Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis
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.
Authors
- Prathamesh Chati (ORCID: https://orcid.org/0000-0002-8972-267X)
- Matthew H. Porteus (ORCID: https://orcid.org/0000-0002-3850-4648)
- Carsten T. Charlesworth (ORCID: https://orcid.org/0000-0002-8588-6204)
- Freja K. Ekman (ORCID: https://orcid.org/0000-0003-3935-4685)
- Kiran R. Majeti (ORCID: https://orcid.org/0009-0003-1087-9549)
- Sridhar Selvaraj (ORCID: https://orcid.org/0000-0002-9736-8391)
- Devesh Sharma (ORCID: https://orcid.org/0000-0003-0761-6732)
- M. Kyle Cromer (ORCID: https://orcid.org/0000-0002-8198-5010)
- Roshani Sinha (ORCID: https://orcid.org/0000-0001-6971-2725)
- Aadit P. Shah (ORCID: https://orcid.org/0000-0001-8672-6643)
- Tammy Tran (ORCID: https://orcid.org/0000-0001-7728-9621)
- Eric Soupène (ORCID: https://orcid.org/0000-0002-1965-5117)
- Benjamin J. Lesch (ORCID: https://orcid.org/0000-0002-2511-3517)
- Sofia E. Luna (ORCID: https://orcid.org/0000-0002-9173-9518)
- Travis McCreary (ORCID: https://orcid.org/0000-0002-1753-6552)
- Simon N. Chu (ORCID: https://orcid.org/0000-0003-3863-1548)
Institutions
- University of California, San Francisco (US)
- UCSF Benioff Children's Hospital (US)
- Stanford Medicine (US)
- Broad Center (US)
- University of San Francisco (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-29
- DOI
- https://doi.org/10.1038/s41467-025-56239-5
- Citations
- 5
- Primary Topic
- Erythropoietin and Anemia Treatment
- Type
- article
- Field-Weighted Citation Impact
- 8.85
Funders
- National Science Foundation
- California Institute for Regenerative Medicine
- American Society of Hematology
- Stanford University
- Hertz Foundation
- Paul and Daisy Soros Fellowships for New Americans
- National Institutes of Health
- University of California, San Francisco
- School of Pharmacy, University of California, San Francisco
- UCSF Foundation