Cellular individuality across the spectrum of heart diseases with implications for new therapeutic targets
Författare
Summary, in English
In Paper I, we sought to develop a protocol for single cell isolation from frozen human hearts. However, a range of protocols was unable to isolate intact cells. Instead, we developed a protocol for isolation of single nuclei and show that nuclear transcriptomes are highly representative of the overall cellular and cytoplasmic transcriptome in human heart cells. By application of this protocol to human hearts and single nuclei RNA sequencing (snRNAseq) we developed a transcriptional atlas of the cell types and molecular profiles of the human heart. In Paper II, we greatly expanded this atlas to >100 human hearts with specific heart diseases and hearts without evidence of heart disease (controls). Compared to control hearts, the largest number of transcriptional differences were observed in dilated cardiomyopathy but most changes were also broadly shared with other conditions. In contrast, the largest number of unique transcriptional differences were seen in arrhythmogenic right ventricular cardiomyopathy. In Paper III, we find increased expression of TSLP in response to strain of cardiac fibroblasts. In addition, cardiac overexpression of TSLP resulted in increased expression of transforming growth factor β in myocardial mast cells, and tissue fibrosis. In Paper IV, we confirmed that the surface area of both cardiomyocytes and their nuclei were increased in HF patients, consistently with different underlying conditions, as compared to controls. Increased mechanical strain of iPS-derived cardiomyocytes also resulted in increased cellular and nuclear size but these changes in nuclear size were not explained by changes in transcriptional activity as reflected by RNA content.
Collectively, this work shows the feasibility of dissecting the molecular pathophysiology of heart diseases from frozen single cardiac nuclei, highlights molecular signatures associated with specific heart muscle conditions, and implicates TSLP as a putative therapeutic target to prevent cardiac remodelling.
Avdelning/ar
Publiceringsår
2024
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Issue
2024:69
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Lund University, Faculty of Medicine
Ämne
- Cardiac and Cardiovascular Systems
Status
Published
Forskningsgrupp
- Molecular Epidemiology and Cardiology
Handledare
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
Försvarsdatum
20 maj 2024
Försvarstid
13:00
Försvarsplats
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63831404031
Opponent
- Bruna Gigante (professor)