Single-Cell Analysis Reveals Regional Reprogramming During Adaptation to Massive Small Bowel Resection in Mice.

Autor:	Seiler KM; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Waye SE; Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Kong W; Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Kamimoto K; Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Bajinting A; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Goo WH; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Onufer EJ; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Courtney C; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Guo J; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Warner BW; Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Morris SA; Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Electronic address: s.morris@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2019; Vol. 8 (3), pp. 407-426. Date of Electronic Publication: 2019 Jun 10.
DOI:	10.1016/j.jcmgh.2019.06.001
Abstrakt:	Background & Aims: The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or "adapt"; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. Methods: Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. Results: Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. Conclusions: Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes-conceivably by engaging the retinoid metabolism pathway-merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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