Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells


Song Yuanbin123ORCID,Shan Liang45ORCID,Gbyli Rana12,Liu Wei12,Strowig Till46ORCID,Patel Amisha12,Fu Xiaoying127ORCID,Wang Xiaman128ORCID,Xu Mina L.9ORCID,Gao Yimeng12ORCID,Qin Ashley12ORCID,Bruscia Emanuela M.10ORCID,Tebaldi Toma1211ORCID,Biancon Giulia12ORCID,Mamillapalli Padmavathi12,Urbonas David4ORCID,Eynon Elizabeth4ORCID,Gonzalez David G.12ORCID,Chen Jie4ORCID,Krause Diane S.2913,Alderman Jonathan4,Halene Stephanie12ORCID,Flavell Richard A.414ORCID


1. Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA.

2. Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.

3. Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

4. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

5. Department of Medicine, Pathology and Immunology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.

6. Helmholtz Centre for Infection Research, Braunschweig, Germany.

7. Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China.

8. Department of Hematology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China.

9. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

10. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.

11. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.

12. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

13. Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.

14. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.


A red-letter day for RBC research The study of primary human red blood cell (huRBC) disorders such as sickle cell disease (SCD) and infectious diseases such as malaria has been hampered by a lack of in vivo models of human erythropoiesis. Song et al. transferred human fetal liver cells into MISTRG mice, which are immunodeficient and are genetically engineered with several human genes involved in hematopoiesis. This approach was unsuccessful because mature huRBCs are rapidly destroyed in the mouse liver. They then used CRISPR-Cas9 to mutate these mice into a fumarylacetoacetate hydrolase–deficient strain, allowing them to replace the mouse liver with engrafted human hepatocytes. These mice exhibited enhanced human erythropoiesis and circulating huRBC survival and could recapitulate SCD pathology when reconstituted with SCD-derived HSCs. Science , this issue p. 1019


Howard Hughes Medical Institute

Bill and Melinda Gates Foundation



Young Scientists Fund of the National Natural Science Foundation of China

The Frederick A. Deluca Foundation

James Hudson Brown - Alexander Brown Coxe Postdoctoral Fellowships


American Association for the Advancement of Science (AAAS)









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