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Responsible editor | Enzyme red blood cells are one of the most common cell types in the human body.
They have been undergoing fierce genetic selection during human evolution.
Red blood cell diseases, including thalassemia and sickle cell anemia, affect approximately 5% of the world’s population.
The healthcare system brings a heavy burden [1].
For the research of human red blood cell development and differentiation and related diseases, artificial hematopoietic stem cells are mainly used for in vitro culture modeling.
Due to species-specific differences in the development of red blood cells, mouse red blood cell development and differentiation models can only provide limited reference for human red blood cell research Value [2,3].
The lack of intact human erythrocyte growth and development models has always been a bottleneck in the development of human erythrocyte research, especially mature erythrocyte research.
As a living model for studying human diseases, the humanized mouse model has great advantages and broad application prospects in elucidating the pathogenesis of human diseases and drug screening [4].
However, none of the existing humanized mouse models can fully support the complete development of human red blood cells, and lack of mature red blood cells to continue in the circulation [5-7].
On March 5, 2021, Science published the study "Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells" online.
Studies have found that humanized mouse liver is the main target organ for human red blood cell removal.
By replacing the mouse liver with human liver, human red blood cells can be fully developed in humanized mice, and mature red blood cells can circulate in the mice.
It truly flows into human blood and provides new humanized mouse research tools for human red blood cell research.
The study first confirmed that the mouse liver was the main organ for removing human red blood cells by infusing human red blood cells.
It was further identified that the red blood cells enriched in the liver were all marked by mouse complement C3, and the reason for the lack of human mature red blood cells in humanized mice was clarified.The liver is an important immune organ with a large number of macrophages and an important place for complement synthesis [8, 9].
The study used MISTRGFah mice.
"MISTRG" is based on the background of Rag-/- and IL2R-/- mice, using gene editing tools to knock-in and physiologically express human M-CSF, IL3/GM-CSF, SIRP α Thrombopoietin [10,11] to better support the survival of human cells in mice.
The research is based on MISTRG mice, using CRISPR/Cas9 technology to knock out the mouse fumarate acetoacetate hydrolase (Fah) gene and successfully replace mouse liver cells with human liver cells.
The study found that in MISTRGFah mice combined with human liver cells, human red blood cells can develop intact and mature human red blood cells enter the circulation.
The study also established a humanized mouse model of sickle cell anemia, and monitored human sickle in the mouse circulation.
Red blood cells in the lung, spleen, liver and kidney reproduce the pathological changes of sickle cell anemia patients.
The humanized mouse model combined with human liver cells established in the study can be used to study red blood cell-related diseases, including alpha and beta thalassemia and sickle cell anemia.
In addition, this model can also be used for the study of hematopoietic stem cell diseases, such as bone marrow dysplasia, red blood cell leukemia, and the study of infectious diseases with complex pathophysiological links between red blood cells and the liver, such as malaria.
The mouse model can open up a new way for preclinical drug screening.
Dr.
Song Yuanbin, Department of Hematology Oncology, Sun Yale University Cancer Center, is the first author of this article, Professor Richard Flavell of Yale University, Professor Stephanie Halene, and Professor Shan Liang of Washington University in St.
Louis (WUSTL) are the corresponding authors of this article.
The completion of this work benefited from Yale University Mina.
Prof.
L.
Xu, Prof.
Diane S.
Krause and Prof.
Emanuela M.
Bruscia provided strong support and selfless help. Recruitment information The research directions of Professor Shan Liang’s laboratory at Washington University in St.
Louis include CARD8 inflammasomes, anti-HIV functions of NK cells and T cells; the interaction mechanism of HIV infection and T cell metabolism; the human immune system in a new humanized mouse model Response to HIV infection.
Professor Shan Liang has published many research papers in internationally renowned journals such as Science and Nature as the corresponding author.
The research group is now looking forward to postdoctoral fellows with enthusiasm for scientific research to join in and explore HIV immunology together.
Stephanie Halene Laboratory of Yale University School of Medicine recruits two postdoctoral professors Stephanie Halene is currently the director of the Department of Hematology at Yale University School of Medicine Cancer Center and has long been engaged in MDS and AML.
Related blood disease research.
Laboratory research includes the role of Spliting Factor, m6A modification, and humanized mouse models in the treatment and prevention of blood diseases, covering mouse breeding, protein interaction, gene editing, bio-information analysis, clinical research, etc.
Level.
In recent years, Stephanie Halene, as the corresponding author, has published many research papers in internationally renowned journals such as Science, Immunity, Blood, and Nature Communications.
The laboratory has an international research team and has close cooperation with many internationally renowned laboratories.
At present, the laboratory plans to carry out research on the effects of new drugs on the treatment of AML and the application of new single-cell sequencing technology in MDS diagnosis.
