TY - JOUR
T1 - Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with KitWv Mutations
AU - Yurino, Ayano
AU - Takenaka, Katsuto
AU - Yamauchi, Takuji
AU - Nunomura, Takuya
AU - Uehara, Yasufumi
AU - Jinnouchi, Fumiaki
AU - Miyawaki, Kohta
AU - Kikushige, Yoshikane
AU - Kato, Koji
AU - Miyamoto, Toshihiro
AU - Iwasaki, Hiromi
AU - Kunisaki, Yuya
AU - Akashi, Koichi
N1 - Funding Information:
We thank the Japanese Red Cross Kyushu Cord Blood Bank for providing the CB samples. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (to K.T., no. 26461424 ), a Grant-in-Aid for Scientific Research on Innovative Areas (to K.A., nos. 22130001 and 22130002 ), a Grant-in-Aid for Challenging Exploratory Research (to K.A., no. 24659463 ), a Grant-in-Aid for Scientific Research (A) (to K.A., no. 25253069 ), a Grant-in-Aid for Scientific Research (B) (to Y. Kunisaki, no. 15H04859 ), a Grant-in-Aid for JSPS Fellows (to T.Y., no. 15J10130 ), a Grant-in-Aid for Young Scientists (A) (to Y. Kikushige, no. 26713034 ), a Grant-in-Aid for Scientific Research (B) (to T.M., no. 23390254 ), a Grant-in-Aid for Scientific Research (C) (to K.K., no. 25461453 ), a Grant-in-Aid for Scientific Research (C) (to H.I., no. 25461424 ), a Grant-in-Aid for Scientific Research on Innovative Areas (to T.M., no. 25115002 ).
Publisher Copyright:
© 2016 The Authors
PY - 2016/9/13
Y1 - 2016/9/13
N2 - In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull 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.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/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 BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.
AB - In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull 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.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/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 BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.
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U2 - 10.1016/j.stemcr.2016.07.002
DO - 10.1016/j.stemcr.2016.07.002
M3 - Article
C2 - 27499200
AN - SCOPUS:84990026467
SN - 2213-6711
VL - 7
SP - 425
EP - 438
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 3
ER -