How Necessary is the Vasculature in the Life of Neural Stem and Progenitor Cells? Evidence from Evolution, Development and the Adult Nervous System

Abstract

Augmenting evidence suggests that such is the functional dependance of neural stem cells (NSCs) on the vasculature that they normally reside in "perivascular niches". Two examples are the "neurovascular" and the "oligovascular" niches of the adult brain, which comprise specialized microenvironments where NSCs or oligodendrocyte progenitor cells survive and remain mitotically active in close proximity to blood vessels (BVs). The often observed co-ordination of angiogenesis and neurogenesis led to these processes being described as "coupled". Here, we adopt an evo-devo approach to argue that some stages in the life of a NSC, such as specification and commitment, are independent of the vasculature, while stages such as proliferation and migration are largely dependent on BVs. We also explore available evidence on the possible involvement of the vasculature in other phenomena such as the diversification of NSCs during evolution and we provide original data on the senescence of NSCs in the subependymal zone stem cell niche. Finally, we will comment on the other side of the story; that is, on how much the vasculature is dependent on NSCs and their progeny.

Keywords: blood vessels; differentiation; migration; neural stem cells; neurogenesis; proliferation; stem cell niche; vasculature.

Figure 1

The role of the vasculature in the life of a neural stem cell (NSC). In this graphic illustration, the different stages in the life of a NSC are shown and the involvement of the vasculature is depicted by the distance of the cells from the blood vessels (BVs). For example, specification and commitment of NSCs appear to happen away from the vessels, whilst proliferation and migration in close proximity.

Figure 2

Proliferation and senescence in the subependymal zone (SEZ). (A,B) High magnification photographs of domains of the SEZ (dorsal in A, middle in B) taken from young adult mouse brain tissue immunostained for PCNA (to mark proliferating cells) and laminin (to mark blood vessels, BVs). Note the existence of multiple proliferating cells around the long BV running in parallel to the lateral ventricle in (B), but also the existence of high proliferative activity in areas distant from BVs in (A). (C–E) High magnification photographs of domains of the SEZ (middle in C,D and ventral in E) taken from young (in C,E) and aged (in D) rat brain tissue immunostained for laminin and chemically stained for senescence-associated β gal (in blue). Arrowheads indicate BVs and arrows senescent cells. Note the significantly lower density of BVs at the non-neurogenic side of the lateral ventricle (at the left of C), the existence of senescent cells along BVs outside the SEZ and the existence of high numbers of senescent cells in the ventral domain of the young-adult rat SEZ (in E). (F) High magnification of adult mouse NSCs isolated from the SEZ and kept in culture. Note the existence of senescent cells (nuclei are counterstained with nuclear fast red). [Antibodies used: rabbit anti-laminin: 1/500 (Abcam), mouse anti-PCNA: 1/500 (Abcam). Alexa goat anti-rabbit 568 and goat anti-mouse 488 (Invitrogen). Biotinylated goat anti-rabbit and DAB staining kit (Vector laboratories). Senescence-associated β gal staining kit (Millipore). Adult NSCs cultured in DMEM/F12 supplemented with B27 (Gibco), FGF2 (20 ng/ml) and EGF (20 ng/ml). All animal work was performed in accordance with the UK Animals (Scientific Procedures) Act 1986 and was approved by the University of Cambridge Animal Welfare and Ethical Review Body].