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THE STEM CELL NICHE

Novel Extracellular Matrix Structures in the Neural Stem Cell Niche Capture the Neurogenic Factor Fibroblast Growth Factor 2 from the Extracellular Milieu

^aDepartment of Tropical Medicine and Infectious Diseases, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA;
^bResearch Institute for Diseases of Old Age, Jutendo University School of Medicine, Tokyo, Japan

Key Words. Neurogenesis • Extracellular matrix • Heparan sulfate proteoglycan • Basement membrane • Meninges Basic fibroblast growth factor

Correspondence: Frederic Mercier, Ph.D., John A. Burns School of Medicine, Department of Tropical Medicine, Medical Microbiology and Pharmacology, 651 Ilalo Street, Honolulu, Hawaii 96813, USA. Telephone: 808-956-5997; Fax: 808-956-9481; e-mail: fmercier{at}pbrc.hawaii.edu

Received January 31, 2007; accepted for publication May 30, 2007.
First published online in STEM CELLS EXPRESS   June 14, 2007.



The novel extracellular matrix structures called fractones are found in the lateral ventricle walls, the principal adult brain stem cell niche. By electron microscopy, fractones were shown to contact neural stem and progenitor cells (NSPC), suggesting a role in neurogenesis. Here, we investigated spatial relationships between proliferating NSPC and fractones and identified basic components and the first function of fractones. Using bromodeoxyuridine (BrdU) for birth-dating cells in the adult mouse lateral ventricle wall, we found most mitotic cells next to fractones, although some cells emerged next to capillaries. Like capillary basement membranes, fractones were immunoreactive for laminin ß1 and 1, collagen IV, nidogen, and perlecan, but not laminin-1, in the adult rat, mouse, and human. Intriguingly, N-sulfate heparan sulfate proteoglycan (HSPG) immunoreactivity was restricted to fractone subpopulations and infrequent subependymal capillaries. Double immunolabel for BrdU and N-sulfate HSPG revealed preferential mitosis next to N-sulfate HSPG immunoreactive fractones. To determine whether N sulfate HSPG immunoreactivity within fractones reflects a potential for binding neurogenic growth factors, we identified biotinylated fibroblast growth factor 2 (FGF-2) binding sites in situ on frozen sections, and in vivo after intracerebroventricular injection of biotinylated FGF-2 in the adult rat or mouse. Both binding assays revealed biotinylated FGF-2 on fractone subpopulations and on infrequent subependymal capillaries. The binding of biotinylated FGF-2 was specific and dependent upon HSPG, as demonstrated in vitro and in vivo by inhibition with heparatinase and by the concomitant disappearance of N-sulfate HSPG immunoreactivity. These results strongly suggest that fractones promote growth factor activity in the neural stem cell niche.

Disclosure of potential conflicts of interest is found at the end of this article.

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