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Recombinant IGF-1/BP3 protects against intestinal injury in a neonatal mouse NEC model

Pediatric Research (2024)Cite this article

Abstract

Background

Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP3) is currently being tested in phase II clinical trials in premature infants to prevent bronchopulmonary dysplasia, but its impact on the neonatal intestine remains unclear. The aim of this study was to determine whether rhIGF-1/BP3 protects against necrotizing enterocolitis (NEC) in mice and to investigate the mechanisms involved.

Methods

Neonatal mice were dam fed or injected intraperitoneally with rhIGF-1/BP3 (or vehicle) and submitted to an experimental NEC model. Serum IGF-1 was assessed by ELISA and intestinal vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression by Western blot. Intestinal endothelial cell proliferation, and enterocyte proliferation and migration were examined by immunofluorescence. Pup survival and histological intestinal injury were determined.

Results

In pups exposed to experimental NEC, serum IBP3-bound IGF-1 level was decreased. Exogenous rhIGF-1/BP3 preserved VEGF and VEGFR2 protein expression, decreased vascular permeability, and preserved endothelial cell proliferation in the small intestine. Furthermore, rhIGF-1/BP3 promoted enterocyte proliferation and migration, which effects were attenuated by inhibiting VEGFR2 signaling, decreased enterocyte apoptosis and decreased systemic and intestinal inflammation. rhIGF-1/BP3 improved survival and reduced the incidence of severe intestinal injury in experimental NEC.

Conclusions

Exogenous rhIGF-1/BP3 protects neonatal mice against experimental NEC via multiple mechanisms.

Impact

  • Exogenous rhIGF-1/BP3 preserves intestinal microvascular development and integrity, promotes enterocyte proliferation and migration, decreases local and systemic inflammation, and protects neonatal mice against NEC.

  • The article adds pre-clinical evidence of a protective role for rhIGF-1/BP3 on the premature gut.

  • It provides evidence supporting the use of rhIGF1/BP3 in premature neonates to protect against NEC.

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Fig. 1: IGF binding protein 3 (IBP3) bound IGF-1 is decreased in the serum of NEC pups.
Fig. 2: Serum concentration of “human” IGF-1 in pups that were injected with rhIGF-1/BP3 (2 mg/kg or 10 mg/kg, ip) or vehicle control, approximately 8 h after birth.
Fig. 3: rhIGF-1/BP3 preserves intestinal VEGF/VEGFR2 expression, endothelial cell proliferation and vascular permeability.
Fig. 4: IGF-1/IBP3 preserved epithelial cell proliferation and migration while mitigating enterocyte apoptosis during experimental NEC.
Fig. 5: IGF-1/IBP3 decreases systemic and local cytokine production.
Fig. 6: rhIGF-1/BP3 improves survival and attenuates tissue injury in experimental NEC.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Marissa Docter for her technical assistance in conducting the NEC model.

Funding

This work was funded by Takeda Pharmaceuticals/Oak Hill Biol (I.G.D.P.), by the National Institute of Health Grants R01 DK116568 (I.G.D.P.), and R01s to X.D.T. including DK123826 and DK129960, US Department of Veterans Affairs Merit Review Award I01BX001690 (X.D.T.), and the Stanley Manne Children’s Research Institute of the Ann & Robert H. Lurie Children’s Hospital of Chicago (I.G.D.P.).

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Xiaocai Yan, Elizabeth Managlia & Isabelle G. De Plaen

  2. Center for Intestinal and Liver Inflammation Research, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, IL, USA

    Xiaocai Yan, Elizabeth Managlia & Isabelle G. De Plaen

  3. Takeda, Cambridge, MA, USA

    Galen Carey & Norman Barton

  4. Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA

    Xiao-Di Tan

  5. Department of Research & Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA

    Xiao-Di Tan

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  1. Xiaocai Yan
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Contributions

X.Y. performed the in vivo experiments. L.M. performed the ELISA study. X.Y. and I.G.D.P. were involved in the overall design of experiments and interpretation of results. X.Y. and I.G.D.P. performed histological evaluation of tissue samples. G.C., N.B. and X.D.T. provided intellectual input for the project. X.Y. and I.G.D.P. wrote the manuscript with input from all authors. I.G.D.P. conceived and orchestrated the project.

Corresponding author

Correspondence to Isabelle G. De Plaen.

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Competing interests

I.G.D.P. received a grant from Shire Human Genetic Therapies, Inc., a member of the Takeda group of companies, for testing rhIGF-1/BP3 in experimental NEC. X.Y., E.M and X.D.T. have no competing interests to declare. G.C. and N.B. were full-time employees of Takeda and stockholders of Takeda Pharmaceutical Company Limited at the time of the study.

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Yan, X., Managlia, E., Carey, G. et al. Recombinant IGF-1/BP3 protects against intestinal injury in a neonatal mouse NEC model. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03069-8

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  • DOI: https://doi.org/10.1038/s41390-024-03069-8

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