Increased plasma levels of stromal-derived factor-1 (SDF-1/CXCL12) enhance human thrombopoiesis and mobilize human colony-forming cells (CFC) in NOD/SCID mice.
OBJECTIVE
Stromal-derived factor-1 (SDF-1/CXCL12) is chemotactic for lympho/hematopoietic stem cells. We have previously shown that increasing peripheral blood (PB) levels of SDF-1 with adenovectors expressing human SDF-1 complementary DNA (ad-SDF-1) leads to hematopoietic stem cell mobilization as well as migration of megakaryocytes and thrombocytosis in mice. Herein, we studied the in vivo effects of ad-SDF-1 and of an analogue peptide of SDF-1 (CTCE-0214) on human hematopoiesis in a xenotransplant model.


METHODS
Sublethally irradiated (300 cGY) NOD/SCID mice transplanted with human cord blood mononuclear cells (CB MNC) were injected with ad-SDF-1 (10(9) plaque forming units, i.v., x 1) or CTCE-0214 (10 mg/kg/dose, i.v. q 24 hours x 7). Effects on megakaryocytopoiesis (CD41+ cells and platelets) as well as stem cell mobilization were monitored.


RESULTS
CB MNC in NOD/SCID mice are able to differentiate into CD41+ cells and platelets, peaking at week 9 at a mean of 3.7 x 10(3)/microL. i.v. injection of ad-SDF-1 increased human CD41+ cells by day 4 in PB and was followed by an increase in human platelet production by day 5, with return to baseline by day 30. Human colony-forming cells (CFC) were mobilized from bone marrow to spleen (by day 6-13) and to PB (by day 13). Human CD34+ and CD33+ cells were mobilized by this treatment as well. A novel SDF-1 peptide agonist (CTCE-0214) also mobilized human CFC and enhanced human thrombopoiesis.


CONCLUSIONS
SDF-1 and its analogue may be of clinical value in stimulating platelet recovery after chemo/radiation treatment as well as in stem cell mobilization.
Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. PerezLE@moffitt.usf.edu
Lia E
LE
Perez
Onder
O
Alpdogan
Jae-Hung
JH
Shieh
Donald
D
Wong
Ahmed
A
Merzouk
Hassan
H
Salari
Richard J
RJ
O'Reilly
Marcel R M
MR
van den Brink
Malcolm A S
MA
Moore
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000819:agonists / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005312:Fetal Blood / Q000166:cytology; D005822:Genetic Vectors / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013926:Thrombopoietin / Q000235:genetics / Q000494:pharmacology; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin