For the first time, researchers at the University of Bristol’s Blood and Transplant Research Unit, and the French National Institute for Blood Transfusion, have captured the moment a red blood cell is ‘squeezed’ while recording the changes that allow it to deform and subsequently recover its shape.
The study, published in Blood Advances, was funded by the European Union’s Horizon 2020 research and innovation programme, NHS Blood & Transplant and through funding from the National Institute for Health Research (NIHR) for the University of Bristol’s Blood and Transplant Research Unit, focusing on red blood cell products.
Joint senior author Dr. Tim Satchwell explains:
“Every day, each red blood cell performs roughly 1,400 full circuits through the heart and around the body. During these circuits, the cell must repeatedly squeeze through incredibly small capillaries (less than half its size) in the organs and brain to deliver oxygen before assuming its recognisable biconcave shape. Prior to this research, no-one knew exactly how this very simple but important cell can adapt to survive those shape changes and remain fully functional throughout its normal lifecycle of 120 days. With this study, we have been able to capture this process for the first time.”
It is incredibly difficult to study the moment a red blood cell squeezes due to how small the cell is and how quickly the cells deform. To achieve this, the scientists combined the use of sensitive mass spectrometry (to detect specific protein changes) with two ways to ‘squeeze’ the cells. One method trapped the cells in a layer of tiny metal spheres and the other used tiny microcapillary channels built into a microscope slide in combination with an extremely fast camera.
The researchers have built the first map of changes that occur in the deforming red blood cell and showed that two specific proteins (which are protein kinases) are needed to allow the cells to deform and recover from squeezing. If one protein alone is stopped from working, this affects the cell’s ability to squeeze and recover; and if both proteins are stopped, the cell doesn’t squeeze at all and gets stuck.
Joint senior author Dr. Ashley Toye, Director of the NIHR Blood and Transplant Research Unit at the University of Bristol, said:
“This study showcases how the ‘simple’ red blood cell undergoes complex changes to adapt to being squeezed in the capillaries of the body and serves as an important platform to answer further questions: do the cells react differently in disease? Do certain people have ‘super squeezable’ cells? What is the function of the remaining changes that were detected? Could different combinations of drugs used to treat medical conditions affect how red blood cells deform?”
The next step for the researchers is to attempt to answer these questions by characterising the deforming red blood cell through the newly uncovered signalling pathways. For now, one thing is certain: the red blood cell is not as simple as previously thought.
Reticulocyte and red blood cell deformation triggers specific phosphorylation events: Pedro L. Moura, Maria A. Lizarralde Iragorri, Olivier Français, Bruno Le Pioufle, Johannes G. G. Dobbe, Geert J. Streekstra, Wassim El Nemer, Ashley M. Toye and Timothy J. Satchwell published in Blood Advances; doi: https://doi.org/10.1182/bloodadvances.2019000545
The University of Bristol NIHR Blood & Transport Research Unit
NIHR Blood and Transplant Research Units (BTRU) are research partnerships between universities and NHS Blood and Transplant (NHSBT). The NIHR BTRU in Red Blood Cell Products is part of and funded by the National Institute of Health Research (NIHR) and is a partnership between the University of Bristol and NHSBT, in collaboration with the University of Warwick, the University of Bath and the University of the West of England. The Director of the BTRU is Dr Ashley Toye. NHSBT is jointly funding the clinical trial with NIHR and also funds some of the parallel research themes being carried out by this Unit.
Our research Red blood cells grown from adult stem cells have the potential to improve the health of people who need regular transfusions throughout their life (e.g. thalassemia, sickle cell and certain cancers). As this is freshly grown blood, it could reduce the frequency of transfusion, reduce the treatment burden for patients and the unwanted side effects of frequent transfusions. To determine whether these treatments can fulfil their potential we will conduct a clinical trial in volunteers to assess the performance of laboratory grown cells compared to donated red blood cells.
We are also conducting a research programme to produce larger volumes of red blood cells.
NHS Blood and Transplant is a joint England and Wales Special Health Authority. We are responsible for ensuring a safe and efficient supply of blood and associated services to the NHS in England. We are also the organ donation organisation for the UK and are responsible for matching and allocating donated organs.
NHS Blood and Transplant has a Research and Development strategy which includes funding and carrying out world leading research, clinical trials and studies.
NHS Blood and Transplant needs to collect 1.4 million units of blood each year to meet the needs of patients across England. Blood donors can search for sessions, book appointments, change/cancel their appointments and change their contact details in real time at www.blood.co.uk
Horizon 2020 is the biggest EU Research and Innovation programme ever with nearly €80 billion of funding available over 7 years (2014 to 2020) – in addition to the private investment that this money will attract. It promises more breakthroughs, discoveries and world-firsts by taking great ideas from the lab to the market.
The National Institute for Health Research (NIHR) is the nation’s largest funder of health and care research. The NIHR:
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The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.