PhD Project - MRC DiMeN Doctoral Training Partnership: Examining the role of metabolism in paediatric cancer initiation using human pluripotent stem cells at University of Sheffield, listed on FindAPhD.com
Our latest preprint:
It is very useful to be able to measure the properties of individual cells in relation to their neighbours in 3D tissues, but it is also complicated & difficult
The talented Matt French devised computational approaches that helped us overcome many of these difficulties
This helps us work out when where & how cells make differentiation decisions by talking to their neighbours during axis elongation
Hope it's useful! Comments welcome
Objective Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). Design ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single-cell RNA sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors’ capacity to integrate and affect functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. Results We found that our protocol consistently gives rise to high yields of a cell population exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons/glia within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed significantly increased basal contractile activity and increased responses to electrical stimulation compared with control tissue. Conclusion Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and increase functional responses in human HSCR patient colonic tissue. Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding authors upon reasonable request. Transcript profiling: RNA-seq data has been deposited in the Gene Expression Omnibus database (<https://www.ncbi.nlm.nih.gov/geo/>) under the accession number GSE252061.
We are currently advertising two 3-year posts in my group, a research assistant and a postdoc, to work on a Yorkshire Cancer Research-funded project at the interface of stem cell biology and cancer modelling. For more details see: https://www.jobs.ac.uk/job/DHT630/research-assistant
and https://www.jobs.ac.uk/job/DHT349/research-associate
Deadline=17th June, please spread the word!
Neuromesodermal progenitor (NMPs) give rise to neural and mesodermal tissues during axis elongation. In their study, Fay Cooper, Anestis Tsakiridis and colleagues reveal the role of Notch signalling in NMP differentiation and its role in Hox gene expression. To learn more about their work, we spoke to first and co-corresponding author, Fay Cooper, and to co-corresponding author Anestis Tsakiridis, Group Leader at the University of Sheffield, UK.
Sally Lowell
