title: Global hypoxia-ischemia induced inflammation and structural changes in the preterm ovine gut which were not ameliorated by mesenchymal stem cell treatment.
abstract: Perinatal asphyxia, a condition of impaired gas exchange during birth, leads to fetal hypoxia-ischemia (HI) and is associated with postnatal adverse outcomes including intestinal dysmotility and necrotizing enterocolitis (NEC). Evidence from adult animal models of transient, locally-induced intestinal HI has shown that inflammation is essential in HI-induced injury of the gut. Importantly, mesenchymal stem cell (MSC) treatment prevented this HI-induced intestinal damage. We therefore assessed whether fetal global HI induced inflammation, injury and developmental changes in the gut and whether intravenous MSC administration ameliorated these HI-induced adverse intestinal effects. In a preclinical ovine model, fetuses were subjected to umbilical cord occlusion (UCO), with or without MSC treatment, and sacrificed 7 days after UCO. Global HI increased the number of myeloperoxidase positive cells in the mucosa, upregulated mRNA levels of interleukin (IL)-1β and IL-17 in gut tissue and caused T-cell invasion in the intestinal muscle layer. Intestinal inflammation following global HI was associated with increased Ki67+ cells in the muscularis and subsequent muscle hyperplasia. Global HI caused distortion of glial fibrillary acidic protein immunoreactivity in the enteric glial cells and increased synaptophysin and serotonin expression in the myenteric ganglia. Intravenous MSC treatment did not ameliorate these HI-induced adverse intestinal events. Global HI resulted in intestinal inflammation and enteric nervous system abnormalities which are clinically associated with postnatal complications including feeding intolerance, altered gastrointestinal transit and NEC. The intestinal histopathological changes were not prevented by intravenous MSC treatment directly after HI, indicating that alternative treatment regimens for cell-based therapies should be explored.
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.|School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
authors.forename: Carolin
authors.initials: C
authors.lastname: Willburger
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
authors.forename: Anja E
authors.initials: AE
authors.lastname: de Jong
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Kloosterboer
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.|School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.|School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Daan R M G
authors.initials: DRMG
authors.lastname: Ophelders
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Harry W M
authors.initials: HWM
authors.lastname: Steinbusch
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.|School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.|School of Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.|School of Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Wolfs
keywords: Enteric nervous system; fetal asphyxia; immune activation; multipotent cells; muscle hyperplasia