Dataset Information

Oral administration of bone marrow-derived mesenchymal stem cells attenuates intestinal injury in necrotizing enterocolitis.

ABSTRACT:

Background

Necrotizing enterocolitis (NEC) is a major cause of morbidity in premature infants. However, effective treatment options for NEC are currently lacking.

Purpose

This study aimed to determine the optimal dose of intraperitoneally administered bone marrow-derived mesenchymal stem cells (BM-MSCs) and investigate the therapeutic potential of orally administered BM-MSCs in NEC.

Methods

Neonatal mice were fed maternal breast milk for the first 2 days of life. On day 3, the neonatal mice were randomly divided into control, negative control, and BM-MSC-treated groups. Lipopolysaccharide (LPS) was administered for 3 days, and cold stress (4°C, 10 minutes) was applied 3 times a day to induce NEC. High-dose (1×106 cells) or low-dose (1×105 cells) BM-MSCs were administered intraperitoneally 1 or 3 times between days 6 and 8 to treat the NEC. The orally administered group received a low dose of BM-MSCs on day 6. Furthermore, except for the control group, intraepithelial cells (IECs) of the small intestine of neonatal mice were treated with LPS and exposed to 5% O2/95% N2 hypoxic stress for 2 hours. Thereafter, each was treated with BM-MSCs.

Results

Tissue injury, apoptosis, and inflammatory marker levels were significantly reduced after BM-MSC administration. Oral administration was as effective as intraperitoneal administration, even at a low dose (1×105 cells) of BM-MSCs. The efficacy of high (1×106 cells) or multiple divided doses of BM-MSCs did not differ from that of low-dose treatment. Significantly improved wound healing was observed after BM-MSC administration to injured IECs.

Conclusion

The oral administration of BM-MSCs is a promising treatment option for NEC in infants. Further human studies of BM-MSCs are necessary to determine the optimal dose required to achieve safe and effective outcomes.

SUBMITTER: Lee YS

PROVIDER: S-EPMC10915455 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Oral administration of bone marrow-derived mesenchymal stem cells attenuates intestinal injury in necrotizing enterocolitis.

Lee Yeong Seok YS Jun Yong Hoon YH Lee Juyoung J

Clinical and experimental pediatrics 20240219 3

<h4>Background</h4>Necrotizing enterocolitis (NEC) is a major cause of morbidity in premature infants. However, effective treatment options for NEC are currently lacking.<h4>Purpose</h4>This study aimed to determine the optimal dose of intraperitoneally administered bone marrow-derived mesenchymal stem cells (BM-MSCs) and investigate the therapeutic potential of orally administered BM-MSCs in NEC.<h4>Methods</h4>Neonatal mice were fed maternal breast milk for the first 2 days of life. On day 3, ...[more]

PMID: 38369803

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Project description:BackgroundNecrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.MethodsFecal samples from human neonates and mouse pups were analyzed by HPLC - MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.ResultsThe levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.ConclusionSuccinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.

Project description:BackgroundNecrotizing enterocolitis (NEC) is an often-lethal disease of the premature infant intestinal tract, exacerbated by significant diagnostic difficulties. In NEC, the intestine exhibits hypoperfusion and dysmotility, contributing to disease pathogenesis. However, these features cannot be accurately and quantitively assessed with current imaging modalities. We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model.MethodsIn this first-in-disease application, we evaluated NEC using PAI to assess intestinal health biomarkers in an experimental model of NEC. NEC was induced in neonatal rats from birth to 4-days. Healthy breastfed (BF) and NEC rat pups were imaged at 2- and 4-days.ResultsIntestinal tissue oxygen saturation was measured with PAI, and NEC pups showed significant decreases at 2- and 4-days. Ultrasound and PAI cine recordings were used to capture intestinal peristalsis and contrast agent transit within the intestine. Intestinal motility, assessed using computational intestinal deformation analysis, demonstrated significant reductions in both early and established NEC. NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay.ConclusionThis preclinical study presents PAI as an emerging diagnostic imaging modality for intestinal disease assessment in premature infants.ImpactNecrotizing enterocolitis (NEC) is a devastating intestinal disease affecting premature infants with significant mortality. NEC presents significant clinical diagnostic difficulties, with limited diagnostic confidence complicating timely and effective interventional efforts. This study is an important foundational first-in-disease preclinical study that establishes the utility for PAI to detect changes in intestinal tissue oxygenation and intestinal motility with NEC disease induction and progression. This study demonstrates the feasibility and exceptional promise for the use of PAI to non-invasively assess oxygenation and motility in the healthy and diseased infant intestine.

Dataset Information

Oral administration of bone marrow-derived mesenchymal stem cells attenuates intestinal injury in necrotizing enterocolitis.

Background

Purpose

Methods

Results

Conclusion

Publications

Oral administration of bone marrow-derived mesenchymal stem cells attenuates intestinal injury in necrotizing enterocolitis.

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