Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation.
Hmgb3 is an X-linked member of a family of sequence-independent chromatin-binding proteins that is preferentially expressed in hematopoietic stem cells (HSC). Hmgb3-deficient mice (Hmgb3(-/Y)) contain normal numbers of HSCs, capable of self-renewal and hematopoietic repopulation, but fewer common lymphoid (CLP) and common myeloid progenitors (CMP). In this study, we tested the hypothesis that Hmgb3(-/Y) HSCs are biased toward self-renewal at the expense of progenitor production. Wild-type and Hmgb3(-/Y) CLPs and CMPs proliferate and differentiate equally in vitro, indicating that CLP and CMP function normally in Hmgb3(-/Y) mice. Hmgb3(-/Y) HSCs exhibit constitutive activation of the canonical Wnt signaling pathway, which regulates stem cell self-renewal. Increased Wnt signaling in Hmgb3(-/Y) HSCs corresponds to increased expression of Dvl1, a positive regulator of the canonical Wnt pathway. To induce hematopoietic stress and a subsequent response from HSCs, we treated Hmgb3(-/Y) mice with 5-fluorouracil. Hmgb3(-/Y) mice exhibit a faster recovery of functional HSCs after administration of 5-fluorouracil compared with wild-type mice, which may be due to the increased Wnt signaling. Furthermore, the recovery of HSC number in Hmgb3(-/Y) mice occurs more rapidly than CLP and CMP recovery. From these data, we propose a model in which Hmgb3 is required for the proper balance between HSC self-renewal and differentiation.
Nemeth
Michael J
MJ
Hematopoiesis Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD 20892-4442, USA.
Kirby
Martha R
MR
Bodine
David M
DM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D000072261:Dishevelled Proteins; D005472:Fluorouracil / Q000494:pharmacology; D025765:HMGB3 Protein / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D025765:HMGB3 Protein; D010750:Phosphoproteins; D051153:Wnt Proteins; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil