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Immunol."],"abstract":"<jats:p>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-C3<jats:sup>\u0394MG2-3<\/jats:sup>). 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 (GdCl<jats:sub>3<\/jats:sub>), respectively, further extended the survival of hRBCs in NOG-C3<jats:sup>\u0394MG2-3<\/jats:sup> mice. Low GdCl<jats:sub>3<\/jats:sub> 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-C3<jats:sup>\u0394MG2-3<\/jats:sup>\/human GM-CSF-IL-3 transgenic mice with Clo-lip treatment. These findings indicate that mouse models harboring hRBCs can be achieved using NOG-C3<jats:sup>\u0394MG2-3<\/jats:sup> mice, which could facilitate studies of human diseases associated with RBCs.<\/jats:p>","DOI":"10.3389\/fimmu.2021.671648","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T09:18:58Z","timestamp":1627377538000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Takuya","family":"Yamaguchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikumi","family":"Katano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iyo","family":"Otsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoji","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Mochizuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohito","family":"Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2017","article-title":"Humanized Mice in Translational Biomedical Research","volume":"7","author":"Shultz","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.2","article-title":"Current Advances in Humanized Mouse Models","volume":"9","author":"Ito","year":"2012","journal-title":"Cell Mol Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2001-12-0207","article-title":"NOD\/SCID\/\u03b3 C Null Mouse: An Excellent Recipient Mouse Model for Engraftment of Human Cells","volume":"100","author":"Ito","year":"2002","journal-title":"Blood J Am Soc Hematol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6477","article-title":"Human Lymphoid and Myeloid Cell Development in NOD\/LtSz-Scid IL2R\u03b3null Mice Engrafted With Mobilized Human Hemopoietic Stem Cells","volume":"174","author":"Shultz","year":"2005","journal-title":"J Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1093933","article-title":"Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice","volume":"304","author":"Traggiai","year":"2004","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401323","article-title":"Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2\u2013Producing Transgenic NOG Mouse","volume":"194","author":"Katano","year":"2015","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.12.005","article-title":"Nonirradiated NOD, B6. 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