Complementary and independent function for Hoxb4 and Bmi1 in HSC activity.
Determinants regulating short- and long-term repopulating hematopoietic stem cell (STR-HSC and LTR-HSC) self-renewal remain largely uncharacterized. To gain further insights into HSC self-renewal, we investigated possible genetic interactions between two well-recognized regulators of this process: Bmi1 and Hoxb4. Using complementation and overexpression strategies in mouse HSCs, we document that Bmi1 is not required for the in vivo expansion of fetal HSCs but is essential for the long-term maintenance of adult HSCs. Importantly, we show that Hoxb4 overexpression induces an expansion of Bmi1(-/-)STR-HSCs leading to a rescue of their repopulation defect. In contrast to Hoxb4, we also show that Bmi1 fails to induce HSC expansion ex vivo. Consistent with these results, we report high levels of Angptl3 and Cbx7 in Hoxb4- and Bmi1-transduced cells, respectively. Together, these results support the emerging concept that fate and sustainability of this fate are two critical components of self-renewal in adult stem cells such as HSCs.
Faubert
A
A
Laboratory of Molecular Genetics of Hematopoietic Stem Cells, Institute for Research in Immunology and Cancer, University of Montréal, Montréal, Québec, Canada H3C 3J7.
Chagraoui
J
J
Mayotte
N
N
Fréchette
M
M
Iscove
N N
NN
Humphries
R K
RK
Sauvageau
G
G
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D015870:Gene Expression; D005816:Genetic Complementation Test; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
C489421:Bmi1 protein, mouse; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D063150:Polycomb Repressive Complex 1