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

• Published in: bioRxiv
• Main Authors: Phansalkar, Ragini S, Krieger, Josephine, Zhao, Mingming, Kolluru, Sai Saroja, Jones, Robert C, Quake, Stephen R, Weissman, Irving L, Bernstein, Daniel, Winn, Virginia D, D'amato, Gaetano, Red-Horse, Kristy
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 26.04.2021
• Subjects: Blood flow; Blood vessels; Cell differentiation; Cell fate; Coronary vessels; Developmental plasticity; Embryogenesis; Gene expression; Heart; Hypoxia; Localization; Septum; Transcription
• DOI: 10.1101/2021.04.25.441380

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. Competing Interest Statement The authors have declared no competing interest.