Mini-guts, macro-insights: unravelling the complexities of cell death and wound healing in intestinal organoids

Intestinal organoids represent three-dimensional in vitro models that closely mimic the structure and physiological functions of the human gut. These "mini-guts" are generated from two primary sources: adult intestinal stem cells (ISCs) or pluripotent stem cells (PSCs). While ISC-derived organoids maintain the specific genetic identity of the donor, making them valuable for personalized medicine, PSC-derived models are particularly useful for studying developmental biology and genetic engineering. This review examines the current methods for generating these organoids and explores their growing role in biomedical research. Specifically, we focus on their application in modeling epithelial injury and wound healing processes. Unlike traditional two-dimensional cell cultures, organoids provide a more accurate environment to observe how the intestinal lining repairs itself after mechanical or chemical damage. Furthermore, these systems have become essential for investigating different modes of cell death including apoptosis, necroptosis, and pyroptosis in the context of infections and chronic inflammatory diseases. Current organoid models have limitations, mainly because they lack vascular, neural, and immune components. We discuss how integrating these models with microfluidic organ-on-chip technologies and co-culture systems can address these challenges. Improving the physiological complexity of intestinal organoids will be critical for translating laboratory findings into effective clinical therapies for gastrointestinal disorders.