Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development
Posted on: 4 June 2021 , updated on: 7 June 2021
Preprint posted on 26 April 2021
Article now published in eLife at http://dx.doi.org/10.7554/eLife.70246
All endothelial roads lead to “Rome”: understanding the cell plasticity of cardiac blood vessels
Selected by Yen Tran, Osvaldo ContrerasCategories: bioinformatics, cell biology, developmental biology
Background
The coronary arteries branch along the coronary groove of the heart and supply oxygenated blood to the myocardium and heart cells. Owing to their essential function, coronary blood vessel formation and maintenance regulate the normal functions of the cardiac muscle. When this “goes wrong,” for example, in diseased coronary blood vessels, cardiac function is severely affected. Coronary diseases (also known as coronary artery disease, or CAD) are rising in the industrialized world, representing the most common cause of heart disease in the United States. Because CAD severely impacts the quality of life of patients and has a significant socioeconomic impact (WHO), understanding the underlying mechanisms of blood vessel development and regulation in homeostasis and disease could open roads for novel and efficient medical applications.
How do coronary vessels develop? The formation of coronary vessels requires two principal cellular sources: sinus venosus (SV)- and endocardium (Endo)-derived endothelial cells (Lupu et al.). The sinus venosus is the inflow tract of the developing heart, and the endocardium is the layer lining inside the cardiac ventricles. At embryonic day E11.5, endothelial cells from SV migrate caudally and contribute to the vessel network in the outer myocardial wall. Conversely, endocardial cells extrapolate inside out and contribute to the vessels network of inner myocardial walls and the septum. Later, the two networks unite and remodel into mature capillaries, arteries and veins before connecting with the aorta and carrying blood flow. Previously, Su et al. used single-cell RNA sequencing (scRNA-seq) to characterize the transcriptomes of SV-derived endothelial cells. However, a direct comparison between Endo- and SV- derived ECs during coronary vessel formation has not been explored.
What is the biological question addressed in this preprint, and why is it important? In an exciting new preprint, Phansalkar et al. take advantage of scRNA-seq combined with endothelial cell lineage-tracing to explore for the first time the dual origins of coronary blood vessels during mouse and human development.
Key findings
To address the origin(s) of endothelial cells during coronary vessel formation, Phansalkar and colleagues integrated single-cell RNA sequencing with lineage tracing of the endocardium (Endo) and sinus venosus (SV) derived endothelial cells (ECs) using BmxCreER and ApjCreER mice, respectively. The authors collected ECs from two embryonic (E12 and E17.5) and adult stages (8 weeks of age). The single-cell data captured most endothelial cell types, and as expected, the proportion of each cell type changed over the developmental course. The E12 coronary vessels contained two capillary plexus (Cap1, Cap2) and one pre-artery (pre-Art) cluster. Later in development, E17.5 coronary ECs resolved two capillaries (Cap1 and Cap2), two arteries (Art1 & Art2), and one vein cluster. The authors found one artery, one vein, and two capillary clusters in adult coronary ECs.
Further characterization of the cell lineages of coronary ECs suggests that the origins and heterogeneity of SV and Endo fade over time. At E12, the Cap1 subpopulation shared molecular signatures with Endo, whereas the Cap2 subpopulation was enriched with SV marker genes. However, these patterns are not preserved at E17.5 and in adults. Remarkably, although E17.5 capillary clusters did not retain their origin’s signature, they were segregated by their location within the heart. Cap2 cells (Kcne3- and Car4+) are associated with the left and right ventricle free walls and dorsal side. Cap1 cells (Kcne3+ and Car4) are located in the septum and ventral side.
Interestingly, differential gene expression of Cap1 and Cap2 reflected the distinct features of cardiac regions. Cap1 cells had high expression of hypoxia-related genes and tip markers, implying that the septum region may be hypoxic and require new blood vessel formation. In addition, Cap2 cells highly expressed shear stress-induced genes, suggesting that this region experiences a higher blood flow rate. Furthermore, most of the Cap1 cells in the septum and ventral areas are tdTomato+, indicating these cells derive from Endo lineage. In the adult, both lineages- and location-based cell heterogeneity disappeared.
Owing to Endo- and SV-derived endothelial cells having similar transcriptomic profiles in adult hearts, the authors sought to understand whether the cellular properties of Endo- and SV-derived ECs change under injury. Although endothelial cells proliferate at high rates, no significant differences were observed in the S-phase progression among both endothelial cell lineages, as evaluated by the incorporation of a nucleotide analog EdU. These findings suggest that endothelial lineage does not influence cell proliferation. In this context, it would be interesting to see the scRNA-seq following cardiac injury using the Bmx lineage-tracing in adult mice.
