Abstract
Despite recent advances in immunodeficient mouse models bearing human red blood cells (hRBCs), the elimination of circulating hRBCs by residual innate immune systems remains a significant challenge. In this study, we evaluated the role of mouse complement C3 in the elimination of circulating hRBCs by developing a novel NOG substrain harboring a truncated version of the murine C3 gene (NOG-C3ΔMG2-3). Genetic C3 deletion prolonged the survival of transfused hRBCs in the circulation. Chemical depletion and functional impairment of mouse macrophages, using clodronate liposomes (Clo-lip) or gadolinium chloride (GdCl3), respectively, further extended the survival of hRBCs in NOG-C3ΔMG2-3 mice. Low GdCl3 toxicity allowed the establishment of hRBC-bearing mice, in which hRBCs survived for more than 4 weeks with transfusion once a week. In addition, erythropoiesis of human hematopoietic stem cells (hHSCs) was possible in NOG-C3ΔMG2-3/human GM-CSF-IL-3 transgenic mice with Clo-lip treatment. These findings indicate that mouse models harboring hRBCs can be achieved using NOG-C3ΔMG2-3 mice, which could facilitate studies of human diseases associated with RBCs.
Highlights
Xenotransplantation in immunodeficient mice has become an essential in vivo model for studying human hematopoietic cell development and hematological diseases [1, 2]
Especially macrophages, have been implicated in the rapid clearance of Human red blood cells (hRBCs) [24]; we investigated the role of mouse complement molecules in the elimination of hRBCs by mouse innate immune cells
We investigated the molecular mechanisms underlying the rapid elimination of hRBCs from mouse circulation and identified mouse C3 as a critical mediator of hRBC depletion
Summary
Xenotransplantation in immunodeficient mice has become an essential in vivo model for studying human hematopoietic cell development and hematological diseases [1, 2]. In the last two decades, significant efforts have been made to expand the repertoire of cell lineages [6,7,8,9,10] and engraft human cells to establish a functional humanized immune system [11,12,13,14]. Numerous mouse strains recapitulating human diseases are available for drug discovery [15,16,17,18]. Some human hematopoietic lineages cannot be generated using the current humanized mouse models. Human red blood cells (hRBCs) are the most abundant cells in the blood, comprising approximately 40% of the hematocrit.
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