Global hypoxia-ischemia induced inflammation and structural changes in the preterm ovine gut which were not ameliorated by mesenchymal stem cell treatment.

Maria Nikiforou,Nico Kloosterboer,Harry W M Steinbusch,Boris W Kramer,Anja E De Jong,Reint K Jellema,Daan R M G Ophelders,Tim Wolfs,Carolin Willburger

doi:10.2119/molmed.2015.00252

Maria Nikiforou, Nico Kloosterboer + Show 7 more

Open Access

https://doi.org/10.2119/molmed.2015.00252

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Journal: Molecular Medicine	Publication Date: Jan 1, 2016
Citations: 8	License type: CC BY 4.0

Affiliation: Maastricht University

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.

Highlights

Perinatal asphyxia is defined as a condition of impaired gas exchange during birth that leads to fetal hypoxia-ischemia (HI) and metabolic acidosis [1,2]
When animals were treated with mesenchymal stem cell (MSC) after umbilical cord occlusion (UCO), elevated numbers of MPO+ cells were found in the villus tips compared with control and MSC-treated animals (Figure 2C)
Fetal HI resulted in significant CD3+ cell influx in the circular muscle 7 d after UCO compared with control, and was not prevented by MSC treatment (Figures 3A, B and D)

Summary

Introduction

Perinatal asphyxia is defined as a condition of impaired gas exchange during birth that leads to fetal hypoxia-ischemia (HI) and metabolic acidosis [1,2]. Numerous studies have recently demonstrated that the inflammatory processes that follow intestinal HI play a key role in the pathophysiology of HIinduced gut injury [10,11,12] This evidence is primarily based on experiments in adult rodent models of transient superior mesenteric artery occlusion, showing that intestinal HI induces gut inflammation with concomitant epithelial lining loss, gut barrier dysfunction and morphological and functional changes in the muscle layers and enteric nervous system (ENS) [12,13,14,15,16,17,18,19]. These studies provide insights into the mechanisms of HI- induced adverse intestinal outcomes, they represent the clinical scenario of locally induced intestinal HI in adults, whereas global HI, which occurs during perinatal asphyxia, leads to HI in multiple organs

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