Both projects have received sufficient financial support and need to recruit 2 postdoctoral fellows.
Welcome all graduated and about to graduate doctoral students to apply.
Applicants please send an email with English CV to contact Dr.
Yimeng Gao: yimeng.
gao@yale.
edu.
Please indicate the subject of the email: Name—Current School—Postdoctoral candidate.
Reprinting needs to know that the copyright of this article belongs to the author of the article.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated. Original link: https://science.
sciencemag.
org/cgi/doi/10.
1126/science.
abe2485 References 1.
Carter R, Mendis KN: Evolutionary and historical aspects of the burden of malaria.
Clin Microbiol Rev 2002, 15(4 ):564-594.
2.
Dzierzak E, Philipsen S: Erythropoiesis: development and differentiation.
Cold Spring Harb Perspect Med 2013, 3(4):a011601.
3.
Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD: Humanized Mouse Models of Clinical Disease.
Annu Rev Pathol 2017, 12:187-215.
4.
Gbyli R, Song Y, Halene S: Humanized mice as preclinical models for myeloid malignancies.
Biochem Pharmacol 2020:113794.
5.
Yurino A, Takenaka K, Yamauchi T, Nunomura T, Uehara Y, Jinnouchi F, Miyawaki K, Kikushige Y, Kato K, Miyamoto T et al: Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations.
Stem Cell Reports 2016, 7(3):425-438.
6.
Rahmig S, Kronstein-Wiedemann R, Fohgrub J, Kronstein N, Nevmerzhitskaya A, Bornhauser M, Gassmann M, Platz A, Ordemann R, Tonn T et al: Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice.
Stem Cell Reports 2016, 7(4):591-601.
7.
Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X et al: A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies.
Nat Commun 2019, 10(1):366.
8.
Robinson MW, Harmon C, O'Farrelly C: Liver immunology and its role in inflammation and homeostasis.
Cell Mol Immunol 2016, 13(3):267-276.
9.
Bilzer M, Roggel F, Gerbes AL: Role of Kupffer cells in host defense and liver disease.
Liver Int 2006, 26(10):1175-1186.
10 .
Rongvaux A, Willinger T, Martinek J, Strowig T,Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK et al: Development and function of human innate immune cells in a humanized mouse model.
Nat Biotechnol 2014, 32(4):364-372.
11.
Deng K, Pertea M, Rongvaux A, Wang LY, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao HP, Zhang H et al: Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
Nature 2015, 517(7534):381-U544.
They have been undergoing fierce genetic selection during human evolution.
Red blood cell diseases, including thalassemia and sickle cell anemia, affect approximately 5% of the world’s population.
The healthcare system brings a heavy burden [1].
For the research of human red blood cell development and differentiation and related diseases, artificial hematopoietic stem cells are mainly used for in vitro culture modeling.
Due to species-specific differences in the development of red blood cells, mouse red blood cell development and differentiation models can only provide limited reference for human red blood cell research Value [2,3].
The lack of intact human erythrocyte growth and development models has always been a bottleneck in the development of human erythrocyte research, especially mature erythrocyte research.
As a living model for studying human diseases, the humanized mouse model has great advantages and broad application prospects in elucidating the pathogenesis of human diseases and drug screening [4].
However, none of the existing humanized mouse models can fully support the complete development of human red blood cells, and lack of mature red blood cells to continue in the circulation [5-7].
On March 5, 2021, Science published the study "Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells" online.
Studies have found that humanized mouse liver is the main target organ for human red blood cell removal.
By replacing the mouse liver with human liver, human red blood cells can be fully developed in humanized mice, and mature red blood cells can circulate in the mice.
It truly flows into human blood and provides new humanized mouse research tools for human red blood cell research.
The study first confirmed that the mouse liver was the main organ for removing human red blood cells by infusing human red blood cells.
It was further identified that the red blood cells enriched in the liver were all marked by mouse complement C3, and the reason for the lack of human mature red blood cells in humanized mice was clarified.The liver is an important immune organ with a large number of macrophages and an important place for complement synthesis [8, 9].
The study used MISTRGFah mice.
"MISTRG" is based on the background of Rag-/- and IL2R-/- mice, using gene editing tools to knock-in and physiologically express human M-CSF, IL3/GM-CSF, SIRP α Thrombopoietin [10,11] to better support the survival of human cells in mice.
The research is based on MISTRG mice, using CRISPR/Cas9 technology to knock out the mouse fumarate acetoacetate hydrolase (Fah) gene and successfully replace mouse liver cells with human liver cells.
The study found that in MISTRGFah mice combined with human liver cells, human red blood cells can develop intact and mature human red blood cells enter the circulation.
The study also established a humanized mouse model of sickle cell anemia, and monitored human sickle in the mouse circulation.
