HIF-1α-stabilizing agent FG-4497 rescues human CD34 + cell mobilization in response to G-CSF in immunodeficient mice

Exp Hematol. 2017 Aug;52:50-55.e6. doi: 10.1016/j.exphem.2017.05.004. Epub 2017 May 17.

Abstract

Granulocyte colony-stimulating factor (G-CSF) is used routinely in the clinical setting to mobilize hematopoietic stem progenitor cells (HSPCs) into the patient's blood for collection and subsequent transplantation. However, a significant proportion of patients who have previously received chemotherapy or radiotherapy and require autologous HSPC transplantation cannot mobilize the minimal threshold of mobilized HSPCs to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are used in the clinical setting. We have shown previously in mice that administration of prolyl 4-hydroxylase domain enzyme (PHD) inhibitors, which stabilize hypoxia-inducible factor (HIF)-1α, synergize with G-CSF in vivo to enhance mouse HSPC mobilization into blood, leading to enhanced engraftment via an HSPC-intrinsic mechanism. To evaluate whether PHD inhibitors could be used to enhance mobilization of human HSPCs, we humanized nonobese, diabetic severe combined immune-deficient Il2rg-/- mice by transplanting them with human umbilical cord blood CD34+ HSPCs and then treating them with G-CSF with and without co-administration of the PHD inhibitor FG-4497. We observed that combination treatment with G-CSF and FG-4497 resulted in significant mobilization of human lineage-negative (Lin-) CD34+ HSPCs and more primitive human Lin-CD34+CD38- HSPCs into blood and spleen, whereas mice treated with G-CSF alone did not mobilize human HSPCs significantly. These results suggest that the PHD inhibitor FG-4497 also increases human HSPC mobilization in a xenograft mouse model, suggesting the possibility of testing PHD inhibitors to boost HSPC mobilization in response to G-CSF in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Cord Blood Stem Cell Transplantation / methods
  • Female
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Flow Cytometry
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Hematopoietic Stem Cell Mobilization*
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Isoquinolines / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Prolyl-Hydroxylase Inhibitors / pharmacology*
  • Time Factors
  • Transplantation, Heterologous

Substances

  • Antigens, CD34
  • FG-4497
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Isoquinolines
  • Prolyl-Hydroxylase Inhibitors
  • Granulocyte Colony-Stimulating Factor