Epithelial Ca 2+ waves triggered by enteric neurons heal the gut
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Abstract
A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer. We used the Drosophila midgut to investigate this question and discovered that during regeneration a subpopulation of cholinergic enteric neurons triggers Ca 2+ currents among enterocytes to promote return of the epithelium to homeostasis. Specifically, we found that down-regulation of the cholinergic enzyme Acetylcholinesterase in the epithelium enables acetylcholine from defined enteric neurons, referred as ARCENs, to activate nicotinic receptors in enterocytes found near ARCEN- innervations. This activation triggers high Ca 2+ influx that spreads in the epithelium through Inx2/Inx7 gap junctions promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki activation and increase of inflammatory cytokines together with hyperplasia, reminiscent of inflammatory bowel diseases. Altogether, we found that during gut regeneration the conserved cholinergic pathway facilitates epithelial Ca 2+ waves that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration which advance the current understanding of how a tissue returns to its homeostatic state after injury and could ultimately help existing therapeutics.
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We found that nAChRβ3 overexpression in ECs significantly expedited recovery of the intestinal epithelium with ISC proliferation and pdm1 expression reaching levels indistinguishable from unchallenged guts in 2 days, half the normal time
Since the balance and transition from repair to homeostasis likely exists to allow sufficient time for healing from injury, I'm curious if the accelerated recovery with overexpression of nAChRbeta3 results in abnormal repair or healing of the gut epithelium or any other abnormalities?
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Overall, we conclude that nAChRβ3 in ECs is essential for gut recovery and recovery-specific enrichment of nAChRβ3 provides an additional level of regulation that likely ensures that ECs are more responsive to ACh while the epithelium transitions to homeostasis
Congratulations!--This is an elegant tour de force investigation into how injured gut epithelium transitions from injury and a state of repair back toward homeostasis. You’ve clearly shown that ECs downregulate Ace and upregulate nAChRbeta3 to become more receptive to ACh. I’m curious if you have any ideas about what signals ECs to downregulate Ace and upregulate nAChRbeta3?
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