Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo.
Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells are suboptimal in these hosts. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. We generated RAG2(-/-)γ(c)(-/-) mice in which we replaced the gene encoding mouse TPO by its human homolog. Homozygous humanization of TPO led to increased levels of human engraftment in the bone marrow of the hosts, and multilineage differentiation of hematopoietic cells was improved, with an increased ratio of myelomonocytic verus lymphoid lineages. Moreover, maintenance of human stem and progenitor cells was improved, as demonstrated by serial transplantation. Therefore, RAG2(-/-)γ(c)(-/-) TPO-humanized mice represent a useful model to study human hematopoiesis in vivo.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Anthony
A
Rongvaux
Tim
T
Willinger
Hitoshi
H
Takizawa
Chozhavendan
C
Rathinam
Wojtek
W
Auerbach
Andrew J
AJ
Murphy
David M
DM
Valenzuela
George D
GD
Yancopoulos
Elizabeth E
EE
Eynon
Sean
S
Stevens
Markus G
MG
Manz
Richard A
RA
Flavell
D000818:Animals; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D013926:Thrombopoietin
Cell Host Microbe. 2009 Jul 23;6(1):5-9
19616761
Annu Rev Immunol. 2003;21:759-806
12615892
Blood. 2008 Feb 1;111(3):981-6
18223171
Nat Biotechnol. 2007 Jan;25(1):91-9
17187059
Nature. 1994 Jun 16;369(6481):533-8
8202154
Clin Immunol. 2010 Apr;135(1):84-98
20096637
Cell Stem Cell. 2007 Dec 13;1(6):685-97
18371409
Cell. 2009 Jul 23;138(2):271-85
19632178
Int J Hematol. 2005 Dec;82(5):389-96
16533740
Nature. 1994 Jun 16;369(6481):568-71
8202159
Nat Immunol. 2007 Dec;8(12):1287-9
18026079
Nature. 1994 Jun 16;369(6481):565-8
8202158
Immunity. 2007 May;26(5):537-41
17521579
J Exp Med. 2001 Apr 16;193(8):917-24
11304552
Nat Immunol. 2007 Dec;8(12):1313-23
17982459
Nat Genet. 1998 Jan;18(1):49-52
9425899
Nat Rev Immunol. 2007 Feb;7(2):118-30
17259968
Blood. 1996 Nov 1;88(9):3306-13
8896394
Stem Cells. 1997;15 Suppl 1:199-203; discussion 204-7
9368342
J Immunol. 2004 Mar 1;172(5):2731-8
14978070
Science. 2004 Apr 2;304(5667):104-7
15064419
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11872-7
12193648
Blood. 2005 Sep 1;106(5):1565-73
15920010
Blood. 2002 Nov 1;100(9):3175-82
12384415
Cell. 2010 Sep 3;142(5):699-713
20813259
J Immunol. 2006 Feb 15;176(4):2053-8
16455958
Nat Biotechnol. 2003 Jun;21(6):652-9
12730667
Nat Med. 1996 Dec;2(12):1329-37
8946831
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2804-8
1372992
Science. 1988 Sep 23;241(4873):1632-9
2971269
N Engl J Med. 1998 Sep 10;339(11):746-54
9731092
Nature. 1994 Jun 16;369(6481):571-4
8202160
Science. 1988 Dec 23;242(4886):1684-6
3201256
Toxicology. 2003 Jun 3;188(1):49-71
12748041
Blood. 2003 Nov 1;102(9):3172-8
12855555
Cold Spring Harb Symp Quant Biol. 2008;73:439-49
19022770
Blood. 1998 Dec 1;92(11):4023-30
9834204
Exp Hematol. 2004 Nov;32(11):1118-25
15539091
Cell Stem Cell. 2007 Dec 13;1(6):635-45
18371405
Cell Stem Cell. 2007 Dec 13;1(6):671-84
18371408
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5320-5
9144235
Cell. 1994 Jul 1;77(7):1117-24
8020099
J Clin Invest. 2002 Aug;110(3):389-94
12163458
Blood. 2004 Dec 15;104(13):3886-93
15319293