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The generation of RBCs in vitro from stem cell sources and the molecular regulation of erythropoiesis in health and disease

School of Biochemistry

About the Project

Development of systems for the generation of red blood cells (RBCs) from stem cell sources (adult peripheral blood, cord blood and induced pluripotent stem cells) in vitro is of great interest to health services globally, as such a product could overcome many of the problems associated with donor blood, in particular the availability of certain rare blood groups and for patients requiring repeat transfusions.

However, adult and cord stem cells have finite expansion potential which presently restricts the number of red cells that can be obtained, greatly impacting the economic viability of producing therapeutic quantities of red cells from these sources. In addition iPSC-derived erythroid cells have severe differentiation defects. We have therefore taken an alternative approach creating immortalized adult erythroid cell lines that recapitulate erythropoiesis, and which provide the first viable approach for a sustainable source of RBCs for therapeutics. Moreover we have used CRISPR gene editing to create designer lines with specific blood group phenotypes and as a universal RBC product.

However, such lines have significant additional potential, and we are using our methodology and gene editing to create lines as disease model systems to study the underlying molecular defects of conditions such as thalassemia, sickle cell disease and congenital dyserythropoietic anaemias, along with the application of these lines as novel drug screening platforms.
We are also interested in the regulation of erythropoiesis, in particular transcription factors such as KLF1. KLF1 is essential for erythropoiesis and mutations in this transcription factor can result in severe red blood cell disorders.
We utilise cell biology, transcriptomic, proteomic. biochemical and molecular biology approaches, including gene editing by CRISPR, shRNAs and ectopic expression, qPCR, multiplex flow cytometry, Fluorescent activated cell sorting, confocal microscopy, TMT labelling coupled Mass Spec.

We are part of the NIHR Blood and Transplant Research Unit (BTRU) to advance research on the manufacture of red blood cells from stem cells and their translation from the lab to human trials, along with researchers at NHS Blood and Transplant (NHSBT, Bristol) and Dr Ash Toye within the University.

Available projects include:
• Creation of cytokine independent erythroid lines to improve viability as therapeutic products and further investigate the regulation of erythropoiesis
• Creation and characterisation of specific disease lines and determination of novel therapeutic approaches
• Creation of lines and determination of how KLF1 mutations result in disease phenotypes, and conversely how some mutations may be utilised as a therapeutic approach for beta thalassemia
• Creating further improved and novel erythroid lines using gene editing approaches as a therapeutic product

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