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 endothelial cells (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 primarily 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 with respect to both lineage and 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 declines 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.

Single cell evaluation of endocardial HAND2 gene regulatory networks reveals critical HAND2 dependent pathways impacting cardiac morphogenesis

“…This suggests that coronary angiogenesis is driven by distinct mechanisms within different regions of the developing heart. The cellular origin of coronary vasculature is a source of some debate, the current consensus being that coronaries of the ventricular free wall are derived from the epicardium and the sinus venosus, whereas interventricular septal coronaries are derived from the ventricular endocardium (Phansalkar et al, 2021; Rhee et al, 2021; Zhang et al, 2016).…”

Vascular endothelial cell development and diversity

“…This phenomenon of ‘convergent differentiation’ has also been seen in olfactory projection neurons 126 , but not in certain populations of haematopoietic cells or tissue-resident macrophages, which retain markers of primed fate potential 127 , 128 . Furthermore, no functional differences have been observed in endothelial cells from either lineage, such that they have largely identical proliferative capacity in response to injury 66 .…”

“…Direct and deep comparisons of capillary endothelial cell transcriptional states from lineage-traced hearts indicated that adult coronary endothelial cells originating from distinct sources do not retain the molecular signatures of their progenitors 66 . This phenomenon of ‘convergent differentiation’ has also been seen in olfactory projection neurons 126 , but not in certain populations of haematopoietic cells or tissue-resident macrophages, which retain markers of primed fate potential 127 , 128 .…”

Endothelial cells during craniofacial development: Populating and patterning the head

“…Using this method, a unique endothelial subtype was identified in the tooth specialised for dentinogenesis ( Matsubara et al, 2022 ). Interestingly, in the cardiac field, developing endothelial cells initially segregated by lineage but later by tissue localisation, with adult endothelial cells being more homogeneous with respect to lineage and location ( Phansalkar et al, 2021 ). Drastic changes in retinal endothelial gene expression were also observed during postnatal development, between P6 and P10 ( Zarkada et al, 2021 ).…”