IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development.
We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit+), stem cell antigen-1 (sca-1+), hematopoietic stem cell (HSC), or CD34+ endothelial precursor cell (EPC) function. Exposure of CD34+ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygen-induced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions.
Chang
Kyung-Hee
KH
Program in Stem Cell Biology, University of Florida, Gainesville, FL 32610, USA.
Chan-Ling
Tailoi
T
McFarland
Evan L
EL
Afzal
Aqeela
A
Pan
Hao
H
Baxter
Louise C
LC
Shaw
Lynn C
LC
Caballero
Sergio
S
Sengupta
Nilanjana
N
Li Calzi
Sergio
S
Sullivan
Sean M
SM
Grant
Maria B
MB
D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007267:Injections; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012160:Retina / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014162:Transfection; D014822:Vitreous Body / Q000378:metabolism
D018952:Antigens, CD34; D018972:Insulin-Like Growth Factor Binding Protein 3; D018950:Lipopolysaccharide Receptors; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit