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Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis

Author

Listed:
  • Aadit P. Shah

    (Stanford University
    Stanford University)

  • Kiran R. Majeti

    (Stanford University)

  • Freja K. Ekman

    (Stanford University
    Stanford University
    Stanford University)

  • Sridhar Selvaraj

    (Stanford University)

  • Devesh Sharma

    (San Francisco
    San Francisco)

  • Roshani Sinha

    (San Francisco
    San Francisco)

  • Eric Soupene

    (San Francisco)

  • Prathamesh Chati

    (San Francisco)

  • Sofia E. Luna

    (Stanford University
    Stanford University)

  • Carsten T. Charlesworth

    (Stanford University)

  • Travis McCreary

    (San Francisco
    San Francisco)

  • Benjamin J. Lesch

    (San Francisco
    San Francisco)

  • Tammy Tran

    (San Francisco
    San Francisco)

  • Simon N. Chu

    (San Francisco
    San Francisco)

  • Matthew H. Porteus

    (Stanford University)

  • M. Kyle Cromer

    (San Francisco
    San Francisco
    San Francisco)

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.

Suggested Citation

  • 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 & Benj, 2025. "Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56239-5
    DOI: 10.1038/s41467-025-56239-5
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    References listed on IDEAS

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    1. Kongtana Trakarnsanga & Rebecca E. Griffiths & Marieangela C. Wilson & Allison Blair & Timothy J. Satchwell & Marjolein Meinders & Nicola Cogan & Sabine Kupzig & Ryo Kurita & Yukio Nakamura & Ashley M, 2017. "An immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells," Nature Communications, Nature, vol. 8(1), pages 1-7, April.
    2. Samantha G. Scharenberg & Edina Poletto & Katherine L. Lucot & Pasqualina Colella & Adam Sheikali & Thomas J. Montine & Matthew H. Porteus & Natalia Gomez-Ospina, 2020. "Engineering monocyte/macrophage−specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Samantha G. Scharenberg & Edina Poletto & Katherine L. Lucot & Pasqualina Colella & Adam Sheikali & Thomas J. Montine & Matthew H. Porteus & Natalia Gomez-Ospina, 2020. "Author Correction: Engineering monocyte/macrophage−specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    4. Renata M. Martin & Jonas L. Fowler & M. Kyle Cromer & Benjamin J. Lesch & Ezequiel Ponce & Nobuko Uchida & Toshinobu Nishimura & Matthew H. Porteus & Kyle M. Loh, 2020. "Improving the safety of human pluripotent stem cell therapies using genome-edited orthogonal safeguards," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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