Abstract
Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence. The cellular mechanism coordinating the balance between HSC quiescence and differentiation is not fully understood. Here, we report that galactose-binding lectin-3 (galectin-3; Gal-3) is upregulated by Tie2 or Mpl activation to maintain quiescence. Conditional overexpression of Gal-3 in mouse HSCs under the transcriptional control of Tie2 or Vav1 promoters (Gal-3 Tg) causes cell cycle retardation via induction of p21. Conversely, the cell cycle of long-term repopulating HSCs (LT-HSCs) in Gal-3-deficient (Gal-3-/-) mice is accelerated, resulting in their exhaustion. Mechanistically, Gal-3 regulates p21 transcription by forming a complex with Sp1, thus blocking cell cycle entry. These results demonstrate that Gal-3 is a negative regulator of cell-cycling in HSCs and plays a crucial role in adult hematopoiesis to prevent HSC exhaustion.
Highlights
Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence
Data are presented as mean values ± S.D. c Relative expression level of mRNA for p16 and p21 family members in BM long-term repopulating HSCs (LT-HSCs) (CD150+CD48−Flt3−LSK) from Gal3+/+ or Gal-3−/− mice (n = 3 biological replicates per genotype, compared by two-sided t test)
Data are presented as mean values ± S.D. i Defective long-term reconstitution capacity of Gal-3−/− LT-HSCs during serial competitive BM-T. (Left) Experimental schema for serial competitive BM-T. (Right) The percentage of Gal-3+/+ or Gal-3−/− donor-derived LT-HSCs (CD45.1−CD150+CD48−Flt3−LSK) was determined at 16 weeks post-transplant for the primary, secondary and third BM-Ts (n = 5 biological replicates per genotype at each BM-T time point, compared by two-sided t test)
Summary
Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence. We report that galactose-binding lectin-3 (galectin-3; Gal-3) is upregulated by Tie[2] or Mpl activation to maintain quiescence. Gal-3 regulates p21 transcription by forming a complex with Sp1, blocking cell cycle entry These results demonstrate that Gal-3 is a negative regulator of cell-cycling in HSCs and plays a crucial role in adult hematopoiesis to prevent HSC exhaustion. Maintenance of the HSCs in an undifferentiated state in vitro remains a major obstacle To overcome this hurdle, characterization of the stem-cell niche is important for understanding the molecular mechanisms whereby stem cells differentiate or selfrenew. By using genetically manipulated mice, i.e., gene ablation and overexpression, we analyze the roles of Gal-3 in quiescent HSCs. We elucidate the mechanisms regulating Gal-3 induction in association with Tie[2] or Mpl activation and its functional relevance for maintaining quiescence in HSCs through the regulation of p21 transcription
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