Journal Article

Estrogen receptor β controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage

Di Leo, A., Warner, M., Gustafsson, J. A., Goverse, G., Gomez-Pinilla, P. J., Matteoli, G., Verstockt, B., De Simone, V., Wu, W., Labeeuw, E., Stakenborg, M., D’Errico, F., Dai, Y.

2018

Overview

Injury to the enteric nervous system (ENS) can cause several gastrointestinal (GI) disorders including achalasia, irritable bowel syndrome, and gastroparesis. Recently, a subpopulation of enteric glial cells with neuronal stem/progenitor properties (ENSCs) has been identified in the adult ENS. ENSCs have the ability of reconstituting the enteric neuronal pool after damage of the myenteric plexus. Since the estrogen receptor β (ERβ) is expressed in enteric glial cells and neurons, we investigated whether a selective ERβ agonist, LY3201, can influence neuronal and glial cell differentiation. Myenteric ganglia from the murine muscularis externa were isolated and cultured in either glial cell medium or neuronal medium. In glial cell medium, the number of glial progenitor cells (Sox10⁺) was increased by fourfold in the presence of LY3201. In the neuronal medium supplemented with an antimitotic agent to block glial cell proliferation, LY3201 elicited a 2.7-fold increase in the number of neurons (neurofilament⁺ or HuC/D⁺). In addition, the effect of LY3201 was evaluated in vivo in two murine models of enteric neuronal damage and loss, namely, high-fat diet and topical application of the cationic detergent benzalkonium chloride (BAC) on the intestinal serosa, respectively. In both models, treatment with LY3201 significantly increased the recovery of neurons after damage. Thus, LY3201 was able to stimulate glial-to-neuron cell differentiation in vitro and promoted neurogenesis in the damaged myenteric plexus in vivo. Overall, our study suggests that selective ERβ agonists may represent a therapeutic tool to treat patients suffering from GI disorders, caused by excessive neuronal/glial cell damage.

• Publisher: National Academy of Sciences
• Subject: Achalasia / Animal models / Animals / Benzalkonium chloride / Biological Sciences / Cell differentiation / Cell Differentiation - physiology / Cell growth / Cell proliferation / Cell Proliferation - physiology / Cells (biology) / Chloride / Damage assessment / Diet, High-Fat / Differentiation (biology) / Disorders / Enteric nervous system / Estrogen Receptor beta - metabolism / Estrogens / Ganglia / Glial cells / Glial stem cells / High fat diet / Humans / In vivo methods and tests / Intestine / Irritable bowel syndrome / Male / Mice / Mice, Inbred C57BL / Myenteric plexus / Myenteric Plexus - cytology / Myenteric Plexus - injuries / Nervous system / Neural stem cells / Neurogenesis / Neuroglia - cytology / Neuroglia - metabolism / Neuronal-glial interactions / Neurons / Neurons - cytology / Neurons - metabolism / Neuroscience / Obesity / Progenitor cells / Sox10 protein / Topical application