A co-culture model of the hippocampal neurogenic niche reveals differential effects of astrocytes, endothelial cells and pericytes on proliferation and differentiation of adult murine precursor cells

Abstract

The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.

Human endothelial cells secrete neurotropic factors to direct axonal growth of peripheral nerves

“…Neurotrophic soluble factors such as nerve growth factor (NGF) also stimulate angiogenesis, demonstrating significant overlap between these signaling pathways. The dynamic relationship between vascular and neural tissues persists in adult tissues, where blood brain barrier models show active signaling between these cell types via soluble factors 16 . In fact, there is evidence that neural stem cells stimulate tube formation in populations of endothelial cells 17 , suggesting that this crosstalk works both ways: neural populations stimulate endothelial populations and vice versa in adult tissues.…”

A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis

“…Circulating immune cells and blood-borne factors travelling through the bloodstream into the brain might be more involved in the regulation of neurogenesis than long thought. The finding that nestin-GFP-expressing hippocampal precursor cells directly contact the niche-resident endothelial cells via vascular endfeet [ 13 , 14 ] supports this hypothesis.…”

Tissue Models for Neurogenesis and Repair in 3D

“…Development of vascular and neuronal tissues occurs simultaneously in utero, and are regulated by significant crosstalk between cellular signals important in the maturation of each individual network . Analysis of signaling events between these cell types in tissue models of the blood brain barrier demonstrates that this dynamic relationship persists throughout the lifespan of each network . Interestingly, the repair process of injured nerves follows a similar process as that found in embryonic development, suggesting that a deeper understanding of how these tissues develop and mature should enhance our ability to understand, and ultimately direct, peripheral nerve regeneration and repair.…”