CD44v9 Emerges in Response to Injury and Contributes to the Regeneration of the Gastric Epithelium

Abstract

Cluster‐of‐differentiation gene 44, in particular CD44 variant isoforms (CD44v), emerges during regeneration of the gastric epithelium in response to injury. In particular, CD44v9 is expressed within Spasmolytic Polypeptide/TFF2‐Expressing Metaplasia (SPEM) glands during gastric repair, but the function is unknown. Here we tested the hypothesis that CD44v9 marks a regenerative cell lineage that plays a functional role in gastric repair. Acetic acid injury was induced in CD44‐deficient (CD44KO) and C57BL/6 (BL6) mice. Mouse‐derived gastric organoids expressing CD44v9 were transplanted at the ulcer site of CD44KO mice. Ulcers, expression of CD44v9, proliferation and histology were measured at days 1, 3, 5 and 7 post‐injury. Human‐derived gastric organoids from elderly patients (>55 years) or young patients (14–20 years) were generated and transplanted into the stomachs of NOD scid gamma (NSG) mice post‐injury. Ulcers were induced in NRGS mice expressing human‐derived immune cells (huNRGS) and the immune phenotype analyzed by CyTOF. CD44v9 expression emerged at the ulcer margin during gastric ulcer repair. Compared to BL6 mice that healed within 7 days post‐injury, CD44KO mice exhibited loss of ulcer repair and gastric epithelial regeneration. Transplantation of CD44v9‐expressing gastric organoids into the stomachs of CD44KO mice promoted ulcer repair. Compared to NSG mice exhibiting loss of CD44v9 expression and gastric repair in response to injury, transplantation of human‐derived gastric organoids from young stomachs promoted repair. Transplantation of organoids derived from aged stomachs did not promote repair. Compared to NRGS mice, huNRGS animals exhibited smaller ulcer sizes and an infiltration of human CD163+ macrophages that correlated with an emergence of CD44v9 expression. Thus, CD44v9 marks a regenerative cell lineage. Macrophages infiltrating the injured gastric mucosa may induce the emergence of CD44v9 during regeneration of the epithelium.Support or Funding InformationThis work was supported by NIH 2 R01 DK083402‐06A1 grant, College of Medicine Bridge Funding Program (Zavros), and the University of Cincinnati Graduate School Dean's Fellowship, Albert J. Ryan Fellowship and 2T32GM105526‐04 (Bertaux‐Skeirik).