Red blood cells in the lung, spleen, liver and kidney reproduce the pathological changes of sickle cell anemia patients.
The humanized mouse model combined with human liver cells established in the study can be used to study red blood cell-related diseases, including alpha and beta thalassemia and sickle cell anemia.
In addition, this model can also be used for the study of hematopoietic stem cell diseases, such as bone marrow dysplasia, red blood cell leukemia, and the study of infectious diseases with complex pathophysiological links between red blood cells and the liver, such as malaria.
The mouse model can open up a new way for preclinical drug screening.
Dr.
Song Yuanbin, Department of Hematology Oncology, Sun Yale University Cancer Center, is the first author of this article, Professor Richard Flavell of Yale University, Professor Stephanie Halene, and Professor Shan Liang of Washington University in St.
Louis (WUSTL) are the corresponding authors of this article.
The completion of this work benefited from Yale University Mina.
Prof.
L.
Xu, Prof.
Diane S.
Krause and Prof.
Emanuela M.
Bruscia provided strong support and selfless help. Recruitment information The research directions of Professor Shan Liang’s laboratory at Washington University in St.
Louis include CARD8 inflammasomes, anti-HIV functions of NK cells and T cells; the interaction mechanism of HIV infection and T cell metabolism; the human immune system in a new humanized mouse model Response to HIV infection.
Professor Shan Liang has published many research papers in internationally renowned journals such as Science and Nature as the corresponding author.
The research group is now looking forward to postdoctoral fellows with enthusiasm for scientific research to join in and explore HIV immunology together.
Stephanie Halene Laboratory of Yale University School of Medicine recruits two postdoctoral professors Stephanie Halene is currently the director of the Department of Hematology at Yale University School of Medicine Cancer Center and has long been engaged in MDS and AML.
Related blood disease research.
Laboratory research includes the role of Spliting Factor, m6A modification, and humanized mouse models in the treatment and prevention of blood diseases, covering mouse breeding, protein interaction, gene editing, bio-information analysis, clinical research, etc.
Level.
In recent years, Stephanie Halene, as the corresponding author, has published many research papers in internationally renowned journals such as Science, Immunity, Blood, and Nature Communications.
The laboratory has an international research team and has close cooperation with many internationally renowned laboratories.
At present, the laboratory plans to carry out research on the effects of new drugs on the treatment of AML and the application of new single-cell sequencing technology in MDS diagnosis.
Both projects have received sufficient financial support and need to recruit 2 postdoctoral fellows.
Welcome all graduated and about to graduate doctoral students to apply.
Applicants please send an email with English CV to contact Dr.
Yimeng Gao: yimeng.
gao@yale.
edu.
Please indicate the subject of the email: Name—Current School—Postdoctoral candidate.
Reprinting needs to know that the copyright of this article belongs to the author of the article.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated. Original link: https://science.
sciencemag.
org/cgi/doi/10.
1126/science.
abe2485 References 1.
Carter R, Mendis KN: Evolutionary and historical aspects of the burden of malaria.
Clin Microbiol Rev 2002, 15(4 ):564-594.
2.
Dzierzak E, Philipsen S: Erythropoiesis: development and differentiation.
Cold Spring Harb Perspect Med 2013, 3(4):a011601.
3.
Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD: Humanized Mouse Models of Clinical Disease.
Annu Rev Pathol 2017, 12:187-215.
4.
Gbyli R, Song Y, Halene S: Humanized mice as preclinical models for myeloid malignancies.
Biochem Pharmacol 2020:113794.
5.
Yurino A, Takenaka K, Yamauchi T, Nunomura T, Uehara Y, Jinnouchi F, Miyawaki K, Kikushige Y, Kato K, Miyamoto T et al: Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations.
Stem Cell Reports 2016, 7(3):425-438.
6.
Rahmig S, Kronstein-Wiedemann R, Fohgrub J, Kronstein N, Nevmerzhitskaya A, Bornhauser M, Gassmann M, Platz A, Ordemann R, Tonn T et al: Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice.
Stem Cell Reports 2016, 7(4):591-601.
7.
Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X et al: A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies.
Nat Commun 2019, 10(1):366.
8.
Robinson MW, Harmon C, O'Farrelly C: Liver immunology and its role in inflammation and homeostasis.
Cell Mol Immunol 2016, 13(3):267-276.
9.
Bilzer M, Roggel F, Gerbes AL: Role of Kupffer cells in host defense and liver disease.
Liver Int 2006, 26(10):1175-1186.
10 .
Rongvaux A, Willinger T, Martinek J, Strowig T,Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK et al: Development and function of human innate immune cells in a humanized mouse model.
Nat Biotechnol 2014, 32(4):364-372.
11.
Deng K, Pertea M, Rongvaux A, Wang LY, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao HP, Zhang H et al: Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
Nature 2015, 517(7534):381-U544.
