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, Xianman 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. Science . 2021 Mar 5;371(6533):1019-1025. doi: 10.1126/science.abe2485. PMID: 33674488
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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.
Mice were generated with the assistance of the Yale CCEH U54 Animal Modeling Core
Last updated: 04-15-2021