Study of catecholaminergic cells in murine heart

Thesis

Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. During my D.Phil, I established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and high-resolution spatially resolved transcriptomics (SrT) analyses. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbhh⁺ -CMs), which is closely associated with the CCS. To further comfirm, genetic fate mapping using DbhCre/Rosa26-tdTomato reporters combined with SrT revealed that Dbh⁺-CM lineage is Hcn4-independent, first emerged in the sinoatrial node at E12.5, then to atrial and ventricular CCS components at E14.5 and became prominent within CCS at perinatal stages. Dbhh⁺ -CM populating CCS occurred concurrently with sympathetic innervation. Electrophysiological optogenetic mapping revealed a fast conduction in DbhCre/ChR2-tdTomato hearts by selectively stimulating Dbh+ -CMs. Furthermore, catecholaminergic-type vesicles were identified in adult cardiomyocytes. Thus, by utilising advanced transcriptomic, genetic and functional analyses, my study provides new insights into mammalian CCS development and heterogeneity. Besides, by combining an improved heart tissueclearing technique with high resolution light sheet fluorescence microscopy (LSFM), I conducted three-dimensional and multi-scale volumetric imaging of ultra-thin planes of murine hearts to visualize the specific cardiomyocyte subpopulations. This method provides a tool for further geometrical and topological analysis of these cell types and the correlation with their physiological function in specific region of the murine heart.

Authors: Sun, T

• DOI: 10.5287/ora-zbwrnb49v
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Bioinformatics; Pharmacology; Physiology; Cardiovascular system--Physiology