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. 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)-1b 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. online address: http://www.molmed.org

Role of microRNA 146a on the healing of cornea alkali burn treated with mesenchymal stem cells

“…MSCs are an important cellular component of the hematopoietic microenvironment, which proliferate and differentiate into a variety of tissues, and have low immunogenicity. Furthermore, MSCs have a high degree of proliferation, self-renewal and pluripotency ( 21 ). Clinical trials confirmed that MSCs may be used in tissue repair ( 22 ).…”

Stem cells and exosomes: promising candidates for necrotizing enterocolitis therapy

“… / [ 14 ] BM-MSC Human Intravenous injection In vivo Preterm fetal sheep with umbilical cord occlusion (25 min) BM-MSCs administrated intravenously do not relieve hypoxia-ischemia induced adverse intestinal events, which may be associated with NEC. / [ 22 ] BM-MSC Adult rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N 2 , 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC and enteric NSC treatments all show a significant decrease in intestinal permeability and improved gut barrier function compared to the control group. There is no significant difference in intestinal permeability or gut barrier function among the four treatment groups.…”

“…Fetus suffering from hypoxia-ischemia is under high risk of intestinal injury and developing NEC. Preterm fetal sheep exposed to umbilical cord occlusion, which induces hypoxic-ischemic events, receive BM-MSC administration intravenously but do not show attenuation in intestinal injury [ 22 ]. These frustrating results inspire researchers to explore the role of other types of stem cells in NEC therapy.…”

The present conception of neonatal microbiome formation

“…Models of artificial intestinal hypoxia-ischemia in adult animals have shown that inflammation is a fundamental factor in intestinal damage. Global hypoxia-ischemia has caused inflammation of the intestines and defects of the intestinal nervous system, which may be associated with postpartum complications such as food intolerance, changes in the gastrointestinal tract and NEC [9].…”