A cell atlas of the human outflow tract of the heart
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Defects affecting the outflow tract (OFT) of the heart represent a third of all congenital heart disease cases. They often result in abnormal blood circulation and/or oxygenation in the neonate and require surgical correction shortly after birth. Correct development and function of the OFT depend on the interaction between different cell types. These cell types contain the same genetic instructions but produce different proteins because they express different genes. We will use new technologies, which will allow us to characterize single-cell expressed genes, to deconstruct the human OFT tissue into its constituent cell types and trace the diverse origins of the cells during embryonic development. Collectively, these results will provide new insight into how healthy and diseased cell states are established, with knock-on implications in disease diagnosis and personalized and regenerative medicine.
Technical Summary
Congenital heart disease is a major birth defect, and defects specifically affecting the outflow tract (OFT) of the heart represent a third of all CHD cases. Septation of the OFT during embryogenesis is crucial to establish the double circulation found in mammals, which separates oxygenated from de-oxygenated blood. The use of model systems has substantially advanced our understanding of the cell lineages that contribute to the mature OFT. However, human development remains significantly underexplored at the molecular level. In addition, a clear relationship between cell lineages and the cell types found in the adult OFT is still lacking. Here we will define the different cells that comprise the OFT (repertoire of transcripts and accessible regulatory elements) and establish their developmental origin. We will perform massively parallel single-nucleus RNA sequencing (snRNA-seq) and single cell assay for transposase-accessible chromatin (ATAC-seq) on human OFT tissues, isolated from developing (three time points) and adult hearts. Data analysis will capture the developmental trajectories of OFT cells and their contribution to the mature OFT. Thus, this project will define the different cell types that form the OFT of the heart and the gene regulatory networks that control their differentiation, improving our understanding of the causes of cardiovascular disease and paving the way for efficient cell reprogramming and the generation of specific cell types.
Planned Impact
Detailed maps of cells in the outflow tract will translate into an improved understanding of the mechanisms underlying cardiovascular disease, the development of better therapies based on cell-type specific targets for drug discovery and will provide novel tools for disease diagnosis. This will have an important impact on society in terms of improvements to health and well-being. In addition, results from this work have the potential to uncover more efficient ways to harness cell reprogramming and generate high fidelity production of specific cell types, which will be of immediate relevance to stem cell researchers, as well as biotechnology companies developing stem cell-based therapies. Defining the gene regulatory networks active in specific cell types will improve our understanding of how cell states are achieved and identify general rules that control gene expression. Therefore, results obtained in this project will be of interest and benefit to researchers in the fields of genomics, transcriptional regulation, and epigenetics. The interdisciplinary nature of this study will provide opportunities to train junior researchers, including undergraduate and postgraduate research students rotating in the lab, as well as postdoctoral researchers, in systems-based approaches and advanced bioinformatics. Acquiring these highly in-demand skills will contribute to the economic competitiveness of the UK.
Publications
Gerrard DT
(2020)
Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders.
in Nature communications
Description | BHF Project Grant-Pharyngeal arch cell signalling in arch artery morphogenesis |
Amount | £273,000 (GBP) |
Organisation | Newcastle University |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2023 |
Description | Decoding the role of vascular smooth muscle cell heterogeneity in cardiovascular disease by single cell genomics |
Amount | £15,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2020 |
End | 04/2024 |
Description | NHS Charities |
Amount | £48,000 (GBP) |
Organisation | Newcastle University |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2021 |
End | 07/2022 |
Description | Human Cell Atlas Consortium |
Organisation | Human Cell Atlas |
Sector | Charity/Non Profit |
PI Contribution | We are contributing by generating maps of cell types in the outflow tract of the heart |
Collaborator Contribution | This is an international consortium with the goal of mapping all cell types present in the human body |
Impact | Outputs will be in the form of single cell datasets that will be made publicly available and research manuscripts |
Start Year | 2018 |
Description | International symposium 'Genome regulation in development and disease' |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | We organised the workshop with the support of UK-India Education and Research Initiative (UKIERI) with the aim of enhancing educational linkages between India and the UK. We have reached about 300 participants, many of which were postgraduate students at India and UK based institutions. |
Year(s) Of Engagement Activity | 2021 |
Description | Pupil research placement |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | We organised a placement for A-level pupils. This was supposed to take place in June 2020 but was cancelled because campus was closed. |
Year(s) Of Engagement Activity | 2020 |
Description | Transcriptional dynamics in developmental biology |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A two day India-UK bilateral symposium on transcriptional dynamics and regulation with research seminars and lectures largely aimed to researchers, postgraduate and undergraduate students. |
Year(s) Of Engagement Activity | 2020 |