A platform to promote safe cell therapies

About the project

Cell replacement therapies aim to heal diseased or injured tissues and organs by replacing the missing or defective cells in the body. Human pluripotent stem cells (hPSCs) represent an essential pillar of such efforts due to their dual ability to proliferate extensively in culture and to differentiate to any cell type. Several clinical trials using hPSC-derived differentiated cells for treatment of diseases and injuries, such as macular degeneration, Parkinson’s disease and spinal cord injury are currently ongoing, with many more therapies also progressing towards the clinical trials. The generation of large numbers of differentiated cells required for cell replacement therapies typically entails expanding undifferentiated hPSC and keeping them in culture for long periods of time. However, a key issue with this process is the appearance of non-random genetic changes (such as gains of chromosomes 1, 12, 17, 20 or X) in hPSCs upon prolonged culture.

Genetically variant hPSCs harbouring recurrent genetic changes outcompete the wild-type cells, thereby achieving clonal dominance in cultures. Such recurrent variants show signs of neoplastic transformation and defects in differentiation, raising concerns that they may pose significant dangers for their use in regenerative medicine. These changes may also affect the use of hPSCs in other applications including drug discovery, toxicology and disease modelling. However, current strategies for detecting genetically variant cells are limited in their sensitivity. Moreover, there are currently no effective strategies for removal of aberrant cells upon their detection.

In this project, in collaboration with Dr Nika Shakiba (University of British Columbia) and Dr Sidhartha Goyal (University of Toronto) you will be developing methods for reliable and sensitive detection of variant cells, and devising strategies for elimination of abnormal cells from expanding hPSC cultures. The outcomes of this work should have far-ranging implications for use of hPSCs in research and medicine.

This project uses stem cell maintenance and differentiation, coupled with state-of-the-art microscopy, physiological, biochemistry and molecular biology approaches, including the use of CRISPR/Cas9.

We encourage applicants to find out more about this exciting project and our vibrant research environment by contacting Professor Ivana Barbaric at i.barbaric@sheffield.ac.uk.

About the team

The Barbaric lab is located in the Centre for Stem Cell Biology at the School of Biosciences, the University of Sheffield. The research in the Barbaric lab focuses on the basic biology of human pluripotent stem cells (hPSCs) and their applications pertinent to regenerative medicine and modelling human disease and development. One of our key research topics is genetic stability of hPSCs. We are focused on understanding both the causes of genetic changes in hPSCs and their consequences for stem cell fate decisions and downstream applications of hPSCs. This project fits with our core interests and builds on strong track record of our team in the area of the genetic stability of hPSCs. We are well equipped for research on hPSCs with excellent cell culture and molecular biology facilities. To find out more about our team, please visit our websites: https://www.thebarbariclab.com/ and https://www.sheffield.ac.uk/biosciences/people/academic-staff/ivana-barbaric