Prolonged inhibition of CXCR4/CXCL12 signaling results in exceptional mobilization along with an expansion of the BM HSPC pool.
Reversible inhibition of CXCR4/CXCL12 axis may represent a novel strategy to restore damaged BM.
Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPC) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated using three structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by applying the antagonists as subcutaneous continuous infusion for two weeks compared to single bolus injection. Moreover a concurrent increase in self-renewing proliferation leading to a 2-4-fold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in CXCR4 antagonist infusion treated bones. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool.
- Submitted October 25, 2016.
- Accepted March 24, 2017.
- Copyright © 2017 American Society of Hematology
To view this item, select one of the options below.
If you already have a subscription, you may gain access using your ASH username and password.
Log in through your institution
Subscribe to the Journal - Subscribe to the print and/or online journal.