Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation

Nat Med. 2006 Jan;12(1):89-98. doi: 10.1038/nm1339. Epub 2005 Dec 11.


The in vivo regulation of hematopoietic stem cell (HSC) function is poorly understood. Here, we show that hematopoietic repopulation can be augmented by administration of a glycogen synthase kinase-3 (GSK-3) inhibitor to recipient mice transplanted with mouse or human HSCs. GSK-3 inhibitor treatment improved neutrophil and megakaryocyte recovery, recipient survival and resulted in enhanced sustained long-term repopulation. The output of primitive Lin(-)c-Kit(+)Sca-1(+) cells and progenitors from HSCs increased upon GSK-3 inhibitor treatment without altering secondary repopulating ability, suggesting that the HSC pool is maintained while overall hematopoietic reconstitution is increased. GSK-3 inhibitors were found to modulate gene targets of Wnt, Hedgehog and Notch pathways in cells comprising the primitive hematopoietic compartment without affecting mature cells. Our study establishes GSK-3 as a specific in vivo modulator of HSC activity, and suggests that administration of GSK-3 inhibitors may provide a clinical means to directly enhance the repopulating capacity of transplanted HSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cell Proliferation
  • Cell Transplantation
  • Cells, Cultured
  • Culture Media, Serum-Free / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Fetal Blood / cytology
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic*
  • Glycogen Synthase Kinase 3 / physiology*
  • Green Fluorescent Proteins / metabolism
  • Hedgehog Proteins
  • Hematopoietic Stem Cells / cytology*
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Megakaryocytes / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mice, Transgenic
  • Models, Biological
  • Neutrophils / cytology
  • Receptors, Notch / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cell Transplantation / methods*
  • Stem Cells
  • Time Factors
  • Trans-Activators / metabolism
  • Wnt Proteins / metabolism


  • Blood Glucose
  • Culture Media, Serum-Free
  • Enzyme Inhibitors
  • Hedgehog Proteins
  • Receptors, Notch
  • Trans-Activators
  • Wnt Proteins
  • Green Fluorescent Proteins
  • Glycogen Synthase Kinase 3