title: The Development of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) During Gastric Repair Is Absent in the Aged Stomach.
abstract: OBJECTIVE
  During aging, physiological changes in the stomach result in more tenuous gastric tissue that is less capable of repairing injury, leading to increased susceptibility to chronic ulceration. Spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) is known to emerge after parietal cell loss and duringHelicobacter pyloriinfection, however, its role in gastric ulcer repair is unknown. Therefore, we sought to investigate if SPEM plays a role in epithelial regeneration.
  
  
  METHODS
  Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium.
  
  
  RESULTS
  Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration.
  
  
  CONCLUSIONS
  These data show the development of SPEM during gastric repair in response to injury that is absent in the aged stomach. In addition, gastric organoids in an injury/transplantation mouse model promoted gastric regeneration.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Engevik
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.affiliation: Nashville VA Medical Center, Department of Surgery, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Environmental Health, Division of Biostatistics and Bioinformatics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Shana
authors.initials: S
authors.lastname: White
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Nina
authors.initials: N
authors.lastname: Bertaux-Skeirik
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Research Center, Cincinnati, Ohio.
authors.forename: Maxime M
authors.initials: MM
authors.lastname: Mahe
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Eitaro
authors.initials: E
authors.lastname: Aihara
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Pathology Research Core, Cincinnati Children's Hospital Medical Research Center, Cincinnati, Ohio.
authors.forename: Betsy
authors.initials: B
authors.lastname: DiPasquale
authors.affiliation: Department of Computer Science and Statistics, Jeju National University, Jeju, South Korea.
authors.forename: Sunghee
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Engevik
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Marshall H
authors.initials: MH
authors.lastname: Montrose
authors.affiliation: Department of Environmental Health, Division of Biostatistics and Bioinformatics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Research Center, Cincinnati, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Helmrath
authors.affiliation: Nashville VA Medical Center, Department of Surgery, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Yana
authors.initials: Y
authors.lastname: Zavros
keywords: CD44v; CD44v, variant isoform of CD44; Cftr, cystic fibrosis transmembrane conductance regulator; CgA, chromagranin A; Clu, Clusterin; Ctss, cathepsin S; DMEM, Dulbecco's modified Eagle medium; DPBS, Dulbecco's phosphate buffered saline; Dmbt1, deleted in malignant brain tumors 1; ES, enrichment score; Epithelial Regeneration; GSEA, gene set enrichment analysis; GSII, Griffonia simplicifolia II; Gastric Cancer; Gpx2, glutathione peroxidase 2 (gastrointestinal); HK, hydrogen potassium adenosine triphosphatase; Human Gastric Organoids; IF, intrinsic factor; Mad2I1, MAD2 mitotic arrest deficient-like 1; Mmp12, matrix metallopeptidase 12 (macrophage elastase); PBS, phosphate-buffered saline; SPEM, spasmolytic polypeptide expressing metaplasia; TFF, trefoil factor; TX, Triton X-100 in PBS; UEA1, ulex europaeus; Wfdc2, WAP 4-disulfide core domain 2; YFP, yellow fluorescent protein; hFGO, human-derived fundic gastric organoid; qRT-PCR, quantitative reverse-transcription polymerase chain reaction