HIF-1α stabilizing agent FG-4997 rescues human CD34(+) cell mobilization in response to G-CSF in immuno-deficient mice.

HIF-1α stabilizing agent FG-4997 rescues human CD34(+) cell mobilization in response to G-CSF in immuno-deficient mice.

Exp Hematol. 2017 May 17;:

Authors: Nowlan B, Futrega K, Brunck ME, Walkinshaw G, Flippin LE, Doran MR, Levesque JP

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

PMID: 28527810 [PubMed - as supplied by publisher]

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