Regenerative Cell and Cell-Free Therapies for Necrotizing Enterocolitis: Progress Toward Clinical Translation

Necrotizing enterocolitis (NEC) remains one of the most devastating gastrointestinal diseases of prematurity, carrying high mortality and long-term morbidity with no targeted disease-modifying therapy currently available. This review synthesizes preclinical and translational evidence for stem cell- and extracellular vesicle (EV)-based regenerative therapies in NEC and identifies the critical steps required for clinical translation.

A narrative review of preclinical studies, systematic reviews, meta-analyses, and early-phase clinical trial data evaluating stem cell-based and cell-free EV therapies for NEC was performed. Evidence was organized across cell populations, mesenchymal stem cells (MSCs), amniotic fluid stem cells (AFSCs), placental-derived stem cells, and neural stem cells, and their derived EVs and exosomes, with synthesis of mechanistic, translational, safety, and ethical considerations.

Multiple stem cell types consistently reduce NEC incidence, severity, and mortality in experimental models. Protective effects are mediated through epithelial regeneration, barrier reinforcement, Wnt/β-catenin pathway activation, immunomodulation, and angiogenesis. Cell-free strategies using MSC- and AFSC-derived EVs reproduce comparable benefits with a more favorable manufacturing and safety profile. Early-phase clinical trials of MSCs in other neonatal conditions confirm short-term tolerability, though no NEC-specific stem cell or EV trial has been completed.

Regenerative cell and cell-free therapies represent a compelling disease-modifying strategy for NEC. Advancing this field requires standardized cell and EV characterization, optimized dosing and delivery protocols, large-animal model validation, and rigorously designed early-phase clinical trials with careful attention to safety, ethics, and regulatory frameworks.

· MSCs and AFSCs reduce NEC incidence and severity via paracrine regenerative mechanisms.. · EVs and exosomes replicate cell therapy benefits, offering safer cell-free alternatives.. · Clinical translation requires standardized protocols, safety data, and ethical frameworks..