Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy

Abstract

IntroductionIntestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease. We examined human intestinal specimens to characterize the enteric nervous system injury that occurs in necrotizing enterocolitis, and then used an animal model of experimental necrotizing enterocolitis to determine whether transplantation of neural stem cells can protect the enteric nervous system from injury.MethodsHuman intestinal specimens resected from patients with necrotizing enterocolitis (n = 18), from control patients with bowel atresia (n = 8), and from necrotizing enterocolitis and control patients undergoing stoma closure several months later (n = 14 and n = 6 respectively) were subjected to histologic examination, immunohistochemistry, and real-time reverse-transcription polymerase chain reaction to examine the myenteric plexus structure and neurotransmitter expression. In addition, experimental necrotizing enterocolitis was induced in newborn rat pups and neurotransplantation was performed by administration of fluorescently labeled neural stem cells, with subsequent visualization of transplanted cells and determination of intestinal integrity and intestinal motility.ResultsThere was significant enteric nervous system damage with increased enteric nervous system apoptosis, and decreased neuronal nitric oxide synthase expression in myenteric ganglia from human intestine resected for necrotizing enterocolitis compared with control intestine. Structural and functional abnormalities persisted months later at the time of stoma closure. Similar abnormalities were identified in rat pups exposed to experimental necrotizing enterocolitis. Pups receiving neural stem cell transplantation had improved enteric nervous system and intestinal integrity, differentiation of transplanted neural stem cells into functional neurons, significantly improved intestinal transit, and significantly decreased mortality compared with control pups.ConclusionsSignificant injury to the enteric nervous system occurs in both human and experimental necrotizing enterocolitis. Neural stem cell transplantation may represent a novel future therapy for patients with necrotizing enterocolitis.

Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment

“…The clinical pathological intestinal characteristics of an hypoxic-ischemic neonate may that disruption of these cells altered the neurochemical phenotype of enteric neurons, reduced transmission to muscle and delayed gastrointestinal transit (65,66). In this study, global HI-induced distortion of enteric glial cells in the ganglia of the myenteric plexus in a similar pattern found in animal models of HI-induced intestinal injury (67) and in neonates with NEC (31). Importantly, distortion of enteric glial cells upon gut HI has been correlated with loss of enteric neurons and impaired neuronal function, with subsequent decreased gastrointestinal motility (18,44,67,68).…”

“…In this study, we showed that global HI in fetal sheep induced intestinal inflammation, muscle thickening, distortion of enteric glial cells and altered neurotransmission. Although we can only speculate about the postnatal consequences of these adverse intestinal outcomes, the detected gut inflammation and ENS abnormalities following HI have been associated with neonatal gastrointestinal complications including loss of barrier integrity, delayed gastrointestinal motility and NEC (31,73,84). Future studies are warranted to investigate whether the detected pathological changes 7 d after UCO will have long-term adverse intestinal effects.…”

“…To test our hypothesis, a clinically relevant intravenous dose of MSCs (28)(29)(30) was administered 1 h after UCO. We assessed the fetal ovine gut 7 d after UCO with respect to mucosal inflammation and injury, muscle abnormalities and changes in the ENS, as these pathophysiological characteristics contribute to feeding intolerance, altered gastrointestinal transit and NEC (31).…”

Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

“…We hypothesized, that hepatocyte growth factor (HGF) and its receptor MET might also be important because HGF supports spinal motor neurons (Ebens et al, 1996), dorsal root ganglion (DRG) subtypes (Maina et al, 1997), retinal ganglion cells (Tönges et al, 2011), and hippocampal neurons (Lim and Walikonis, 2008). Our prior studies also suggested HGF expression in the ENS (Vohra et al, 2006). Finally, we were intrigued by the protective effect of HGF in rodent colitis models (Tahara et al, 2003;Mukoyama et al, 2005;Numata et al, 2005;Oh et al, 2005;Hanawa et al, 2006;Kanbe et al, 2006), and hypothesized that this might be mediated through MET-expressing enteric neurons.…”

“…Whole-mount myenteric plexus analysis was performed using 8 -12-week-old mice (n ϭ 3-6) as described previously (Wang et al, 2010). Briefly, gut was opened along the mesenteric border, pinned to Sylgard, fixed [4% paraformaldehyde (PFA), 30 min, 25°C], and then dissected to separate muscle layers from submucosa.…”