Comparison and Investigation of Exosomes from Human Amniotic Fluid Stem Cells and Human Breast Milk in Alleviating Neonatal Necrotizing Enterocolitis

Abstract

In view of the devastating impact of neonatal necrotizing enterocolitis (NEC) on newborns, the research on its intervention is particularly important. Although exosomes from human amniotic fluid stem cells (AFSC) and human breast milk (HBM) can protect against NEC, their mechanisms remain unclear. Here, we intend to compare the intervention effects of two types of exosomes on NEC mouse model and reveal their respective regulatory mechanisms. In general, both AFSC-derived exosomes (AFSC-exos) and HBM-derived exosomes (HBM- exos) can alleviate NEC- associated intestinal injury, significantly reduce NEC score, and reduce systemic and ileal inflammation and NEC related brain injury during experimental NEC. However, the mode and mechanism of action of the two sources of exosomes were not identical. In vivo, the number of ileal crypts was more significantly restored after HBM-exos intervention than AFSC-exos, and in vitro, HBM-exos preferentially inhibited the inflammatory response of intestinal epithelial cells (IECs), whereas AFSC-exos preferentially regulated the migration of IECs. Mechanistically, GO and KEGG analyses revealed the different therapeutic mechanisms of AFSC-exos and HBM-exos in NEC. Taken together, our results illustrate that AFSC-exos and HBM-exos reduce the severity of experimental NEC and intestinal damage through different mechanisms, supporting the potential of cell-free or breast milk free exosome therapy for NEC. Graphical Abstract

Immersed in a reservoir of potential: amniotic fluid-derived extracellular vesicles

“…The shift in interest was promoted by research studies increasingly implying that the therapeutic effect of stem cells is mediated by the extracellular paracrine factors exerted via EVs [38]. Many research studies have demonstrated the successful utility of AFSC-EVs in pre-clinical models to treat different pathologies including necrotizing enterocolitis [51,52,100,101], hypoplastic neonatal lungs [65,116,117] and wound healing [104,105]. AF composition is dynamic and often represents the gestation-dependent development of fetal organs [118,119].…”

“…As a cell-free product loaded with bioactive molecules, they contain many desirable properties. EVs have been shown to modulate inflammation [58,[100][101][102], curb oxidative stress [103] and augment wound healing [104,105], ultimately leading to tissue regeneration. Moreover, as a natural cell-derived product, EVs present advantages such as biocompatibility and minimal toxicity for recipients.…”

Gut Microbiome–Brain Axis as an Explanation for the Risk of Poor Neurodevelopment Outcome in Preterm Infants with Necrotizing Enterocolitis

“…Despite a lack of complete understanding of the mechanism of NEC pathogenesis, the microbiome and the understanding of its role in NEC development has led to the microbiome being a possible area of interest for prevention and treatment [68]. The means of altering the microbiome in beneficial ways which have been shown to decrease the incidence of NEC and thus may prevent NEC include breastfeeding, antibiotic stewardship, and the use of probiotics [9,[68][69][70][71]. However, there is still risk associated with the use of probiotics due to the immature immune systems of preterm infants.…”

Progress in Research on Stem Cells in Neonatal Refractory Diseases

“…McCulloh et al concluded that exosomes derived from SCs were not significantly different from SCs when treating NEC mice and significantly reduced NEC incidence and severity [ 138 , 139 ]. In vitro, exosomes derived from human breast milk SCs (HBM-exos) preferentially inhibited the inflammatory response of intestinal epithelial cells, whereas exosomes from hAFSCs (AFSC-exos) preferentially regulated the migration of intestinal epithelial cells; in vivo, the number of ileal crypts recovered faster after intervention with HBM-exos ( Figure 15 ) [ 140 ]. BM-MSCs produce a variety of soluble mediators, such as cytokines, growth factors, microRNAs, and exosomes, to mitigate NEC-related injury [ 141 ].…”

“… Comparison of the effects of AFSC-exo and HBM-exo interventions in mouse models of NEC. Both exosomes reduce NEC-related intestinal damage, significantly reduce NEC scores, and reduce systemic and ileal inflammation and NEC-related brain damage [ 140 ]. …”