Modelling developmental haematopoiesis in vitro
My enthusiasm for the molecular and cellular mechanisms underlying cell fate decisions started during my undergraduate degree in Medical Science at the University of Birmingham. With a keen interest in stem cell and cancer biology, I sought to gain a research project in the summer following my second year. I successfully gained a competitively funded position in Dr Laura O’Neill’s laboratory investigating the effect of histone demethylase inhibition on X-inactivation in female mouse embryonic stem cells.
Subsequently, in my final year at Birmingham, I joined the lab of Professor John Frampton as a research student under the supervision of Dr Giacomo Volpe to investigate the role of the transcriptional repressor, GFI1, in cytogenetically-normal AML. Through siRNA mediated knockdown of GFI1 in AML cell lines, I confirmed in silico data suggesting high levels of GFI1 are correlated with a transcriptional profile previously described as conferring poor survival. This data was then written up in my prize-winning dissertation and made a significant contribution to a publication (Volpe et al., 2017). Following my graduation with first-class honours from the University of Birmingham in July 2017, I moved to the University of Oxford in October 2017 to join Professor Catherine Porcher’s laboratory in the Weatherall Institute of Molecular Medicine to study for my DPhil in Medical Science.
My DPhil project aims to unpick the reasons underlying the incomplete development of haematopoietic stem cells from current in vitro differentiation cultures of embryonic stem cells and more closely recapitulate the timing, strength and combination of signals that occur during embryonic development. To assess the success of these novel culture conditions, we will use multiple cellular and molecular methods to evaluate the presence of intermediates that reflect those seen in vivo, such as imaging, single cell genomics/transcriptomics, flow cytometry and cell-based replating assays. Ultimately, this model will allow the dissection of key molecular mechanisms underlying the cell fate decisions leading to HSC emergence. This is of particular interest in the human system, as it will allow the investigation of species-specific mechanisms not accessible using embryonic dissection for ethical reasons. Additionally, differentiation of induced (i)PSCs could allow the generation of patient-specific HSCs, reducing the need for bone marrow donors and immunosuppressants.
Volpe, G., D. S. Walton, D. E. Grainger, C. Ward, P. Cauchy, D. Blakemore, D. J. L. Coleman, P. N. Cockerill, P. Garcia and J. Frampton (2017). "Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature." Scientific Reports 7(1): 11148