title: Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration.
abstract: Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: K A
authors.initials: KA
authors.lastname: Schall
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: K A
authors.initials: KA
authors.lastname: Holoyda
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: C N
authors.initials: CN
authors.lastname: Grant
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: D E
authors.initials: DE
authors.lastname: Levin
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: E R
authors.initials: ER
authors.lastname: Torres
authors.affiliation: Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: A
authors.initials: A
authors.lastname: Maxwell
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: H A
authors.initials: HA
authors.lastname: Pollack
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: R A
authors.initials: RA
authors.lastname: Moats
authors.affiliation: Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California; Department of Pediatrics and Department of Biochemistry and Molecular Biology, Keck School of Medicine at University of Southern California, Los Angeles, California; and.
authors.forename: M R
authors.initials: MR
authors.lastname: Frey
authors.affiliation: Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: A
authors.initials: A
authors.lastname: Darehzereshki
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California;
authors.forename: D
authors.initials: D
authors.lastname: Al Alam
authors.affiliation: Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California; Department of Cardiothoracic Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California.
authors.forename: C
authors.initials: C
authors.lastname: Lien
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California; Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California; tgrikscheit@chla.usc.edu.
authors.forename: T C
authors.initials: TC
authors.lastname: Grikscheit
mesh_terms: D000220:Adaptation, Biological / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D049109:Cell Proliferation; D013505:Digestive System Surgical Procedures / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D007422:Intestines / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008297:Male; D012778:Short Bowel Syndrome / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D015431:Weight Loss; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D000963:Antimetabolites; C511797:IGF1RA protein, zebrafish; D029961:Zebrafish Proteins; D007334:Insulin-Like Growth Factor I; D001973:Bromodeoxyuridine
keywords: Egf receptor; Igf; adaptation; intestinal failure; intestinal stem cell; short bowel syndrome