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

Yuanbin Song; Liang Shan; Rana Gbyli; Wei Liu; Till Strowig; Amisha Patel; Xiaoying Fu; Xiaman Wang; Mina L Xu; Yimeng Gao; Ashley Qin; Emanuela M Bruscia; Toma Tebaldi; Giulia Biancon; Padmavathi Mamillapalli; David Urbonas; Elizabeth Eynon; David G Gonzalez; Jie Chen; Diane S Krause; Jonathan Alderman; Stephanie Halene; Richard A Flavell

doi:10.1126/science.abe2485

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

Science. 2021 Mar 5;371(6533):1019-1025. doi: 10.1126/science.abe2485.

Authors

Yuanbin Song^#^{1

2

3}, Liang Shan^#^{4

5}, Rana Gbyli^#^{1

2}, Wei Liu^{1

2}, Till Strowig^{6

7}, Amisha Patel^{1

2}, Xiaoying Fu^{1

2

8}, Xiaman Wang^{1

2

9}, Mina L Xu¹⁰, Yimeng Gao^{1

2}, Ashley Qin^{1

2}, Emanuela M Bruscia¹¹, Toma Tebaldi^{1

2

12}, Giulia Biancon^{1

2}, Padmavathi Mamillapalli^{1

2}, David Urbonas⁶, Elizabeth Eynon⁶, David G Gonzalez¹³, Jie Chen⁶, Diane S Krause^{2

10

14}, Jonathan Alderman⁶, Stephanie Halene^#^{15

2}, Richard A Flavell^#^{4

16}

Affiliations

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. liang.shan@wustl.edu stephanie.halene@yale.edu richard.flavell@yale.edu.
⁵ Department of Medicine, Pathology and Immunology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
⁷ Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁸ Department of Laboratory Medicine, Shenzhen Children's Hospital, Shenzhen, People's Republic of China.
⁹ Department of Hematology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
¹⁰ Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
¹¹ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
¹² Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
¹³ Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁴ Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁵ 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. liang.shan@wustl.edu stephanie.halene@yale.edu richard.flavell@yale.edu.
¹⁶ Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.

^# Contributed equally.

Abstract

In vivo models that recapitulate human erythropoiesis with persistence of circulating red blood cells (RBCs) have remained elusive. We report an immunodeficient murine model in which combined human liver and cytokine humanization confer enhanced human erythropoiesis and RBC survival in the circulation. We deleted the fumarylacetoacetate hydrolase (Fah) gene in MISTRG mice expressing several human cytokines in place of their murine counterparts. Liver humanization by intrasplenic injection of human hepatocytes (huHep) eliminated murine complement C3 and reduced murine Kupffer cell density. Engraftment of human sickle cell disease (SCD)-derived hematopoietic stem cells in huHepMISTRGFah ^-/- mice resulted in vaso-occlusion that replicated acute SCD pathology. Combined liver-cytokine-humanized mice will facilitate the study of diseases afflicting RBCs, including bone marrow failure, hemoglobinopathies, and malaria, and also preclinical testing of therapies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anemia, Sickle Cell / blood*
Animals
Blood Circulation*
Cytokines / metabolism
Disease Models, Animal*
Erythrocytes / cytology*
Erythropoiesis / genetics
Erythropoiesis / physiology*
Female
Gene Deletion
Hematopoietic Stem Cells / cytology
Humans
Hydrolases / genetics
Liver / physiology
Mice*
Mice, Mutant Strains
Middle Aged

Substances

Cytokines
Hydrolases
fumarylacetoacetase

Abstract

Publication types

MeSH terms

Substances

Grants and funding