The germ layer: foundation of mesenchymal stem cell therapeutic destiny

Stem cells represent a pivotal resource in clinical applications. Accumulating evidence indicates that their functional properties are closely associated with their tissue origin, particularly embryonic germ layer specification, which may govern the developmental heterogeneity and microenvironmental niche preferences of stem cells. This review provides a systematic comparison of stem cells originating from the surface ectoderm, neural crest ectoderm, and mesoderm, highlighting their distinct molecular signatures, functional properties, and therapeutic utility. These stem cells exhibit conserved expression of core pluripotency factors while simultaneously maintaining germ layer-specific markers that dictate their functional divergence in tissue regeneration, immunomodulation, apoptosis regulation, and angiogenic modulation. Stem cells acquire germ layer-specific regulatory characteristics that intrinsically determine their biological destiny, including their biological functions, differentiation potential, and clinical applicability. This review provides a deeper understanding of germ layer-dependent properties, which will enhance the rational selection of stem cell sources for targeted therapies.