An ancient cholinergic cell triad of a light-sensitive, a pigmented and a glial cell could regulate stemness.

A close spatiotemporal relation between end of mitosis, of butyryl- (BChE) and then acetylcholinesterase (AChE) expressions in early neural tissues has been established, yet the underlying mechanisms are not understood. With this observation in mind, cell culture work analyzing cholinergic functions in the developing vertebrate retina was revealing. For proper cell stratification in avian and rodent retinal 3D-reaggregates (organoids) and explants, Müller glial cells (MCs) and the retinal pigmented epithelium (RPE) are essential actors. Network formation depends on a ChAT+ amacrine cell and BChE+ MCs. Further, cholinergic effects at the photoreceptor (PR) to RPE interface remain unclear. Acetylcholine (ACh) reportedly is produced in, and released from PRs, which is received by alpha-7 nicotinic acetylcholine receptors (α7-nAChRs) on adjacent RPE cells. If properly activated, RPE cells in turn signal ACh back to MCs. Notably, MCs under certain conditions act as stem cells in retinal regeneration. Hence, we postulate that a cholinergic signaling loop between MCs, PRs and RPE, which probably already constituted an ancient proto eye, can regulate stem cells. Since a similar cholinergic triad regulates skin regeneration, comparable cholinergic triads could appear at the core of stem cell biology, deserving more research (e.g., cancer biology, tissue regeneration).