TY - JOUR
T1 - Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment
AU - Nikiforou, Maria
AU - Willburger, Carolin
AU - de Jong, Anja E.
AU - Kloosterboer, Nico
AU - Jellema, Reint K.
AU - Ophelders, Daan R. M. G.
AU - Steinbusch, Harry W. M.
AU - Kramer, Boris W.
AU - Wolfs, Tim G. A. M.
PY - 2016
Y1 - 2016
N2 - 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. 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 euthanized 7 d after UCO. Global HI increased the number of myeloperoxidase-positive cells in the mucosa, upregulated messenger RNA (mRNA) levels of interleukin (IL)-1 beta 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 necrotizing enterocolitis. 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.
AB - 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. 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 euthanized 7 d after UCO. Global HI increased the number of myeloperoxidase-positive cells in the mucosa, upregulated messenger RNA (mRNA) levels of interleukin (IL)-1 beta 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 necrotizing enterocolitis. 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.
U2 - 10.2119/molmed.2015.00252
DO - 10.2119/molmed.2015.00252
M3 - Article
SN - 1076-1551
VL - 22
SP - 244
EP - 257
JO - Molecular Medicine
JF - Molecular Medicine
ER -