skip to primary navigationskip to content
 

Blood Cell Production

Human pluripotent stem cells (hPSC) can be maintained and expanded in vitro for prolonged periods and can be induced to differentiate towards virtually any cell type. Therefore, they offer huge opportunities for basic research and clinical applications. Platelets and red cells are enucleated and therefore can be irradiated prior to administration to patients. This opens the possibility of generating banks of genetically-modified hPSCs from which advanced cellular therapies can be generated.

Megakaryocyte production from hPSCs

Current haematopoietic differentiation protocols from PSCs are hampered by a lack of efficiency, complicated cell handling, expensive cytokine cocktails, and the use of serum and xenogenic feeder cells, which all preclude clinical application of the end product. We are applying a forward programming method based on the overexpression of key transcriptional regulators to “force” cellular identity for the production of megakaryocytes (MK), the blood platelet progenitors. In addition, using novel genome editing technologies, we are exploring novel ways to forward programme hPSCs to megakaryocytes. Cellular maturation varies from one hPSC line to the other and in collaboration with Professor Nicole Soranzo (Wellcome Trust Sanger Institute, WTSI) we are investigating the genetic and epigenetic determinant of hPSC-derived MK maturation variability.

Key people: Dr Thomas Moreau, Dr Amanda Evans, Miss Maria Colzani, Miss Amanda Dalby, Mr Wing Han-Wu, Mr Yumi Yan, Dr. Cedric Ghevaert.

Collaborators: Dr Nicole Soranzo (WTSI), Dr Barry Rosen (WTSI), Dr Marloes Tijssen (Department of Haematology), Dr Ludovic Vallier (Department of Surgery), Professor Roger Pedersen (Department of Surgery).

Red cell production from hPSCs

The production of red cells from hPSCs is hampered by the fact that the cells produced have an embryonic phenotype, in particular expression of embryonic and fetal globins rather than adult globins and poor enucleation rate. We are part of the BloodPahrma consortium, funded through a strategic initiative from the Wellcome Trust. Its aim is to produce red cells from hPSCs for transfusion into humans and to carry out first-in-man studies with cells produced in the laboratory. We are using our expertise in the forward programming approach to enforce an adult phenotype to PSC-derived red cells.

Key people: Dr Marloes Tijssen, Dr Nicola Foad, Mr Yumi, Dr. Cedric Ghevaert.

Key collaborators: BloodPharma Consortium: Professor Marc Turner (SNBTS), Professor Lesley Forrester (University of Edinburgh), Dr Jo Mountford (University of Glasgow), Roslin Cells, Cell Therapy Catapult.

Disease Modelling

Induced PSCs (iPSCs) can be derived from somatic cells from patients and used for basic research into disease mechanisms. The genes responsible for Gray Platelet Syndrome (NBEAL2) and Thrombocytopenia with Absent Radii (RBM8A) were identified in 2011/2012 by Prof Ouwehand’s and my group, respectively. We are now using patient-derived iPSCs to investigate the role of these genes in megakaryocyte maturation and platelet formation.

Key people: Dr Amanda Evans, Dr Thomas Moreau, Dr. Cedric Ghevaert.

Collaborators: Professor Willem Ouwehand (Department of Haematology), Dr Jose Guererro (Department of Haematology), Dr Deborah French (CHOP, Philadelphia).