Inhibiting hydrogen sulfide production in umbilical stem cells reduces their protective effects during experimental necrotizing enterocolitis

Natalie A. Drucker, Jan P. te Winkel, W. Christopher Shelley, Kenneth Olson, Troy A. Markel

Research output: Contribution to journalArticle

Abstract

Introduction: Umbilical mesenchymal stem cells (USC) have been shown to reduce illness in animal models of necrotizing enterocolitis (NEC), possibly through the paracrine release of hydrogen sulfide (H 2 S). We hypothesized that animals treated with USCs with inhibited H 2 S synthesis would exhibit more severe disease. Methods: NEC was induced in five-day-old mouse pups by formula feeding and hypoxic and hypothermic stress. Experimental groups received intraperitoneal injection of either saline vehicle or 80,000cells/gram of one of the following cell types: USC, USCs with negative-control siRNA, or USCs with targeted siRNA inhibition of the H 2 S-producing enzymes. Pups were monitored by clinical assessment and after euthanasia, intestine and lung histologic injury were scored. Tissue was homogenized, and concentrations of IL-6, IL-10, and VEGF were determined by ELISA. For statistical analysis, p < 0.05 was considered significant. Results: Animals treated with negative-control siRNA USCs were significantly improved compared to vehicle. Clinical sickness scores as well as intestinal and lung histologic injury scores in the targeted siRNA groups were significantly worse when compared to the negative-control siRNA group. IL-6, IL-10, and VEGF had varying patterns of expression in the different groups. Conclusion: Inhibition of H 2 S production in USCs reduces the beneficial effects of these cells during therapy in experimental NEC. Level of evidence: Animal studies are typically described as “foundational evidence” without a true level assigned. Type of study: Animal Study.

Original languageEnglish (US)
JournalJournal of Pediatric Surgery
DOIs
StatePublished - Jan 1 2019

Fingerprint

Umbilicus
Hydrogen Sulfide
Necrotizing Enterocolitis
Small Interfering RNA
Stem Cells
Lung Injury
Mesenchymal Stromal Cells
Interleukin-10
Vascular Endothelial Growth Factor A
Interleukin-6
Euthanasia
Cell- and Tissue-Based Therapy
Intraperitoneal Injections
Intestines
Animal Models
Enzyme-Linked Immunosorbent Assay
Control Groups
Enzymes

Keywords

  • Animal model
  • Hydrogen sulfide
  • Intestine
  • Necrotizing enterocolitis
  • Umbilical stromal cell

ASJC Scopus subject areas

  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

Inhibiting hydrogen sulfide production in umbilical stem cells reduces their protective effects during experimental necrotizing enterocolitis. / Drucker, Natalie A.; te Winkel, Jan P.; Shelley, W. Christopher; Olson, Kenneth; Markel, Troy A.

In: Journal of Pediatric Surgery, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Introduction: Umbilical mesenchymal stem cells (USC) have been shown to reduce illness in animal models of necrotizing enterocolitis (NEC), possibly through the paracrine release of hydrogen sulfide (H 2 S). We hypothesized that animals treated with USCs with inhibited H 2 S synthesis would exhibit more severe disease. Methods: NEC was induced in five-day-old mouse pups by formula feeding and hypoxic and hypothermic stress. Experimental groups received intraperitoneal injection of either saline vehicle or 80,000cells/gram of one of the following cell types: USC, USCs with negative-control siRNA, or USCs with targeted siRNA inhibition of the H 2 S-producing enzymes. Pups were monitored by clinical assessment and after euthanasia, intestine and lung histologic injury were scored. Tissue was homogenized, and concentrations of IL-6, IL-10, and VEGF were determined by ELISA. For statistical analysis, p < 0.05 was considered significant. Results: Animals treated with negative-control siRNA USCs were significantly improved compared to vehicle. Clinical sickness scores as well as intestinal and lung histologic injury scores in the targeted siRNA groups were significantly worse when compared to the negative-control siRNA group. IL-6, IL-10, and VEGF had varying patterns of expression in the different groups. Conclusion: Inhibition of H 2 S production in USCs reduces the beneficial effects of these cells during therapy in experimental NEC. Level of evidence: Animal studies are typically described as “foundational evidence” without a true level assigned. Type of study: Animal Study.",
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