited and regional Runx1-mediated dedifferentiation of CMs is neither an artificial occurrence generated in the petri dish nor a meaningless adaptation mechanism, but instead dynamically shapes cardiac remodeling processes of the ischemic heart to prevent further organ damage and resulting functional restrictions in an auto- and paracrine way of intercellular communication.
Verknüpfung zu Publikationen oder weiteren Datensätzen
