IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development
- Kyung-Hee Chang*,†,
- Tailoi Chan-Ling‡,
- Evan L. McFarland‡,
- Aqeela Afzal†,
- Hao Pan*,†,
- Louise C. Baxter‡,
- Lynn C. Shaw*,†,
- Sergio Caballero*,†,
- Nilanjana Sengupta*,†,
- Sergio Li Calzi*,†,
- Sean M. Sullivan§, and
- Maria B. Grant*,†,¶
- *Program in Stem Cell Biology,
- †epartment of Pharmacology and Therapeutics, and
- §Department of Pharmaceutics, University of Florida, Gainesville, FL 32610; and
- ‡Department of Anatomy, University of Sydney, Sydney NSW 2006, Australia
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Edited by Judah Folkman, Harvard Medical School, Boston, MA, and approved May 9, 2007 (received for review March 8, 2007)
Abstract
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.
Footnotes
- ¶To whom correspondence should be addressed. E-mail: grantma{at}pharmacology.ufl.edu
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Author contributions: S.M.S. and M.B.G. designed research; K.-H.C., T.C.-L., E.L.M., A.A., H.P., L.C.B., S.C., N.S., S.L.C., and M.B.G. performed research; S.M.S. contributed new reagents/analytic tools; T.C.-L., A.A., L.C.S., and M.B.G. analyzed data; and A.A. and M.B.G. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
- Abbreviations:
- BM,
- bone marrow;
- EPC,
- endothelial precursor cell;
- GS isolectin,
- Griffonia simplicifolia isolectin B4;
- HSC,
- hematopoietic stem cell;
- LDL,
- low-density lipoprotein;
- OIR,
- oxygen-induced retinopathy;
- Pn,
- postnatal day n;
- ROP,
- retinopathy of prematurity.
- © 2007 by The National Academy of Sciences of the USA
