Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78

Cell Stem Cell. 2011 Oct 4;9(4):330-44. doi: 10.1016/j.stem.2011.07.016.


Hematopoietic stem cells (HSCs) are maintained in hypoxic niches in endosteal regions of bones. Here we demonstrate that Cripto and its receptor GRP78 are important regulators of HSCs in the niche. Flow cytometry analyses revealed two distinct subpopulations of CD34(-)KSL cells based on the expression of GRP78, and these populations showed different reconstitution potential in transplantation assays. GRP78(+)HSCs mainly reside in the endosteal area, are more hypoxic, and exhibit a lower mitochondrial potential, and their HSC capacity was maintained in vitro by Cripto through induction of higher glycolytic activity. Additionally, HIF-1α KO mice have decreased numbers of GRP78(+)HSCs and reduced expression of Cripto in the endosteal niche. Furthermore, blocking GRP78 induced a movement of HSCs from the endosteal to the central marrow area. These data suggest that Cripto/GRP78 signaling is an important pathway that regulates HSC quiescence and maintains HSCs in hypoxia as an intermediary of HIF-1α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bone and Bones / cytology
  • Cell Hypoxia / genetics
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • Glycolysis
  • Heat-Shock Proteins / metabolism*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / genetics
  • Stem Cell Niche
  • Time Factors
  • Up-Regulation / genetics


  • Biomarkers
  • Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Receptors, Cell Surface
  • Tdgf1 protein, mouse
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins c-akt
  • molecular chaperone GRP78