The Adventure of Red Blood Cells

Much like Little Red Riding Hood engaging with various characters on her journey, red blood cells (RBCs) encounter numerous cell types while transporting oxygen throughout the human body. Their voyage begins in the bone marrow and concludes in the spleen, liver, and bone marrow again, where macrophages engulf them. The spleen is often referred to as the RBCs' graveyard, primarily tasked with removing aged or damaged cells.

Known as erythrocytes, RBCs derive their name from the glycoprotein erythropoietin (EPO), secreted by the kidneys when oxygen levels drop. EPO stimulates the production of RBCs in the bone marrow through a process called erythropoiesis. RBCs account for almost 99% of the blood's cellular makeup, serving the vital function of transporting oxygen from the lungs to body tissues.

Upon formation in the bone marrow, RBCs travel through capillaries to the heart, entering in a deoxygenated state via the vena cava. From there, they navigate through the atria and ventricles, exiting the heart through semilunar valves. RBCs then journey to the lungs via the pulmonary artery to collect oxygen, transforming into oxygenated cells. They return to the heart through the pulmonary vein and are subsequently pumped into the aorta, delivering oxygenated blood to the abdomen and lower limbs. Remarkably, this entire circulation process takes less than a minute!

The Color of Life

Blood is often described as the essence of life, nourishing every cell by delivering oxygen and essential nutrients. The bright red hue of RBCs comes from hemoglobin, a protein that comprises four heme groups, each containing an iron atom. This iron binds with oxygen, absorbing blue-green light and reflecting red-orange light, giving blood its characteristic color. When iron is bound to oxygen, the heme groups change shape, transforming from a dome-like structure to a flat disc, which explains the color difference between oxygenated and deoxygenated blood. Interestingly, blood color varies widely across species, depending on the respiratory pigment present; for example, crabs have blue blood, while some ice fish possess clear blood, and earthworms have green blood.

Lab-Grown Red Blood Cells

As technology advances, the possibility of lab-grown blood has emerged. The RESTORE trial—short for Recovery and Survival of Stem Cell Originated Red Cells—represents a collaboration among NHS Blood and Transplant, the University of Bristol, and several other organizations. This innovative clinical trial aims to produce red blood cells from donor stem cells and perform mini-transfusions to assess their longevity and effectiveness compared to standard donor blood. The hypothesis is that these lab-produced RBCs will have a longer lifespan and superior performance in circulation. Conditions like anemia, thalassemia, and sickle cell disease frequently require long-term blood transfusions, and while bone marrow transplants exist, they are not common due to inherent risks. The potential availability of high-quality blood on demand could significantly improve patient care, particularly in generating rare blood types and reducing immune responses during transfusions.

Acknowledging the Pioneers in This Field

• Red Cell Laboratory, Sanguine Research. Amsterdam, Netherlands. https://www.sanquin.org/research/group-leader-overview/red-cell-laboratory/index
• Red Cell Centre — Molecular Diagnostics Laboratory, Synnovis. London, UK. https://www.synnovis.co.uk/departments-and-laboratories/red-cell-centre-molecular-diagnostics-laboratory
• Red Cell Disorders Laboratory, University of Washington. Seattle, Washington, USA. https://testguide.labmed.uw.edu/guideline/red_cell_disorders Twitter: @UWMedicine
• The Peters Lab, The Jackson Laboratory. Bar Harbor, Maine, US. https://www.jax.org/research-and-faculty/research-labs/the-peters-lab# Twitter: @jacksonlab
• The Red Blood Cell Laboratory, University of California San Francisco. San Francisco, California, US. https://rbclab.ucsf.edu/
• Bristol BioDesign Institute, University of Bristol. Bristol, England, UK. https://www.bristol.ac.uk/research/impact/stories/red-blood-cells/ ; Twitter: @BristolUni
• Sankaran Lab, Harvard Stem Cell Institute, Harvard University. Cambridge, Massachusetts, US. https://www.bloodgenes.org/ ; Twitter: @harvardstemcell
• Bonnet Lab, The Francis Crick Institute. London, UK. https://www.crick.ac.uk/research/labs/dominique-bonnet ; Twitter: @TheCrick
• Duraisingh Lab, Harvard School of Public Health, Harvard University. Boston, Massachusetts, US. https://www.hsph.harvard.edu/duraisingh-lab/
• Red Cell Haematology, King’s College London. London, UK. https://www.kcl.ac.uk/research/red-cell-haematology ; Twitter: @KingsCollegeLon

References

1. Thiagarajan, Perumal et al. “How Do Red Blood Cells Die?” Frontiers in Physiology vol. 12 655393. 15 Mar. 2021, doi:10.3389/fphys.2021.655393
2. Mebius, Reina E, and Georg Kraal. “Structure and Function of the Spleen.” Nature Reviews. Immunology vol. 5,8 (2005): 606–16. doi:10.1038/nri1669
3. Bhoopalan, Senthil Velan et al. “Erythropoietin Regulation of Red Blood Cell Production: From Bench to Bedside and Back.” F1000Research vol. 9 F1000 Faculty Rev-1153. 18 Sep. 2020, doi:10.12688/f1000research.26648.1
4. 11. Lew, in Comprehensive Sampling and Sample Preparation (Ed.: J. Pawliszyn), Academic Press: Oxford, 2012, pp 95.
5. The Journey of a Red Blood Cell | Lorne Laboratories UK. Lorne Laboratories Ltd. https://www.lornelabs.com/news-events/blog/the-journey-of-a-red-blood-cell (accessed March 30, 2024).
6. Schechter, Alan N. “Hemoglobin Research and the Origins of Molecular Medicine.” Blood vol. 112,10 (2008): 3927–38. doi:10.1182/blood-2008-04-078188.
7. Lutz, Diana. “The Many Colors of Blood.” ChemMatters (2010). American Chemical Society. https://teachchemistry.org/chemmatters/february-2010/the-many-colors-of-blood (accessed April 2, 2024).
8. 21. of Bristol, RESTORE clinical trial. https://www.bristol.ac.uk/btru/work/trial/ (accessed April 3, 2024).
9. Kutikuppala, Lakshmi Venkata Simhachalam et al. “Transfusions with Laboratory-Grown Red Blood Cells: A New Development in Science.” Experimental Hematology vol. 119–120 (2023): 1–2. doi:10.1016/j.exphem.2023.01.004
10. Marengo-Rowe, Alain J. “The Thalassemias and Related Disorders.” Proceedings (Baylor University. Medical Center) vol. 20,1 (2007): 27–31. doi:10.1080/08998280.2007.11928230
11. Kale, Sampreeti Sri Sai et al. “Breakthrough in the Scientific World: Lab-Grown Red Blood Cells Used in Transfusions.” Asian Journal of Transfusion Science vol. 17,1 (2023): 143–144. doi:10.4103/ajts.ajts_148_22

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