Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1.
The chemokine stroma-derived factor-1 (SDF-1) is produced within the bone marrow and mediates chemokinesis and chemotaxis on a variety of cell types that express the CXCR4 receptor. SDF-1-responsive cell types include monocytes and macrophages, B and T lymphocytes, platelets and megakaryocytes, and CD34+ cells, including both hematopoietic progenitors and stem cells. We have used intravenous injection of a replication-incompetent adenovector expressing the SDF-1 gene to elevate serum levels of SDF-1 in Balb/c and SCID mice. Within 3 to 5 days there was a marked leukocytosis, predominantly involving monocytes, and a three-fold increase in platelets. In addition, AdSDF-1 mobilized CFU-GM, CFU-s, and cells with long-term repopulating potential. We have identified a bone marrow-derived, circulating endothelial stem cell characterized by expression of the VEGFR2 (Flk-1/KDR). This cell exhibits a chemotactic and chemokinetic response to SDF-1 and VEGF. We have elevated serum levels of VEGF165 using intravenous adenovector gene delivery and compared this to an adenovector expressing angiopoietin-1 alone or in combination with VEGF. VEGF elevation was associated with rapid mobilization of hematopoietic stem and progenitor cells and a population of Flk-1-positive endothelial progenitors. In contrast angiopoietin induced a delayed mobilization of endothelial and hematopoietic progenitors. The combination of VEGF and angiopoietin produced a more prolonged elevation of these progenitors in the circulation with increased proliferation of capillaries and expansion of sinusoidal spaces in the marrow.
Moore
M A
MA
Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. m-moore@ski.mskcc.org
Hattori
K
K
Heissig
B
B
Shieh
J H
JH
Dias
S
S
Crystal
R G
RG
Rafii
S
S
D000256:Adenoviridae / Q000235:genetics; D042683:Angiopoietin-1; D000818:Animals; D001853:Bone Marrow / Q000098:blood supply / Q000473:pathology; D002452:Cell Count; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000235:genetics / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D003114:Colony-Forming Units Assay; D016228:Endothelial Growth Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005822:Genetic Vectors / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007964:Leukocytosis / Q000209:etiology*; D008222:Lymphokines / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000209:etiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects; D017978:Receptors, Growth Factor / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology*; D013234:Stem Cells / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor