title: Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function.
abstract: Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Division of Pediatric Surgery, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California;
authors.forename: Christa N
authors.initials: CN
authors.lastname: Grant
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Salvador Garcia
authors.initials: SG
authors.lastname: Mojica
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Sala
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California;
authors.forename: J Ryan
authors.initials: JR
authors.lastname: Hill
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Division of Pediatric Surgery, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California;
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Levin
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Division of Pediatric Surgery, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California;
authors.forename: Allison L
authors.initials: AL
authors.lastname: Speer
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Division of Pediatric Surgery, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California;
authors.forename: Erik R
authors.initials: ER
authors.lastname: Barthel
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Zachos
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Division of Pediatric Surgery, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, California; tgrikscheit@chla.usc.edu.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Grikscheit
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000378:metabolism; D001692:Biological Transport; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004063:Digestion; D004847:Epithelial Cells / Q000502:physiology / Q000637:transplantation / Q000648:ultrastructure; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation* / Q000648:ultrastructure; D007421:Intestine, Small / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009940:Organoids; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D019108:Tight Junctions / Q000502:physiology / Q000648:ultrastructure; D013997:Time Factors; D046509:Tissue Culture Techniques; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D020346:Aquaporins; D017923:Sodium-Hydrogen Exchangers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: intestinal failure; intestinal stem cell; regenerative medicine; short bowel syndrome; tissue engineering