​​From stem cells to red cells

Full project title: From stem cells to red cells: lab-grown blood, mechanosensation and mechanisms of sickle cell disease 

Project lead for CBR: Dr Tim Satchwell

My lab, based within the Centre of Biomedical Research at UWE Bristol, focuses on the fascinating process of red blood cell development from haematopoietic stem cells. We use primary human haematopoietic stem cells isolated from peripheral blood alongside immortalised erythroblast cell lines to model erythropoiesis in vitro.

To become the highly specialised, deformable biconcave discs that define mature red blood cells, erythroid progenitors undergo extensive intracellular and membrane remodelling. This includes complete extrusion of the nucleus, resulting in a cell that contains no DNA. While this is central to red blood cell function, it prevents direct genetic manipulation of mature cells.

To overcome this, we genetically modify undifferentiated stem cells and erythroid precursor cells prior to differentiation, using a variety of approaches, including CRISPR-based gene editing. These engineered cells are then directed to develop into red blood cells. This strategy allows us to model red cell disorders, investigate the mechanisms underlying disrupted erythropoiesis, and manipulate cell surface proteins to study their function and interactions, as well as to produce red blood cells with novel characteristics.

By combining these approaches, we aim to advance understanding of both normal and pathological red blood cell development and cellular interactions, while contributing to efforts to produce high-quality lab-grown red blood cells for transfusion.

Current projects in my lab focus on the final stages of reticulocyte maturation in circulation, including the role that interactions with endothelial cells lining blood vessels may play in driving this process. We are also excited to be beginning a new project investigating the role of mechanosensory proteins, particularly Piezo1, in both red blood cell development and their passage through narrow capillaries. In addition, we are exploring how Piezo1 activity and phosphorylation dynamics contribute to red blood cell sickling and pathology in sickle cell disease.

Our work is supported by funding from the Royal Society and the BBSRC.

• Martins Freire C, King NR, Dzieciatkowska M, Stephenson D, Moura PL, Dobbe J, Streekstra G, D'Alessandro A, Toye AM, Satchwell TJ. (2024). Complete absence of GLUT1 does not impair human terminal erythroid differentiation. Blood Advances. 8(19):5166-5178. 
• Karamatic Crew V*, Tilley LA*, Satchwell TJ*, AlSubhi SA, Jones B, Spring FA, Walser PJ, Martins Freire C, Murciano N, Rotordam MG, Woestmann SJ, Hamed M, Alradwan R, AlKhrousey M, Skidmore I, Lewis S, Hussain S, Jackson J, Latham T, Kilby MD, Lester WA, Becker N, Rapedius M, Toye AM, Thornton NM. (2023). Missense mutations in PIEZO1, encoding the Piezo1 mechanosensor protein, define the Er red blood cell antigens. Blood. Jan 12;141(2):135-146.  
• Moura PL, Lizarralde Iragorri MA, Français O, Le Pioufle B, Dobbe JGG, Streekstra GJ, El Nemer W, Toye AM*, Satchwell TJ*. (2019). Reticulocyte and red blood cell deformation triggers specific phosphorylation events. Blood Advances. Sep 10;3(17):2653-2663. 
• Satchwell TJ*#, Wright KE*#, Haydn-Smith KL, Sánchez-Román Terán F, 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. Aug 23;10(1):3806. 
• Hawksworth J*, Satchwell TJ*, Meinders M, Daniels DE, Regan F, Thornton NM, Wilson MC, Dobbe JG, Streekstra GJ, Trakarnsanga K, Heesom KJ, Anstee DJ, Frayne J, Toye AM. (2018). Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing. EMBO Molecular Medicine. Apr 26. pii: e8454. 

For further information about the project, please contact Dr Tim Satchwell (tim.satchwell@uwe.ac.uk).