Next, using scRNA-seq analyses, the authors explored whether mouse and human coronary vessels share similar transcriptomic features, cellular states, and trajectories at different developmental stages. Smart-seq2 of two prominent human blood vessel fractions (CD31+ and CD36+) were combined and compared to the mouse scRNA-seq data through Label Transfer analysis. These results found shared developmental cues and endothelial cell lineages and states between the two species. Similar findings were found for the capillary-to-artery transition, as mouse endothelial cells mapped to the different human artery subclusters described by the authors. Remarkably, trajectory analyses of murine arterial cellular states suggested the progression of a single immature state -not found in adult artery endothelial cells- into two continuous and mature states, which also exist in the adult human heart. Using trajectory analysis, the authors also suggested that capillary endothelial cells give rise to arteries, as previously described in mouse heart development. The capillary-to-artery transition could be happening simultaneously at two different heart regions, reinforcing their previous findings concerning the defining role of heart location or microenvironment on blood vessel formation. However, detailed spatiotemporal studies of these cell subpopulations should corroborate these findings.
Motivated by the fact that coronary artery disease is a significant cause of death in the industrialized world, the authors closely analyzed the transcriptomes of the three different arterial cells during development, aiming to find potential genes that could shed light on disease progression and biomarkers. They found striking differences in their maturation states that correlated with differential gene expression and progression of artery arborization. In addition, their findings also highlighted the potential role of newly discovered transcription factors in Art subpopulations, including PRDM16, GATA2, and IRF6. Human-enriched genes involved in neurotransmission (e.g., GABA and Glutamate receptors) were not expressed in the mouse. The latter findings could open the way into potential new genes to target coronary diseases.
What we liked about this preprint
Most bioinformatic analyses of scRNA-seq data focus on the divergence state of cells during commitment and differentiation. Interestingly, here the authors use single-cell analysis and lineage tracing to address an opposite process, called convergent differentiation. In this context, two or more lineage origins contribute to the same endpoint cell state. Here, the authors addressed the converging state of endocardium and sinus venous-derived ECs onto capillary plexus. They found that the descendant capillary cells ‘remember’ their origins at the beginning of convergence but lose their origin memories during the converge trajectory and adopt location-based molecular properties when residing in different cardiac regions. By the end of this process, all capillary cells become indistinguishable by origin and location.
In conclusion, this preprint provides complete mouse and human single-cell datasets from the initiation of coronary vessel formation at embryonic stages to adulthood. The similarities between mouse and human coronary ECs single-cell data validate the usability of the mouse to understand human blood vessel development and speculatively might provide therapeutic windows to the high prevalence of coronary artery disease.
Future directions and questions to the authors
- Intriguingly, the author chose 10X Genomics for coronary ECs at embryonic days E12 and E17.5 and Smart-seq2 for the remaining data. Why these different single-cell technologies? Given that Smart-seq2 captures full-length mRNA while 10X Genomics uses a 5’ or 3’-tag sequencing method, could their parallel use introduce bias in the number of genes recovered and subsequent comparisons?
- The authors suggested that coronary capillary clusters at E12 are distinguished based on either SV- or Endo-derived gene signatures. What criteria did you use for selecting these gene signatures for the classification of Cap1 and Cap2?
- In figure 3g, the authors quantified the number of Car4+ cells associated with tdTomato+ lineage and distinct cardiac regions at E17.5. The results clearly show an enrichment of tdTomato+/Car4- in the septum and ventral cardiac areas, whereas this location-based heterogeneity is lost in the adult. Do you have similar quantitative results in the adult?
- Are there any differences in the proliferative or cell cycle progression capabilities of endothelial cell lineages (Endo- vs SV-derived) during heart development?
- What do the authors think about the existence of different subclusters of immature (one) and mature (two) arteries with the absence or presence of smooth muscle? At what extent endothelial cell developmental trajectories are determined by smooth muscle cells or vice versa?
References
Lupu, IE., De Val, S. & Smart, N. Coronary vessel formation in development and disease: mechanisms and insights for therapy. Nat Rev Cardiol 17, 790–806 (2020). https://doi.org/10.1038/s41569-020-0400-1
Su, T., Stanley, G., Sinha, R. et al. Single-cell analysis of early progenitor cells that build coronary arteries. Nature 559, 356–362 (2018). https://doi.org/10.1038/s41586-018-0288-7
World Health Organization (WHO): https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Accessed June the 3rd, 2021.
doi: https://doi.org/10.1242/prelights.29382
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