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Published September 15, 2020 | Supplemental Material + Published
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EGFR in enterocytes & endothelium and HIF1α in enterocytes are dispensable for massive small bowel resection induced angiogenesis


Background: Short bowel syndrome (SBS) results from significant loss of small intestinal length. In response to this loss, adaptation occurs, with Epidermal Growth Factor Receptor (EGFR) being a key driver. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with angiogenesis. Further, we have found that small bowel resection (SBR) is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor 1-alpha (HIF1α). Methods: We ablated EGFR in the epithelium and endothelium as well as HIF1α in the epithelium, ostensibly the most hypoxic element. Using these mice, we determined the effects of these genetic manipulations on intestinal blood flow after SBR using photoacoustic microscopy (PAM), intestinal adaptation and angiogenic responses. Then, given that endothelial cells require a stromal support cell for efficient vascularization, we ablated EGFR expression in intestinal subepithelial myofibroblasts (ISEMFs) to determine its effects on angiogenesis in a microfluidic model of human small intestine. Results: Despite immediate increased demand in oxygen extraction fraction measured by PAM in all mouse lines, were no differences in enterocyte and endothelial cell EGFR knockouts or enterocyte HIF1α knockouts by POD3. Submucosal capillary density was also unchanged by POD7 in all mouse lines. Additionally, EGFR silencing in ISEMFs did not impact vascular network development in a microfluidic device of human small intestine. Conclusions: Overall, despite the importance of EGFR in facilitating intestinal adaptation after SBR, it had no impact on angiogenesis in three cell types–enterocytes, endothelial cells, and ISEMFs. Epithelial ablation of HIF1α also had no impact on angiogenesis in the setting of SBS.

Additional Information

© 2020 Onufer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: April 13, 2020; Accepted: July 16, 2020; Published: September 15, 2020. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. This work was supported by NIH RO1 DK104698 (Warner), The Digestive Diseases Research Core Center of the Washington University School of Medicine (NIH #P30DK52574), the Children's Surgical Sciences Research Institute of the St. Louis Children's Hospital Foundation, and NIH T32 DK077653. Competing interests: LVW has financial interests in Microphotoacoustics, Inc., which did not support this work. AKA reports receiving research support from Verastem, Selexys, Karyopharm, Cell Works, Cleave Bioscience, Glycomimetics, Abbvie and Vasculox, none of which supported this work. AKA is also the founder and owner of Targeted Therapeutics LLC and Cellatrix LLC, neither of which supported this work. All other authors have no other financial conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Author Contributions: Conceptualization: Emily J. Onufer, Brad W. Warner. Formal analysis: Emily J. Onufer, Bola Aladegbami, Toru Imai, Kristen Seiler, Lihong V. Wang. Funding acquisition: Brad W. Warner. Investigation: Emily J. Onufer, Bola Aladegbami, Toru Imai, Kristen Seiler, Adam Bajinting, Cathleen Courtney, Stephanie Sutton, Aiza Bustos, Junjie Yao, Cheng-Hung Yeh, Anne Sescleifer. Methodology: Emily J. Onufer, Jun Guo, Brad W. Warner. Supervision: Jun Guo. Visualization: Emily J. Onufer, Toru Imai, Kristen Seiler. Writing – original draft: Emily J. Onufer, Bola Aladegbami, Kristen Seiler. Writing – review & editing: Emily J. Onufer, Lihong V. Wang, Jun Guo, Brad W. Warner.

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Published - journal.pone.0236964.pdf

Supplemental Material - journal.pone.0236964.s001.pdf

Supplemental Material - journal.pone.0236964.s002.xlsx


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