Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development

Abstract

Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells "remember" their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources-the endocardium (Endo) and sinus venosus (SV)-but whether transcriptional or functional differences related to origin are retained is unknown. We addressed this by combining lineage tracing with single-cell RNA sequencing (scRNAseq) in embryonic and adult mouse hearts. Shortly after coronary development begins, capillary ECs transcriptionally segregated into two states that retained progenitor-specific gene expression. Later in development, when the coronary vasculature is well-established but still remodeling, capillary ECs again segregated into two populations, but transcriptional differences were related to tissue localization rather than lineage. Specifically, ECs in the heart septum expressed genes indicative of increased local hypoxia and decreased blood flow. Adult capillary ECs were more homogeneous and lacked indications of either lineage or location. In agreement, SV- and Endo-derived ECs in adult hearts displayed similar responses to injury. Finally, scRNAseq of developing human coronary vessels indicated that the human heart followed similar principles. Thus, over the course of development, transcriptional heterogeneity in coronary ECs is first influenced by lineage, then by location, until heterogeneity disappears in the homeostatic adult heart. These results highlight the plasticity of ECs during development, and the validity of the mouse as a model for human coronary development.

Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression

“…Trajectory inference analysis also revealed subsequent arterial specification of capillary EC. This predicted cellular transition in the human fetal heart was also recently identified by Phansalkar el al 19 , thus collectively providing human relevance to current understanding of coronary artery development derived from murine studies [7][8][9] . However, in addition to confirming the upregulation of known mediators of arterial specification such as HEY1 40 and SOX17 53 , MECOM was also identified as having a role in the establishment of an arterial EC identity.…”

“…This suggests that SMAD1 may mediate angiogenesis within hypoxic regions in the developing heart wall, although this will require further investigation to verify. The existence of two capillary populations with distinct transcriptional signatures, including the differential expression of KIT and INMT, was recently confirmed in an independent study from Phansalkar et al 19 which performed low throughput scRNA-seq on EC isolated from 11-, 14-and 22-week human fetal hearts.…”

“…In addition, improvements in high throughput scRNA-seq platforms have facilitated the characterisation of tens of thousands of cells in parallel, thus allowing for 'atlas' studies to map the gene expression profile of entire organs during embryogenesis 10 . In recent years, such scRNA-seq studies have mapped the transcriptional profile of both murine and human heart development [11][12][13][14][15][16][17][18][19] . In the study by Cui et al 13 , scRNA-seq was conducted using cells isolated from specific regions of 18 human fetal hearts, ranging from 5 -24 weeks gestation.…”