Targeted antagonism of CXCR4 mobilizes progenitor cells under investigation for cardiovascular disease.
OBJECTIVE
Bone marrow (BM)-derived cells may repair cardiovascular injury but populations of interest circulate in small numbers. Cytokines such as granulocyte-colony-stimulating factor mobilize cells under investigation for this purpose, including CD133+ but require injections over multiple days and may promote inflammation. The purpose of this study was to evaluate the effects of a novel CXCR4 inhibitor (plerixafor), previously shown to mobilize CD34+ stem cells, on CD133+ mobilization and markers of inflammation.


METHODS
Healthy subjects received a single subcutaneous injection of plerixafor in escalating doses: 240 mcg/kg (n = 3), 320 mcg/kg (n = 5) and 400 mcg/kg (n = 7). CD133+ and CD133+/VEGFR-2+ cells were measured by flow cytometry at baseline, then 4-6 h following plerixafor injection. Markers of inflammation in serum were measured at baseline, then again 10 h following injection of the 400 mcg/kg dose.


RESULTS
Across all doses, white blood cells increased on average three-fold from baseline values. CD133+ cells increased on average 24-fold (from 616 +/- 141 cells/mL to 14 713 +/- 4423 cells/mL, P = 0.0064) without clear evidence of a dose effect. CD133+/VEGFR-2+ cells ranged from 0 to 20 cells/mL at baseline and from 0 to 124 cells/mL following plerixafor administration, although the rarity of these cells precluded a statistical analysis of this population. C-reactive protein and serum amyloid type A were not increased after the 400 mcg/kg dose. Pro-inflammatory cytokine levels were undetectable before and after plerixafor, except for macrophage inflammatory protein-1 beta, which increased slightly but significantly after the 400 mcg/kg dose of plerixafor (P = 0.0156).


CONCLUSIONS
CD133+ cells are mobilized into the circulation following a single injection of the CXCR4 antagonist plerixafor, without clear evidence for systemic activation of inflammation. This effect may be of importance in cell-based approaches for treating cardiovascular diseases.
Blum
Arnon
A
Translational Medicine Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA.
Childs
Richard W
RW
Smith
Aleah
A
Patibandla
Sushmitha
S
Zalos
Gloria
G
Samsel
Leigh
L
McCoy
J Philip
JP
Calandra
Gary
G
Csako
Gyorgy
G
Cannon
Richard O
RO
D000071916:AC133 Antigen; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D001596:Benzylamines; D001772:Blood Cell Count; D002318:Cardiovascular Diseases / Q000628:therapy*; D000080027:Cyclams; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010455:Peptides / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D000071916:AC133 Antigen; D015703:Antigens, CD; D001596:Benzylamines; D000080027:Cyclams; D006023:Glycoproteins; D006571:Heterocyclic Compounds; C000606023:PROM1 protein, human; D010455:Peptides; D019718:Receptors, CXCR4; C088327:plerixafor