Stem cell-based tactics in the remodeling and treatment of intestinal diseases

Intestinal diseases are imposing a prevalent socioeconomic burden worldwide, which is largely attributed to the disrupted homeostasis of gut-immune crosstalk including gut microbiota dysbiosis and immunomodulatory imbalance. Stem cells are unique cell populations with self-renewal and multi-lineage differentiation properties, and current literature has indicated the remarkable applications in early embryogenesis, disease remodeling and novel cytotherapy via diverse modes of action (e.g., direct- or trans-differentiation, cytokine paracrine, and bidirectional immunomodulation). Of them, human pluripotent stem cells (hPSCs) and the derivatives, including the self-organizing organoids, have been vastly employed for intestinal disease remodeling, while mesenchymal stem/stromal cells (MSCs) and the microvesicles are adopted for multifarious intestinal disorder intervention. In this review article, we mainly focus on the progressions in stem cell-based disease remodeling (intestinal lineage and organoid induction from hPSCs) and cellular therapy for intestinal diseases (e.g., inflammatory bowel disease, infectious intestinal diseases, and colorectal cancer), together with the underlying repair mechanisms (e.g., target genes and signaling pathways). Furthermore, the promising prospective and the concomitant challenges of stem cell-based preclinical and clinical investigations upon intestinal disorders are also outlined, including ethical considerations and supervision, heterogeneity and standardization, integration with novel biotechnologies (e.g., single-cell RNA sequencing, intracellular tracing, gene-editing and three-dimensional bioprinting). Collectively, our findings will supply profitable references and facilitate the development of stem cell-based mechanistic investigation and regenerative medicine for intestinal diseases.