title: Intestinal smooth muscle phenotype determines enteric neuronal survival via GDNF expression.
abstract: Intestinal inflammation causes initial axonal degeneration and neuronal death, as well as the proliferation of intestinal smooth muscle cells (ISMC), but subsequent axonal outgrowth leads to re-innervation. We recently showed that expression of glial cell-derived neurotrophic factor (GDNF), the critical neurotrophin for the post-natal enteric nervous system (ENS) is upregulated in ISMC by inflammatory cytokines, leading us to explore the relationship between ISMC growth and GDNF expression. In co-cultures of myenteric neurons and ISMC, GDNF or fetal calf serum (FCS) was equally effective in supporting neuronal survival, with neurons forming extensive axonal networks among the ISMC. However, only GDNF was effective in low-density cultures where neurons lacked contact with ISMC. In early-passage cultures of colonic circular smooth muscle cells (CSMC), polymerase chain reaction (PCR) and western blotting showed that proliferation was associated with expression of GDNF, and the successful survival of neonatal neurons co-cultured on CSMC was blocked by vandetanib or siGDNF. In tri-nitrobenzene sulfonic acid (TNBS)-induced colitis, immunocytochemistry showed the selective expression of GDNF in proliferating CSMC, suggesting that smooth muscle proliferation supports the ENS in vivo as well as in vitro. However, high-passage CSMC expressed significantly less GDNF and failed to support neuronal survival, while expressing reduced amounts of smooth muscle marker proteins. We conclude that in the inflamed intestine, smooth muscle proliferation supports the ENS, and thus its own re-innervation, by expression of GDNF. In chronic inflammation, a compromised smooth muscle phenotype may lead to progressive neural damage. Intestinal stricture formation in human disease, such as inflammatory bowel disease (IBD), may be an endpoint of failure of this homeostatic mechanism.
authors: Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors: T Y
authors: TY
authors: Han
authors: Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors: S
authors: S
authors: Lourenssen
authors: Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors: K G
authors: KG
authors: Miller
authors: Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada. Electronic address: blennerm@queensu.ca.
authors: M G
authors: MG
authors: Blennerhassett
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D018920:Coculture Techniques; D003092:Colitis / Q000503:physiopathology; D017615:Enteric Nervous System / Q000187:drug effects / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008297:Male; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D014302:Trinitrobenzenesulfonic Acid
keywords: GDNF; intestine; neuron; neurotrophin; smooth muscle proliferation