Summary

Red blood cell development in health and disease.

In the bone marrow, red blood cells (RBC) are constantly being produced from hematopoietic stem cells (also called progenitor cells), a process called erythropoiesis. The peripheral blood of an individual also contains a host of progenitor cells that can be induced to undergo erythropoiesis. We are developing culture techniques to maximize the production of red blood cells from peripheral blood for the study of erythropoiesis. This involves exploration of the use of synthetic scaffolds environments for blood production and also interactions with stromal cells. The eventual aim being to manufacture enough RBC for transfusion purposes or novel therapeutics.

During the process of erythropoiesis, red blood cell progenitors undergo a remarkable transformation; they become smaller, express a variety of erythroid specific proteins (e.g. Haemoglobin and band 3 (AE1)), lose their nucleus and remodel their membrane to generate the nascent reticulocyte and then go on to mature further to the recognizable biconcave red blood cell. Whilst undergoing these substantial morphological changes the progenitor cell must assemble and selectively retain key membrane protein complexes (e.g. band 3 (AE1) and Rhesus proteins). These membrane protein complexes give the RBC membrane its unique antigenic and structural properties and facilitate efficient gas exchange. Very little is known about how multiprotein complexes are assembled or correctly localized during erythropoiesis or why specific alterations in membrane protein composition occur in red cell diseases such as Hereditary Spherocytosis. This is another area of focus for the lab.

The lab uses biochemical and cell biology techniques to monitor the expression and interactions of erythroid specific proteins throughout differentiation in health and disease. We are also manipulating RBC progenitor protein expression. This work will greatly enhance our knowledge of the structure-function relationships within the RBC membrane and will identify the stages and mechanisms whereby membrane protein composition is altered during normal differentiation process and during human disease. This also helps us to form a benchmark of normal erythropoiesis to explore the viability of blood cells produced using embryonic stem cells, immortalised cells or human induced pluripotent stem cells. The lab is also a member of the BrisSynBio Centre, and here we aim to use our ability to culture RBCs and manipulate them to develop the RBC as a synthetic biology chassis for novel functionality or a vehicle for novel therapeutics.

Biography

Teaching

Science and Society

Health Sciences: Biochemistry - Bristol Dental School

Cellular Processes

Science in Society

Molecular Cell Biology

Research and Communication Skills

Advanced Options in Biochemistry

Expertise

My PhD with Prof. Owen Jones (University of Bristol) was on the generation of reactive oxygen species by neutrophils and non-phagocytic cells, with a focus on free radical damage in Alzheimer?s Disease. I then joined the laboratory of Prof. Mike Tanner where I developed my interest in the red blood cell AE1 and the kidney version of this protein. After Professor Tanner's retirement, I moved to Professor George Bantings laboratory where I have continued to work on AE1 trafficking and interactions.

Memberships

Organisations

School of Biochemistry

Other sites

• Biochemistry

Links

• Bristol Blood and Transfusion Unit website

Recent publications

• Severn, CE, Eissa, AM, Langford, CR, Parker, A, Walker, M, Dobbe, JG, Streekstra, GJ, Cameron, NR & Toye, AM, 2019, ‘Ex vivo culture of adult CD34+ stem cells using functional highly porous polymer scaffolds to establish biomimicry of the bone marrow niche’. Biomaterials, vol 225.
• Pellegrin, S, Haydn-Smith, K, Hampton-O'Neil, L, Hawley, B, Heesom, K, Fermo, E, Bianchi, P & Toye, A, 2019, ‘Transduction with BBF2H7/CREB3L2 upregulates SEC23A protein in erythroblasts and partially corrects the hypo-glycosylation phenotype associated with CDAII’. British Journal of Haematology, vol 184., pp. 876-881
• Satchwell, TJ, Wright, KE, Haydn-Smith, KL, Terán, FS, Moura, PL, Hawksworth, J, Frayne, J, Toye, AM & Baum, J, 2019, ‘Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements’. Nature Communications, vol 10.
• Trakarnsanga, T, Ferguson, D, Daniels, D, Griffiths, R, Wilson, M, Mordue, K, Andrienko, T, Condie, A, McCahill, A, Mountford, JC, Toye, A, Anstee, D & Frayne, J, 2019, ‘Vimentin expression is retained in erythroid cells differentiated from human iPSC and ESC and indicates dysregulation in these cells early in differentiation’. Stem Cell Research and Therapy, vol 10.
• Hampton-O'Neil, L, Severn, C, Gurung, S, Cross, S, Nobes, C & Toye, A, 2019, ‘Ephrin/Eph receptor interaction facilitates macrophage recognition of differentiating human erythroblasts’. Haematologica, vol 104.
• Moura, PL, Hawley, BR, Dobbe, JGG, Streekstra, GJ, Rab, M, Bianchi, P, van Wijk, R, Toye, AM & Satchwell, T, 2019, ‘PIEZO1 gain-of-function mutations delay reticulocyte maturation in hereditary xerocytosis’. Haematologica.
• Moura, PL, Iragorri, MAL, Francais, O, Le Pioufle, B, Dobbe, JGG, Streekstra, GJ, El Nemer, W, Toye, AM & Satchwell, T, 2019, ‘Reticulocyte and red blood cell deformation triggers specific phosphorylation events’. Blood Advances, vol 3., pp. 2653-2663
• Gurevich, D, Severn, C, Twomey, C, Greenhough, A, Cash, J, Toye, A, Mellor, H & Martin, P, 2018, ‘Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression’. EMBO Journal, vol 37.
• Abbas, YM, Toye, AM, Rubinstein, JL & Reithmeier, RA, 2018, ‘Band 3 function and dysfunction in a structural context’. Current Opinion in Hematology, vol 25., pp. 163-170
• Huisjes, R, Satchwell, TJ, Verhagen, LP, Schiffelers, RM, van Solinge, WW, Toye, AM & van Wijk, R, 2018, ‘Quantitative measurement of red cell surface protein expression reveals new biomarkers for hereditary spherocytosis’. International Journal of Laboratory Hematology.

View complete publications list in the University of Bristol publications system