Abstract
This study investigates glio-vascular interactions in human fetal brain at midgestation, specifically examining the expression and immunolocalization of the CXCL12/CXCR4/CXCR7 ligand-receptor axis and its possible role in the vascular patterning of the developing brain. At midgestation, the telencephalic vesicles are characterized by well developed radial glia cells (RGCs), the first differentiated astrocytes and a basic vascular network mainly built of radial vessels. RGCs have been recognized to contribute to cerebral cortex neuro-vascular architecture and have also been demonstrated to act as a significant source of neural cells (Rakic, Brain Res 33:471–476, 1971; Malatesta et al, Development 127:5253–5263, 2000). According to our hypothesis CXCL12, a potent migration and differentiation chemokine released by RGCs, may act as a linking factor coordinating neuroblast migration with vessel growth and patterning through the activation of different ligand/receptor axes. The obtained results support this hypothesis showing that together with CXCR4/CXCR7-reactive neuroblasts, which migrate in close association with CXCL12 RGCs, layer-specific subsets of CXCL12 RGCs and astrocytes specifically contact the microvessel wall. Moreover, the CXCL12/CXCR4/CXCR7 system appears to be directly involved in microvessel growth, its members being differentially expressed in angiogenically activated microvessels and vascular sprouts.
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M.V.C. Pragnell is gratefully acknowledged for language help.
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This work has been funded by grants from Fondazione Cassa di Risparmio di Puglia (FCRP 2010) and from the Italian Ministry of the University and Scientific Research (MIUR), project PRIN 2008.
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Communicated by: Maurizio Scarpa
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Supplementary material 1
A gallery of steps in human forebrain vascularization, from a preplate stage (A) to the cortex pre-lamination stage at midgestation (I). Microvessels are revealed by immunostaining for vessel basal lamina components, collagen IV (A, B, D, E, G, I) and fibronectin (C, F, H). The first penetrating microvessels (A, D, G), a capillary loop (B), radial stem vessels (C). E and F, details of stage G and C, respectively. Initial (H) and late (I) formation of H-shaped collaterals. MZ, marginal zone; CP, cortical plate; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone. Immunolabelling with rabbit anti-collagen type IV (1:100 dilution; Acris Antibodies; Hiddenhausen, Germany) and rabbit anti-fibronectin (1:500 dilution; Millipore, Billerica, MA, USA), nuclear counterstaining with propidium iodide (Molecular Probes). (JPEG 386 kb)
Supplementary material 2
A schematic outline of cerebral cortex, radial astrocytes depicted in Fig. 6. In the cortex, radial astrocytes appear strongly labelled by both GFAP and CXCL12, with complete overlapping of the two markers. In type 1 and 2 the nucleus is positioned on the top, close to the short, basal processes and to the origin of recurrent processes (arrowhead), while radial astrocytes type 3 and 4 have an upside-down position. (JPEG 60 kb)
Supplementary material 3
A short series of single optical planes showing GFAP/CXCL12high RGC and astrocyte perivascular contacts (projection image in Fig. 5f). (AVI 153605 kb)
Supplementary material 4
Triple immunostaining with GFAP, CXCL12, and collagen type-IV. A cortex microvessel (asterisk) showing a CXCL12-reactive endothelial cell (arrow) and perivascular GFAP/CXCL12high astrocyte endfeet (arrowhead). (JPEG 111 kb)
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Virgintino, D., Errede, M., Rizzi, M. et al. The CXCL12/CXCR4/CXCR7 ligand-receptor system regulates neuro-glio-vascular interactions and vessel growth during human brain development. J Inherit Metab Dis 36, 455–466 (2013). https://doi.org/10.1007/s10545-012-9574-y
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DOI: https://doi.org/10.1007/s10545-012-9574-y