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DOI: 10.1055/s-0041-1740068
The Future of Red Cell Transfusion Lies in Cultured Red Cells
Funding We would like to thank the Commonwealth Scholarship Commission in UK, London, and University of Bristol for funding the training of the first author in Transfusion and Transplantation Sciences (including studies on red cell cultures) at NHS Blood and Transplant at Filton.Abstract
Blood is a very important resource for healthcare-based services and there has been a consistently increasing demand for it in most parts of the world. Poor volunteer-based collection system, high-risk of transfusion-transmitted infections, and emergence of new pathogens as evident from the ongoing Coronavirus Disease 2019 (COVID-19) pandemic are potential challenges to the global healthcare systems. It is imperative to explore safe and reliable alternatives to red cell transfusions. Ex vivo culture of red cells (cRBCs) from different sources such as hematopoietic stem cells (HSCs), pluripotent stem cells, and immortalized progenitors (e.g., BELA-2 cells) could revolutionize transfusion medicine. cRBC could be of great diagnostic and therapeutic utility. It may provide a backup in times of acute shortages in patients with rare blood groups, and in cases with multiple antibodies or sickle cell anemia. The CRISP-Cas9 system has been used to develop personalized, multi-compatible RBCs for diagnostic reagents and patients with multiple allo-antibodies. cRBC could be practically feasible for pediatric patients, who require small quantities of red cell transfusions. cRBC produced under good manufacturing practice (GMP) conditions has been reported to survive in human blood circulation for more than 26 days. Recently, a phase I randomized controlled clinical trial called RESTORE was initiated to assess the survival and recovery of cRBCs. However, feasible technological advancement is required to produce enough cRBCs for clinical use. It is crucial to identify sustainable sources for large-scale production of clinically useful cRBCs. Although the potential cost of one unit of cRBC is extrapolated to be around US$ 8000, it is a life-saving product for patients having rare blood groups and is a “ready to use” source of phenotype-matched, homogenous young red cells in emergency situations.
Authors' Contributions
Rizwan Javed and Deepak K. Mishra contributed to conceptualization of the study. Lorraine Flores and Saurabh Jayant Bhave contributed to the design of the study. Saurabh Jayant Bhave and Asheer Jawed defined the intellectual content. Rizwan Javed, Asheer Jawed, and Lorraine Flores contributed to literature research. Rizwan Javed contributed to manuscript preparation. Lorraine Flores, Asheer Jawed, and Deepak K. Mishra contributed to manuscript editing. Saurabh Jayant Bhave, Asheer Jawed, and Deepak K. Mishra contributed to manuscript review.
Publication History
Article published online:
13 December 2021
© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Seghatchian J. The secrets of human stem cell-derived transfusable RBC for targeted large-scale production and clinical applications: A fresh look into what we need most and lessons to be learned. Transfus Apheresis Sci 2020; 59 (04) 102862
- 2 World Health Organization (WHO) Factsheet 2013. https://www.who.int/gho/publications/world_health_statistics/2013/en/ Accessed February 2, 2020.
