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

Ragini Phansalkar,Stephen R Quake,Irving Weissman,Virginia D Winn,Kristy Red-Horse,Robert C Jones,Mingming Zhao,Daniel Bernstein,Sai Saroja Kolluru,Josephine Krieger,Gaetano D'Amato

doi:10.7554/elife.70246

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.

Highlights

During embryonic development, progenitor tissue sources produce new cell types through shifts in epigenetic and transcriptional states
Much research addresses how new cell types form, yet there is less focus on how the transcriptional or chromatin states of progenitor cells relate to gene expression in their descendants, that is, what do mature cells ‘remember’ about their history? This question is intriguing in cases where multiple progenitor sources contribute to the same cell type, since different origins could result in different behaviors or responses to injury and disease
A tamoxifen-inducible BmxCreER (Ehling et al, 2013) mouse was crossed with the RosatdTomato Cre reporter, which labels a high percentage of the Endo (94.44% of Endo cells labeled at e12.5), but does not mark the sinus venosus (SV) (3.61% of SV cells labeled at e12.5) (D’Amato et al, 2021)

Summary

Introduction

Progenitor tissue sources produce new cell types through shifts in epigenetic and transcriptional states. We used scRNAseq of lineage-traced ECs from mouse hearts at various stages of development to show that while SV- and Endo-d erived capillary cells initially retained some source-specific gene expression patterns, these differences were only present at an early stage of development. We propose a model in which the transcriptional state of non-proliferative coronary ECs is initially influenced by their lineage, by regional differences in environmental factors, until both of these signatures fade in adulthood These findings highlight the importance of environmental factors in influencing EC behavior and validate mice as a representative model for human coronary development

Results

E SE enriched in Endo

C Reduction in Cap1 and loss of Art3 in adult human coronary ECs

Discussion

Materials and methods