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

Abstract

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.

Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

“…In vitro studies further support the utility of phytoestrogens, including DAI, LQ, and SE to remodel neural circuits by preventing synapse loss induced by the HIV-1 viral protein, Tat (Bertrand et al 2014(Bertrand et al , 2015. Phytoestrogens are one of the few compounds that show potential to restore synaptic connectivity after exposure to HIV-1 Tat (Bertrand et al 2015) and do so via an ERβ specific mechanism; although other synthetic SERBA compounds have been shown to enhance recovery of neurons following damage (D'Errico et al 2018). Furthermore, the clinical importance of SERBAs is demonstrated by their progression into clinical trials and experimental studies of other neurodegenerative diseases, including Parkinsons disease (McFarland et al 2013) and Alzheimer's disease (Zhao et al 2013).…”

Enteric Glia: S100, GFAP, and Beyond

“…As shown by the same group, Sox2 and PLP1 positive cells serve as neuronal precursor cells in vivo under inflammatory conditions (Belkind‐Gerson et al, ). Still, the precise molecular mechanisms of this glial–neuron differentiation are not well understood, but could be based on estrogenic receptor signaling (D'Errico et al, ). Whether these neuronal precursor cells are fully differentiated EGCs with functional properties or represent a unique premature population of EGCs or neuronal precursor cells resembling EGCs remains to be investigated.…”

“…The antagonization of neurokinin‐2 receptor signaling inhibits neuroinflammation, reactive gliosis, and increased neuronal contractions (Delvalle et al, ). On the molecular level, the glial proliferation is associated with estrogenic receptor signaling (D'Errico et al, ). The switch of the EGC phenotype or reactive gliosis may promote altered contractility under pathologic conditions.…”

Enteric Neurogenesis During Life Span Under Physiological and Pathophysiological Conditions

“…Accordingly to these data, several studies indicate the presence of enteric neuronal precursors in postnatal and adult gut tissues in vitro using isolated enteric stem or precursor cells (Rauch et al, ; Metzger et al, , ). The presence of the estrogen receptor ß was also shown in the human ENS (D'Errico et al, ). Thus, the transfer of the results obtained in mice to patients is conceivable.…”

“…The conditional in vivo KO of PTEN (nestin‐PTEN cKO mice) leads to an increased number and size of neurons in the MP (Kulkarni et al, ). A more recent study demonstrated the impact of the estrogen receptor signaling in enteric neurogenesis in vitro and in vivo (D'Errico et al, ). Both enteric neurons and glial cells express estrogen receptor ß.…”