Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis
Abstract Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is cruc...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56239-5 |
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| author | Aadit P. Shah Kiran R. Majeti Freja K. Ekman Sridhar Selvaraj Devesh Sharma Roshani Sinha Eric Soupene Prathamesh Chati Sofia E. Luna Carsten T. Charlesworth Travis McCreary Benjamin J. Lesch Tammy Tran Simon N. Chu Matthew H. Porteus M. Kyle Cromer |
| author_facet | Aadit P. Shah Kiran R. Majeti Freja K. Ekman Sridhar Selvaraj Devesh Sharma Roshani Sinha Eric Soupene Prathamesh Chati Sofia E. Luna Carsten T. Charlesworth Travis McCreary Benjamin J. Lesch Tammy Tran Simon N. Chu Matthew H. Porteus M. Kyle Cromer |
| author_sort | Aadit P. Shah |
| collection | DOAJ |
| description | Abstract Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO is among the most expensive media components. To address this challenge, we develop highly optimized small molecule-inducible synthetic EPO receptors (synEPORs) using design-build-test cycles and genome editing. By integrating synEPOR at the endogenous EPOR locus in O-negative induced pluripotent stem cells, we achieve equivalent erythroid differentiation, transcriptomic changes, and hemoglobin production using small molecules compared to EPO-supplemented cultures. This approach dramatically reduces culture media costs. Our strategy not only addresses RBC production challenges but also demonstrates how protein and genome engineering can introduce precisely regulated cellular behaviors, potentially improving scalable manufacturing of a wide range of clinically relevant cell types. |
| format | Article |
| id | doaj-art-e697085028b54932a61c99c01da9de10 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e697085028b54932a61c99c01da9de102025-02-02T12:31:15ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56239-5Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesisAadit P. Shah0Kiran R. Majeti1Freja K. Ekman2Sridhar Selvaraj3Devesh Sharma4Roshani Sinha5Eric Soupene6Prathamesh Chati7Sofia E. Luna8Carsten T. Charlesworth9Travis McCreary10Benjamin J. Lesch11Tammy Tran12Simon N. Chu13Matthew H. Porteus14M. Kyle Cromer15School of Medicine, Stanford UniversityDepartment of Pediatrics, Stanford UniversitySchool of Medicine, Stanford UniversityDepartment of Pediatrics, Stanford UniversityDepartment of Surgery, University of California, San FranciscoDepartment of Surgery, University of California, San FranciscoBenioff Children’s Hospital Oakland, University of California, San FranciscoDepartment of Biological & Medical Informatics, University of California, San FranciscoSchool of Medicine, Stanford UniversityDepartment of Genetics, Stanford UniversityDepartment of Surgery, University of California, San FranciscoDepartment of Surgery, University of California, San FranciscoDepartment of Surgery, University of California, San FranciscoDepartment of Surgery, University of California, San FranciscoDepartment of Pediatrics, Stanford UniversityDepartment of Surgery, University of California, San FranciscoAbstract Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO is among the most expensive media components. To address this challenge, we develop highly optimized small molecule-inducible synthetic EPO receptors (synEPORs) using design-build-test cycles and genome editing. By integrating synEPOR at the endogenous EPOR locus in O-negative induced pluripotent stem cells, we achieve equivalent erythroid differentiation, transcriptomic changes, and hemoglobin production using small molecules compared to EPO-supplemented cultures. This approach dramatically reduces culture media costs. Our strategy not only addresses RBC production challenges but also demonstrates how protein and genome engineering can introduce precisely regulated cellular behaviors, potentially improving scalable manufacturing of a wide range of clinically relevant cell types.https://doi.org/10.1038/s41467-025-56239-5 |
| spellingShingle | Aadit P. Shah Kiran R. Majeti Freja K. Ekman Sridhar Selvaraj Devesh Sharma Roshani Sinha Eric Soupene Prathamesh Chati Sofia E. Luna Carsten T. Charlesworth Travis McCreary Benjamin J. Lesch Tammy Tran Simon N. Chu Matthew H. Porteus M. Kyle Cromer Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis Nature Communications |
| title | Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis |
| title_full | Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis |
| title_fullStr | Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis |
| title_full_unstemmed | Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis |
| title_short | Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis |
| title_sort | engineering synthetic signaling receptors to enable erythropoietin free erythropoiesis |
| url | https://doi.org/10.1038/s41467-025-56239-5 |
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