Novel extracellular matrix structures in the neural stem cell niche capture the neurogenic factor fibroblast growth factor 2 from the extracellular milieu.
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 beta1 and gamma1, collagen IV, nidogen, and perlecan, but not laminin-alpha1, 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.
Kerever
Aurelien
A
John A. Burns School of Medicine, Department of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu, Hawaii 96813, USA.
Schnack
Jason
J
Vellinga
Dirk
D
Ichikawa
Naoki
N
Moon
Chris
C
Arikawa-Hirasawa
Eri
E
Efird
Jimmy T
JT
Mercier
Frederic
F
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D000368:Aged; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008297:Male; D008578:Meninges / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley
D019812:Heparan Sulfate Proteoglycans; D016222:Fibroblast Growth Factor 2