Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations
In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenot...
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| Veröffentlicht in: | Stem cell reports 2016-09, Vol.7 (3), p.425-438 |
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| creator | Yurino, Ayano Takenaka, Katsuto Yamauchi, Takuji Nunomura, Takuya Uehara, Yasufumi Jinnouchi, Fumiaki Miyawaki, Kohta Kikushige, Yoshikane Kato, Koji Miyamoto, Toshihiro Iwasaki, Hiromi Kunisaki, Yuya Akashi, Koichi |
| description | In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis. |
| doi_str_mv | 10.1016/j.stemcr.2016.07.002 |
| format | Article |
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Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis.</description><identifier>EISSN: 2213-6711</identifier><identifier>DOI: 10.1016/j.stemcr.2016.07.002</identifier><identifier>PMID: 27499200</identifier><language>eng</language><publisher>United States</publisher><subject>Alleles ; Animals ; Biomarkers ; Bone Marrow ; Cell Differentiation - genetics ; Cell Self Renewal - genetics ; Erythropoiesis - genetics ; Erythropoiesis - immunology ; Genotype ; Graft Survival ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - metabolism ; Humans ; Mice ; Mice, Knockout ; Mutation ; Myeloid Cells - cytology ; Myeloid Cells - metabolism ; Proto-Oncogene Proteins c-kit - genetics ; Proto-Oncogene Proteins c-kit - metabolism ; Thrombopoiesis - genetics ; Thrombopoiesis - immunology ; Transplantation, Heterologous</subject><ispartof>Stem cell reports, 2016-09, Vol.7 (3), p.425-438</ispartof><rights>Copyright © 2016 The Authors. Published by Elsevier Inc. 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Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis.</description><subject>Alleles</subject><subject>Animals</subject><subject>Biomarkers</subject><subject>Bone Marrow</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Self Renewal - genetics</subject><subject>Erythropoiesis - genetics</subject><subject>Erythropoiesis - immunology</subject><subject>Genotype</subject><subject>Graft Survival</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mutation</subject><subject>Myeloid Cells - cytology</subject><subject>Myeloid Cells - metabolism</subject><subject>Proto-Oncogene Proteins c-kit - genetics</subject><subject>Proto-Oncogene Proteins c-kit - metabolism</subject><subject>Thrombopoiesis - genetics</subject><subject>Thrombopoiesis - immunology</subject><subject>Transplantation, Heterologous</subject><issn>2213-6711</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UE1LAzEUDILYUvsPRHKsh65JdjebHKVUW2wRpOJxydfSlN2kbrJK8c8b8eMd5jHD8GZ4AFxhlGGE6e0hC9F0qs9IYhmqMoTIGRgTgvM5rTAegWkIB5SGc0wKfAFGpCo4JwiNwefS7YVTRsNno7wL0cYhWu-gb-Bq6ISDy_4U970_emuCDVA4DXeJd_Jfsi6pcN11g_PaNFZZ4yLc-iGYhNq08MPGPXy0cfb6fgO3QxTfEeESnDeiDWb6uyfg5X65W6zmm6eH9eJuMz8QXsa50pJWqGSCNk1ZFKYRjFEpZEErShqucsmZomXFUQLBeUmkVkwyTRVVGrN8AmY_d4-9fxtMiHVngzJtK5xJJWvMCCp5znOSrNe_1kF2RtfH3naiP9V_D8u_AIsxcCY</recordid><startdate>20160913</startdate><enddate>20160913</enddate><creator>Yurino, Ayano</creator><creator>Takenaka, Katsuto</creator><creator>Yamauchi, Takuji</creator><creator>Nunomura, Takuya</creator><creator>Uehara, Yasufumi</creator><creator>Jinnouchi, Fumiaki</creator><creator>Miyawaki, Kohta</creator><creator>Kikushige, Yoshikane</creator><creator>Kato, Koji</creator><creator>Miyamoto, Toshihiro</creator><creator>Iwasaki, Hiromi</creator><creator>Kunisaki, Yuya</creator><creator>Akashi, Koichi</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20160913</creationdate><title>Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations</title><author>Yurino, Ayano ; Takenaka, Katsuto ; Yamauchi, Takuji ; Nunomura, Takuya ; Uehara, Yasufumi ; Jinnouchi, Fumiaki ; Miyawaki, Kohta ; Kikushige, Yoshikane ; Kato, Koji ; Miyamoto, Toshihiro ; Iwasaki, Hiromi ; Kunisaki, Yuya ; Akashi, Koichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j295t-cdb67058a6ff544efa886bab46762f9c3b98c65790657a9952bdc8b8d6c6cd183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>Biomarkers</topic><topic>Bone Marrow</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Self Renewal - genetics</topic><topic>Erythropoiesis - genetics</topic><topic>Erythropoiesis - immunology</topic><topic>Genotype</topic><topic>Graft Survival</topic><topic>Hematopoietic Stem Cell Transplantation</topic><topic>Hematopoietic Stem Cells - cytology</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mutation</topic><topic>Myeloid Cells - cytology</topic><topic>Myeloid Cells - metabolism</topic><topic>Proto-Oncogene Proteins c-kit - genetics</topic><topic>Proto-Oncogene Proteins c-kit - metabolism</topic><topic>Thrombopoiesis - genetics</topic><topic>Thrombopoiesis - immunology</topic><topic>Transplantation, Heterologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yurino, Ayano</creatorcontrib><creatorcontrib>Takenaka, Katsuto</creatorcontrib><creatorcontrib>Yamauchi, Takuji</creatorcontrib><creatorcontrib>Nunomura, Takuya</creatorcontrib><creatorcontrib>Uehara, Yasufumi</creatorcontrib><creatorcontrib>Jinnouchi, Fumiaki</creatorcontrib><creatorcontrib>Miyawaki, Kohta</creatorcontrib><creatorcontrib>Kikushige, Yoshikane</creatorcontrib><creatorcontrib>Kato, Koji</creatorcontrib><creatorcontrib>Miyamoto, Toshihiro</creatorcontrib><creatorcontrib>Iwasaki, Hiromi</creatorcontrib><creatorcontrib>Kunisaki, Yuya</creatorcontrib><creatorcontrib>Akashi, Koichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Stem cell reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yurino, Ayano</au><au>Takenaka, Katsuto</au><au>Yamauchi, Takuji</au><au>Nunomura, Takuya</au><au>Uehara, Yasufumi</au><au>Jinnouchi, Fumiaki</au><au>Miyawaki, Kohta</au><au>Kikushige, Yoshikane</au><au>Kato, Koji</au><au>Miyamoto, Toshihiro</au><au>Iwasaki, Hiromi</au><au>Kunisaki, Yuya</au><au>Akashi, Koichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations</atitle><jtitle>Stem cell reports</jtitle><addtitle>Stem Cell Reports</addtitle><date>2016-09-13</date><risdate>2016</risdate><volume>7</volume><issue>3</issue><spage>425</spage><epage>438</epage><pages>425-438</pages><eissn>2213-6711</eissn><abstract>In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis.</abstract><cop>United States</cop><pmid>27499200</pmid><doi>10.1016/j.stemcr.2016.07.002</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Stem cell reports, 2016-09, Vol.7 (3), p.425-438 |
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| subjects | Alleles Animals Biomarkers Bone Marrow Cell Differentiation - genetics Cell Self Renewal - genetics Erythropoiesis - genetics Erythropoiesis - immunology Genotype Graft Survival Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Humans Mice Mice, Knockout Mutation Myeloid Cells - cytology Myeloid Cells - metabolism Proto-Oncogene Proteins c-kit - genetics Proto-Oncogene Proteins c-kit - metabolism Thrombopoiesis - genetics Thrombopoiesis - immunology Transplantation, Heterologous |
| title | Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations |
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