title: Intestinal epithelial stem/progenitor cells are controlled by mucosal afferent nerves.
abstract: BACKGROUND
  The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice.
  
  
  METHODS
  Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal (3)H-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves.
  
  
  RESULTS
  Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or (3)H-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments.
  
  
  CONCLUSIONS
  Enteric nerves are of importance in maintaining the intestinal epithelial barrier.
authors.affiliation: Section of Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. ove.lundgren@fysiologi.gu.se
authors.forename: Ove
authors.initials: O
authors.lastname: Lundgren
authors.forename: Mats
authors.initials: M
authors.lastname: Jodal
authors.forename: Madeleine
authors.initials: M
authors.lastname: Jansson
authors.forename: Anders T
authors.initials: AT
authors.lastname: Ryberg
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D017615:Enteric Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055786:Gene Knockout Techniques; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D008297:Male; D051379:Mice; D009475:Neurons, Afferent / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics; D013937:Thymidine Kinase / Q000378:metabolism
chemical_list: D011976:Receptors, Muscarinic; D018000:Receptors, Peptide; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D004247:DNA; D002772:Cholera Toxin; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D002211:Capsaicin