Cholinergic Enhancement of Cell Proliferation in the Postnatal Neurogenic Niche of the Mammalian Spinal Cord

Abstract

The region surrounding the central canal (CC) of the spinal cord is a highly plastic area, defined as a postnatal neurogenic niche. Within this region are ependymal cells that can proliferate and differentiate to form new astrocytes and oligodendrocytes following injury and cerebrospinal fluid contacting cells (CSFcCs). The specific environmental conditions, including the modulation by neurotransmitters that influence these cells and their ability to proliferate, are unknown. Here, we show that acetylcholine promotes the proliferation of ependymal cells in mice under both in vitro and in vivo conditions. Using whole cell patch clamp in acute spinal cord slices, acetylcholine directly depolarized ependymal cells and CSFcCs. Antagonism by specific nicotinic acetylcholine receptor (nAChR) antagonists or potentiation by the α7 containing nAChR (α7*nAChR) modulator PNU 120596 revealed that both α7*nAChRs and non‐α7*nAChRs mediated the cholinergic responses. Using the nucleoside analogue EdU (5‐ethynyl‐2'‐deoxyuridine) as a marker of cell proliferation, application of α7*nAChR modulators in spinal cord cultures or in vivo induced proliferation in the CC region, producing Sox‐2 expressing ependymal cells. Proliferation also increased in the white and grey matter. PNU 120596 administration also increased the proportion of cells coexpressing oligodendrocyte markers. Thus, variation in the availability of acetylcholine can modulate the rate of proliferation of cells in the ependymal cell layer and white and grey matter through α7*nAChRs. This study highlights the need for further investigation into how neurotransmitters regulate the response of the spinal cord to injury or during aging. Stem Cells 2015;33:2864–2876

Regenerative Potential of Ependymal Cells for Spinal Cord Injuries Over Time

“…Previous work has shown that embryonic spinal cord stem cells and adult ependymal cells give rise to different proportions of neural cell types (Kalyani et al, 1997, Barnabe-Heider et al, 2010), our data support that further therapies should focus on the recruitment of ependymal cells and their differentiation to oligodendrocyte rather than into neurons to increase functional recovery. Previous studies showed that exogenous growth factors can modulate oligodendrocyte proliferation and suggested that this would be a beneficial target for further drug discovery and therapies for SCI (Corns et al, 2015). Our data agrees with this argument and further indicates that modulating stem cell differentiation towards the oligodendrocyte lineage will be influenced by age-dependent differences in intrinsic stem cell potential.…”

Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors

“…Several previous studies have shown that neurotransmitters influence neurogenesis both during embryonic development and in the adult brain and spinal cord in several species, e.g. in mammals, salamanders and zebrafish 21 22 23 24 . The role of dopamine signalling in neurogenesis in the mammalian brain was addressed in different experimental settings, which collectively indicated region- and cell-type specific effects.…”

Purinergic signalling in a latent stem cell niche of the rat spinal cord

“…resorption of cilia [39]) in this cellular compartment with major functional consequences. Interestingly, it has been recently demonstrated that signalling via nicotinic acetylcholine receptors modulates cell proliferation of ependymal cells in the spinal cord [40], highlighting the importance of neurotransmitter regulation of progenitor cell behaviour.…”