Inhibition of BMP2 and BMP4 Represses Barrett’s Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 15; no. 5; pp. 1199 - 1217
• Main Authors: Correia, Ana C.P., Straub, Danielle, Read, Matthew, Hoefnagel, Sanne J.M., Romero-Pinedo, Salvador, Abadía-Molina, Ana C., Clemons, Nicholas J., Wang, Kenneth, Calpe, Silvia, Phillips, Wayne, Krishnadath, Kausilia K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023; Elsevier
• Subjects: Adenocarcinoma - pathology; Animals; Barrett Esophagus - drug therapy; Barrett Esophagus - pathology; Barrett’s Esophagus; BMP2; BMP4; Bone Morphogenetic Protein 4 - metabolism; Carcinoma, Squamous Cell - pathology; Epithelium - pathology; Hedgehog Proteins - metabolism; Llama-Derived Single-Domain Antibody; Mice; Original Research; Preclinical Models; Targeted Therapy; Barrett’s Esophagus; BE; BMP; EAC; PPI; Preclinical Models; DGERD; Targeted Therapy; BMP4; GFP; BMP2; SHH; TGF-β; SCJ; Llama-Derived Single-Domain Antibody; PCR; SQ
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2023.01.003

Barrett’s esophagus is considered to be a metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett’s esophagus is considered to be driven by sonic hedgehog mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models whether targeting canonical BMP signaling could be an effective treatment for Barrett’s esophagus. Selective inhibition of BMP2 and BMP4 within an in vivo organoid model of Barrett’s esophagus inhibited development of columnar Barrett’s cells, while favoring expansion of squamous cells. Silencing of noggin, a natural antagonist of BMP2, BMP4, and BMP7, in a conditional knockout mouse model induced expansion of a Barrett’s-like neo-columnar epithelium from multi-lineage glands. Conversely, in this model specific inhibition of BMP2 and BMP4 led to the development of a neo-squamous lineage. In an ablation model, inhibition of BMP2 and BMP4 resulted in the regeneration of neo-squamous epithelium after the cryoablation of columnar epithelium at the squamocolumnar junction. Through lineage tracing the generation of the neo-squamous mucosa was found to originate from K5+ progenitor squamous cells. Here we demonstrate that specific inhibitors of BMP2 and BMP4 attenuate the development of Barrett’s columnar epithelium, providing a novel potential strategy for the treatment of Barrett’s esophagus and the prevention of esophageal adenocarcinoma. [Display omitted]