Cellular heterogeneity in cardiovascular regeneration and repair

The heart consists of a multitude of different specialized cells, which communicate with each other to ensure aproper cardiac function every second of our life. If the heart gets injured, for example after a heart attack (myocardial infarction) or in heart failure due to chronic disease, the roles and phenotypes of these specialized cells can profoundly change. Cells can undergo transient phenotypic changes, including the reactivation of embryonic pathways, making them more plastic and hence allowing them to contribute to tissue regeneration in the injured heart.

For deeper understanding of cellular heterogeneity, we use novel single-cell RNA sequencing technologies, to trace the gene expression patterns of individual cells in the heart. This allows us not only to break down global changes of the individual cell types, but also to find and describe the kinetics of rare subpopulations of cells and how they communicate with each other.

Our group is highly interested in the function of endothelial cells which acquire mesenchymal characteristics (Endothelial to mesenchymal transition, EndMT) after infarction. It was not clear whether these phenotypic changes contribute to fibrosis or allow the cells to migrate and promote neovascularization. We have recently shown that EndMT cells clonally expand and undergo proliferation (Manavski et al.,2018). Using lineage tracing, we highlighted the transient nature of this process after infarction. We showed that endothelial cells were not undergoing a complete transition towards mesenchymal lineage but rather a mesenchymal activation, allowing them to migrate and expand (Tombor et al., 2021). Mechanistically, we have shown that EndMT comes in line with the rearrangement of histone modifications, such as H3K9me3 demethylation, of mesenchymal gene loci, facilitated by the histone demethylase Jmjd2b, allowing the cells to undergo transition (Glaser et al., 2020). 

Ongoing studies focus on more detailed insights into cellular heterogeneity in several cell types as well as their function in regeneration and repair. Here, our broad access to patient samples allows us to study human cardiac heterogeneity, to investigate clinically relevant disease states, including identification of novel disease- and cell type-specific signatures (Nicin et al., 2021, 2022).

References:

1. Manavski Y., et al. Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization. Circ Res. 2018;122(5):670-677. doi:10.1161/CIRCRESAHA.117.312310
2. Tombor, L.S., et al. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nat Commun 12, 681 (2021). doi.org/10.1038/s41467-021-20905-1
3. Glaser S.F., et al. The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. PNAS 2020, 117 (8) 4180-4187; DOI: 10.1073/pnas.1913481117
4. Nicin, L., et al. Single Nuclei Sequencing Reveals Novel Insights into the Regulation of Cellular Signatures in Children with Dilated Cardiomyopathy. Circulation. 2021. doi:10.1161/CIRCULATIONAHA.120.051391.
5. Nicin, L., et al. Nat Cardiovascular. Research.