2009-2010 Sabbatical fellow at Centro de Investigacion Principe Felipe, Spain
2008-2009 Reader in Stem Cell Biology, Newcastle University
2004–2008 Senior Lecturer in Stem Cell Biology, Newcastle University
2003–2004 Lecturer in Stem Cell Biology, Newcastle University
1998–2003 Senior Research Associate, Department of Biological Sciences, Durham University
1994–1998 Junior Research Associate, Department of Human Genetics, Newcastle University
Dr. Carla Mellough
Dr. Irina Neganova
Dr Joseph Collin
Dr Katarzyna Tilgner
Mr. Mahmoud Khazim
Mr. Oliver Baylis
Mr. Charles 0ssei-Bempong
Mr. Shibo Jin
Ms. Ellie Meader
My group’s research is focused on three key stem cell areas, namely: (i) understanding of self renewal in human pluripotent stem cells; (ii) generation of functional and transplantable blood and retinal cells from human pluripotent stem cells and (iii) clinical translations of our basic biology studies to treat corneal and retinal blindness.
(i) Our studies in this area have largely concentrated on understanding of cell cycle regulation and DNA damage response in human pluripotent stem cell as well as the role of pluripotency network and signalling pathways and how these underpin the maintenance of pluripotent phenotype and maintenance of genomic stability. These studies have resulted in several peer review manuscripts which have been published in Hum. Mol. Genet., Oncogene, J. Cell Biology and Stem Cells. In the last four years we have initiated a large number of miRNA and proteomic studies with the aim of understanding factors that regulate G1 to S transition in human pluripotent stem cells and their role in maintenance and induction of pluripotency. One of the most fascinating aspects of stem cell development in the last four years has been induction of pluripotency in differentiated cells. My group in collaboration with Dr Lyle’s Armstrong’s group has now established more than 400 iPSC lines using various integrative and non integrative methods. These cell lines are being used in various comparative studies of pluripotency and differentiation. Most importantly we have combined this technology with our established haematopoietic differentiation methods to initiate disease modelling in patients diagnosed with Ligase IV/ XLF deficiency and Fanconi anaemia. These disease models link directly to our studies of cell cycle regulation and DNA repair and are giving us some interesting insights on the role of DNA repair pathways during induction of pluripotency which we intend to pursue in the next five years.
(ii) Over the last 5 years we have been able to establish a very efficient model of human ESC differentiation to haematopoietic lineages which results in long term multi-lineage haematopoietic engraftment into immunocompromised recipients at levels higher (16.26%) than described previously (paper was published by Cell Stem Cell and accompanied by two commentaries one in Cell Stem Cell and one in Nature Reports Stem Cells). Using this differentiation model, we have established a transcriptional network which we are using to understand the role of key transcription factors and miRNAs that govern not just haematopoietic differentiation from human pluripotent stem cells, but also lineage specification to red and white blood cells.
(iii) A cornerstone of our work has been the clinical implementation of corneal stem cell therapy in patients with limbal stem cell deficiency. Work carried out in my group in collaboration with Mr Figueiredo, Dr Kolli and Dr Ahmad has resulted in definition of a GMP compatible culture system for expansion of limbal epithelial cells which have been transplanted into patients with unilateral limbal stem cell deficiency. In the last four years, eight patients have been transplanted successfully and now have a greatly improved vision and quality of life. This is the first example of corneal transplantations in the UK carried out in the absence of any animal derived ingredients. Funded by the MRC UK, we are pursuing these transplants in a larger number of patients. In parallel to this program, my group has been pursuing differentiation of human pluripotent stem cells to rod and cone photoreceptors using GMP acceptable protocols in collaboration with Mr. Steel and Dr. Sernagor. We have established an efficient differentiation system that achieves higher efficiency in a shorter time window than published studies. Our current efforts are concentrated on testing whether the human pluripotent stem cell derived cone and rod photoreceptors do engraft and contribute to restoration of vision in animal models of retinal degeneration. Using our iPSC expertise, we have been able to establish iPSC from retinitis pigmentosa patients which we intend to subject to gene correction using zinc finger nuclease technology. With the same technology we are also trying to target reporter genes to key retinal factors that control rod and cone commitment, thus enabling us to track their emergence during differentiation process and initiate studies of their transcriptome and proteome.