A zebrafish model of intestinal epithelial damage reveals macrophages and igfbp1a as major modulators of mucosal healing.

Promoting intestinal regeneration and enhancing mucosal healing have emerged as promising therapeutic alternatives for treating intestinal disorders that compromise epithelial barrier integrity and function. However, the cellular and molecular mechanisms underlying these processes remain poorly understood. This knowledge gap is partly due to the lack of reliable and cost-effective in vivo models for studying the mechanisms governing intestinal damage and regeneration. Here, we developed a controlled, inducible, and targeted intestinal epithelial cell (IEC) ablation transgenic zebrafish model that recapitulates features of intestinal damage and regeneration observed in humans. Single-cell RNAseq and live imaging revealed accumulation of macrophages in the recovering intestine, contributing to its regeneration. Furthermore, we observed overexpression of insulin-like growth factor binding protein 1a (igfbp1a) during intestinal damage. Morpholino-mediated knockdown of igfbp1a exacerbated intestinal damage and impaired subsequent regeneration. In summary, we introduced a novel zebrafish model of intestinal damage that enables in vivo high-throughput screening for identifying and validating novel modulators of mucosal healing and intestinal regeneration.