Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence.
Self-renewal is a defining characteristic of stem cells; however, the molecular pathways underlying its regulation are poorly understood. Here, we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell-cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes is associated with the TGF-beta pathway, which serves a major role in maintaining HSC quiescence. Prospectively isolated, Pbx1-deficient LT-HSCs display altered transcriptional responses to TGF-beta stimulation in vitro, suggesting a possible mechanism through which Pbx1 maintenance of stem cell quiescence may in part be achieved.
Ficara
Francesca
F
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Murphy
Mark J
MJ
Lin
Min
M
Cleary
Michael L
ML
D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D019070:Cell Lineage; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C083400:PBX1 protein, human