- 3 Trakarnsanga K, Griffiths RE, Wilson MC. et al. An immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells. Nat Commun 2017; 8: 14750
- 4 Hebiguchi M, Hirokawa M, Guo YM. et al. Dynamics of human erythroblast enucleation. Int J Hematol 2008; 88 (05) 498-507
- 5 Ubukawa K, Guo YM, Takahashi M. et al. Enucleation of human erythroblasts involves non-muscle myosin IIB. Blood 2012; 119 (04) 1036-1044
- 6 Bouhassira EE. Concise review: production of cultured red blood cells from stem cells. Stem Cells Transl Med 2012; 1 (12) 927-933
- 7 Fibach E, Manor D, Oppenheim A, Rachmilewitz EA. Proliferation and maturation of human erythroid progenitors in liquid culture. Blood 1989; 73 (01) 100-103
- 8 Giarratana MC, Kobari L, Lapillonne H. et al. Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat Biotechnol 2005; 23 (01) 69-74
- 9 Douay L, Giarratana MC. Ex vivo generation of human red blood cells: a new advance in stem cell engineering. Methods Mol Biol 2009; 482: 127-140
- 10 Neildez-Nguyen TM, Wajcman H, Marden MC. et al. Human erythroid cells produced ex vivo at large scale differentiate into red blood cells in vivo. Nat Biotechnol 2002; 20 (05) 467-472
- 11 Leberbauer C, Boulmé F, Unfried G, Huber J, Beug H, Müllner EW. Different steroids co-regulate long-term expansion versus terminal differentiation in primary human erythroid progenitors. Blood 2005; 105 (01) 85-94
- 12 Dolznig H, Kolbus A, Leberbauer C. et al. Expansion and differentiation of immature mouse and human hematopoietic progenitors. Methods Mol Med 2005; 105: 323-344
- 13 Carotta S, Pilat S, Mairhofer A. et al. Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells. Blood 2004; 104 (06) 1873-1880
- 14 Migliaccio AR, Whitsett C, Migliaccio G. Erythroid cells in vitro: from developmental biology to blood transfusion products. Curr Opin Hematol 2009; 16 (04) 259-268
- 15 Migliaccio G, Sanchez M, Masiello F. et al. Humanized culture medium for clinical expansion of human erythroblasts. Cell Transplant 2010; 19 (04) 453-469
- 16 Migliaccio G, Masiello F, Tirelli V. et al. Under HEMA conditions, self-replication of human erythroblasts is limited by autophagic death. Blood Cells Mol Dis 2011; 47 (03) 182-197
- 17 England SJ, McGrath KE, Frame JM, Palis J. Immature erythroblasts with extensive ex vivo self-renewal capacity emerge from the early mammalian fetus. Blood 2011; 117 (09) 2708-2717
- 18 Baek EJ, Kim HS, Kim S, Jin H, Choi TY, Kim HO. In vitro clinical-grade generation of red blood cells from human umbilical cord blood CD34+ cells. Transfusion 2008; 48 (10) 2235-2245
- 19 Flygare J, Rayon Estrada V, Shin C, Gupta S, Lodish HF. HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal. Blood 2011; 117 (12) 3435-3444
- 20 Lee JCM, Gimm JA, Lo AJ. et al. Mechanism of protein sorting during erythroblast enucleation: role of cytoskeletal connectivity. Blood 2004; 103 (05) 1912-1919
- 21 Lee HY, Gao X, Barrasa MI. et al. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal. Nature 2015; 522 (7557): 474-477
- 22 The European Collection of Cell Cultures Handbook (Online). Accessed August 1, 2018 at https://www.phe-culturecollections.org.uk/media/101902/ecacc_lab_handbook.pdf
- 23 Javed R, Tilley L, Frayne J, Crew V. Extended blood group genotyping of immortalized erythroid cell line BEL-A2 using next generation whole exome sequencing. Vox Sang 2019; 114 (Suppl. 01) 26
- 24 NHS Blood and Transplant- Clinical Trials Unit. RESTORE 2021. Accessed June 30, 2021 at: https://www.nhsbt.nhs.uk/clinical-trials-unit/current-trials-and-studies/restore/
- 25 Housler GJ, Miki T, Schmelzer E. et al. Compartmental hollow fiber capillary membrane-based bioreactor technology for in vitro studies on red blood cell lineage direction of hematopoietic stem cells. Tissue Eng Part C Methods 2012; 18 (02) 133-142
- 26 Seo Y, Shin KH, Kim HH, Kim HS. Current advances in red blood cell generation using stem cells from diverse sources. Stem Cells Int 2019; 2019: 9281329
- 27 Hawksworth J, Satchwell TJ, Meinders M. et al. Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing. EMBO Mol Med 2018; 10 (06) e8454
- 28 Anstee DJ, Gampel A, Toye AM. Ex-vivo generation of human red cells for transfusion. Curr Opin Hematol 2012; 19 (03) 163-169
- 29 Douay L, Andreu G. Ex vivo production of human red blood cells from hematopoietic stem cells: what is the future in transfusion?. Transfus Med Rev 2007; 21 (02) 91-100
- 30 Timmins NE, Nielsen LK. Blood cell manufacture: current methods and future challenges. Trends Biotechnol 2009; 27 (07) 415-422
- 31 Zeuner A, Martelli F, Vaglio S, Federici G, Whitsett C, Migliaccio AR. Concise review: stem cell-derived erythrocytes as upcoming players in blood transfusion. Stem Cells 2012; 30 (08) 1587-1596