Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells
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...
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| Published in | Science (American Association for the Advancement of Science) Vol. 371; no. 6533; pp. 1019 - 1025 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
05.03.2021
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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
Liver- and cytokine-humanized immunodeficient mice can effectively model human red blood cell disorders.
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 huHepMISTRG
Fah
−/−
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. |
|---|---|
| AbstractList | 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 (
) 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 huHepMISTRG
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. 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 Liver- and cytokine-humanized immunodeficient mice can effectively model human red blood cell disorders. 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 huHepMISTRG Fah −/− 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. 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 huHepMISTRG Fah −/− 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. 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.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. A red-letter day for RBC researchThe 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. 1019In 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. |
| Author | Song, Yuanbin Liu, Wei Biancon, Giulia Flavell, Richard A. Gao, Yimeng Chen, Jie Bruscia, Emanuela M. Urbonas, David Gonzalez, David G. Tebaldi, Toma Eynon, Elizabeth Strowig, Till Wang, Xiaman Halene, Stephanie Alderman, Jonathan Qin, Ashley Krause, Diane S. Xu, Mina L. Fu, Xiaoying Mamillapalli, Padmavathi Gbyli, Rana Shan, Liang Patel, Amisha |
| AuthorAffiliation | 13 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA 2 Yale Stem Cell Center, 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 10 Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA 8 Department of Hematology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China 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 7 Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China 9 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA 11 Department of Cellular, Computational and Integrative Biology (CIBIO), University of T |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33674488$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works |
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| License | Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions: Conceptualization: S.H., R.A.F., Y.S., and L.S.; methodology: S.H., R.A.F., Y.S., and L.S.; investigation: Y.S., L.S., R.G., A.P., X.F., X.W., A.Q., W.L., Y.G., E.M.B., M.L.X., T.S., D.G.G., J.C., T.T., G.B., P.M., and D.U.; data analysis: Y.S., L.S., R.G., D.S.K., and S.H.; validation: Y.S., L.S., R.G., and S.H.; writing original draft: S.H., Y.S., L.S., and R.G.; writing review and editing: S.H., R.A.F., Y.S., and L.S.; funding acquisition: S.H. and R.A.F.; resources: R.G., A.P., and J.A.; project administration: S.H., R.A.F., E.E., and J.A.; supervision: S.H. and R.A.F. |
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| Snippet | 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... In vivo models that recapitulate human erythropoiesis with persistence of circulating red blood cells (RBCs) have remained elusive. We report an... A red-letter day for RBC researchThe study of primary human red blood cell (huRBC) disorders such as sickle cell disease (SCD) and infectious diseases such as... |
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| SubjectTerms | Anemia, Sickle Cell - blood Animal models Animals Blood Blood Circulation Bone marrow Cell density Complement component C3 CRISPR Cytokines Cytokines - metabolism Disease Models, Animal Erythrocytes Erythrocytes - cytology Erythropoiesis Erythropoiesis - genetics Erythropoiesis - physiology Female Fetuses Fumarylacetoacetase Gene Deletion Genetic engineering Hematopoiesis Hematopoietic Stem Cells - cytology Hepatocytes Humanization Humans Hydrolases - genetics Immunodeficiency In vivo methods and tests Infectious diseases Liver Liver - physiology Liver transplantation Malaria Mice Mice, Mutant Strains Middle Aged Occlusion Pathology Sickle cell disease Stem cell transplantation Stem cells Survival Vector-borne diseases |
| Title | Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells |
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