Beyond the MSC Paradigm: Toward Unified Concepts, Methods and Applications in Secretome Research

The secretome has evolved from a protein-centered concept into a dynamic and multidimensional communication system comprising soluble proteins, extracellular vesicles, metabolites, lipids, nucleic acids, and other bioactive components. Despite major advances in secretome research, the field remains fragmented across biological systems and has been particularly dominated by studies of mesenchymal stromal/stem cells (MSCs). This review provides a unifying perspective on secretome biology across mammalian, plant, fungal, and bacterial systems. We examine the evolution of secretome definitions, classical and unconventional secretion pathways, and emerging analytical approaches, including mass spectrometry, metabolic labeling, single-cell and spatial secretomics, multi-omics integration, and artificial intelligence. We further discuss applications in biomarker discovery, liquid biopsy, regenerative medicine, cancer biology, biotechnology, and cell-free therapeutics, together with current challenges in standardization, reproducibility, manufacturing, and clinical translation. Moving beyond an MSC-centered framework toward tissue-, cell-type-, and organism-resolved secretome mapping may enable more comprehensive communication atlases and support the development of predictive biomarkers, precision therapeutics, and rationally engineered secretome-based products.