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. Flavel

doi:10.1126/science.abe2485

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. KrauseJonathan Alderman, Stephanie Halene, Richard A. Flavel

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Pages (from-to)	1019-1025
Number of pages	7
Journal	Science
Volume	371
Issue number	6533
DOIs	https://doi.org/10.1126/science.abe2485
State	Published - Mar 5 2021

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Song, Y., Shan, L., Gbyli, R., Liu, W., Strowig, T., Patel, A., Fu, X., Wang, X., Xu, M. L., Gao, Y., Qin, A., Bruscia, E. M., Tebaldi, T., Biancon, G., Mamillapalli, P., Urbonas, D., Eynon, E., Gonzalez, D. G., Chen, J., ... Flavel, R. A. (2021). Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells. Science, 371(6533), 1019-1025. https://doi.org/10.1126/science.abe2485

@article{d77d43522d1b4e6aa75d1a7977a8624d,

title = "Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells",

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.",

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

year = "2021",

month = mar,

day = "5",

doi = "10.1126/science.abe2485",

language = "English",

volume = "371",

pages = "1019--1025",

journal = "Science",

issn = "0036-8075",

number = "6533",

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Song, Y, Shan, L, Gbyli, R, Liu, W, Strowig, T, Patel, A, Fu, X, Wang, X, Xu, ML, Gao, Y, Qin, A, Bruscia, EM, Tebaldi, T, Biancon, G, Mamillapalli, P, Urbonas, D, Eynon, E, Gonzalez, DG, Chen, J, Krause, DS, Alderman, J, Halene, S & Flavel, RA 2021, 'Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells', Science, vol. 371, no. 6533, pp. 1019-1025. https://doi.org/10.1126/science.abe2485

TY - JOUR

T1 - Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells

AU - Song, Yuanbin

AU - Shan, Liang

AU - Gbyli, Rana

AU - Liu, Wei

AU - Strowig, Till

AU - Patel, Amisha

AU - Fu, Xiaoying

AU - Wang, Xiaman

AU - Xu, Mina L.

AU - Gao, Yimeng

AU - Qin, Ashley

AU - Bruscia, Emanuela M.

AU - Tebaldi, Toma

AU - Biancon, Giulia

AU - Mamillapalli, Padmavathi

AU - Urbonas, David

AU - Eynon, Elizabeth

AU - Gonzalez, David G.

AU - Chen, Jie

AU - Krause, Diane S.

AU - Alderman, Jonathan

AU - Halene, Stephanie

AU - Flavel, Richard A.

PY - 2021/3/5

Y1 - 2021/3/5

N2 - 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.

AB - 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.

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U2 - 10.1126/science.abe2485

DO - 10.1126/science.abe2485

M3 - Article

C2 - 33674488

AN - SCOPUS:85102245129

SN - 0036-8075

VL - 371

SP - 1019

EP - 1025

JO - Science

JF - Science

IS - 6533

ER -

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

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