title: Maturity and age influence chief cell ability to transdifferentiate into metaplasia.
abstract: The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1-/-mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss. Mist1-/-mice treated with DMP-777 showed fewer chief cell to SPEM transitions. Mist1-/-mice treated with L635 demonstrated significantly fewer proliferative SPEM cells compared with control mice. Thus immature chief cells were unable to transdifferentiate efficiently into SPEM after acute parietal cell loss. To determine whether chief cell age affects transdifferentiation into SPEM, we used tamoxifen to induce YFP expression in chief cells of Mist1CreER/+;RosaYFPmice and subsequently treated the cells with L635 to induce SPEM at 1 to 3.5 mo after tamoxifen treatment. After L635 treatment to induce acute parietal cell loss, 43% of all YFP-positive cells at 1 mo posttamoxifen were SPEM cells, of which 44% of these YFP-positive SPEM cells were proliferative. By 2 mo after tamoxifen induction, only 24% of marked SPEM cells were proliferating. However, by 3.5 mo after tamoxifen induction, only 12% of marked chief cells transdifferentiated into SPEM and none were proliferative. Thus, as chief cells age, they lose their ability to transdifferentiate into SPEM and proliferate. Therefore, both functional maturation and age limit chief cell plasticity.
  
  
  
  Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of chief cells. Nevertheless, the intrinsic properties of chief cells that influence transdifferentiation have been largely unknown. We now report that the ability to transdifferentiate into SPEM is impaired in chief cells that lack full functional maturation, and as chief cells age, they lose their ability to transdifferentiate. Thus chief cell plasticity is dependent on both cell age and maturation.
authors.affiliation: Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.|Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Weis
authors.affiliation: Nashville Veterans Affairs Medical Center, Nashville, Tennessee.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.|Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Petersen
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jared A
authors.initials: JA
authors.lastname: Weis
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.|Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Meyer
authors.affiliation: Nashville Veterans Affairs Medical Center, Nashville, Tennessee.|Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.|Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Choi
authors.affiliation: Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St. Louis, Missouri.
authors.forename: Jason C
authors.identifier: 0000-0002-0402-4662
authors.initials: JC
authors.lastname: Mills
authors.affiliation: Nashville Veterans Affairs Medical Center, Nashville, Tennessee; jim.goldenring@vanderbilt.edu.|Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.|Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology*; D019872:Chief Cells, Gastric / Q000378:metabolism / Q000473:pathology*; D005753:Gastric Mucosa / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D013270:Stomach / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C491312:Bhlha15 protein, mouse; C451060:spasmolytic polypeptide
keywords: Mist1; SPEM; lineage mapping; progenitor cell; spasmolytic polypeptide-expressing metaplasia; transdifferentiation