@article{5bd70ac3691d4811b8e5eb881a5e5808,
title = "Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells",
abstract = "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 (HSPCs) 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 by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold 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 bones treated with a CXCR4 antagonist infusion. 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.",
author = "Darja Karpova and Ritchey, {Julie K.} and Holt, {Matthew S.} and Grazia Abou-Ezzi and Darlene Monlish and Lena Batoon and Susan Millard and Gabriele Spohn and Eliza Wiercinska and Ezhil Chendamarai and Wei Yang and Stephanie Christ and Leah Gehrs and Schuettpelz, {Laura G.} and Klaus Dembowsky and Pettit, {Allison R.} and Rettig, {Michael P.} and Halvard Bonig and {Di Persio}, {John F.}",
note = "Funding Information: This work was supported by Grants No. R01CA83845, R01CA152329, R21CA110489, R21CA132269, R21CA141523, P01CA101937, and P50CA94056 from the National Institutes of Health (NIH), National Cancer Institute (NCI) (J.F.D.). D.K. is a past scholar of the German Academic Exchange Service (postdoctoral fellowship 57054578 [2014-2016]). H.B. is a member of LOEWE Cell and Gene Therapy Frankfurt faculty, funded by Hessian Ministry of Higher Education, Research and the Arts (III L 4-518/17.004 [2013]) and was also supported by Deutsche Forschungsgemeinschaft grant BO3553/1-1. The Siteman Cancer Center is partially supported by NCI Cancer Center Support Grant No. P30CA91842 and by Institute of Clinical and Translational Sciences/Clinical and Translational Science Award Grant No. UL1RR024992 from the NIH, National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research. Publisher Copyright: {\textcopyright} 2017 by The American Society of Hematology.",
year = "2017",
month = may,
day = "25",
doi = "10.1182/blood-2016-10-746909",
language = "English",
volume = "129",
pages = "2939--2949",
journal = "Blood",
issn = "0006-4971",
number = "21",
}