Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

Karpova, Darja, Ritchey, Julie K., Holt, Matthew S., Abou-Ezzi, Grazia, Monlish, Darlene, Batoon, Lena, Millard, Susan, Spohn, Gabriele, Wiercinska, Eliza, Chendamarai, Ezhil, Yang, Wei, Christ, Stephanie, Gehrs, Leah, Schuettpelz, Laura G., Dembowsky, Klaus, Pettit, Allison R., Rettig, Michael P., Bonig, Halvard and DiPersio, John F. (2017) Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells. Blood, 129 21: 2939-2949. doi:10.1182/blood-2016-10-746909


Author Karpova, Darja
Ritchey, Julie K.
Holt, Matthew S.
Abou-Ezzi, Grazia
Monlish, Darlene
Batoon, Lena
Millard, Susan
Spohn, Gabriele
Wiercinska, Eliza
Chendamarai, Ezhil
Yang, Wei
Christ, Stephanie
Gehrs, Leah
Schuettpelz, Laura G.
Dembowsky, Klaus
Pettit, Allison R.
Rettig, Michael P.
Bonig, Halvard
DiPersio, John F.
Title Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells
Journal name Blood   Check publisher's open access policy
ISSN 1528-0020
0006-4971
Publication date 2017-05-01
Year available 2017
Sub-type Article (original research)
DOI 10.1182/blood-2016-10-746909
Open Access Status Not yet assessed
Volume 129
Issue 21
Start page 2939
End page 2949
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
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.
Keyword G-Csf
Rapid Mobilization
Stem/progenitor Cells
Endothelial Niches
B-Lymphopoiesis
In-Vitro
Antagonist
Amd3100
Mice
Cyclophosphamide
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P50 CA094056
R21 CA110489
R50 CA211466
R21 CA132269
UL1 RR024992
R01 CA152329
R01 CA083845
P30 CA091842
P01 CA101937
UL1 TR000448
R21 CA141523
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
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