The multifaceted role of mesenchymal stem cells in infectious diseases: antimicrobial properties, immunomodulation and tissue repair.

Background: Mesenchymal stem cells (MSCs) have emerged as promising therapeutic agents for infectious diseases owing to their antimicrobial, immunomodulatory, and tissue regenerative properties. Beyond their well-established role in tissue repair, MSCs and their secretome directly influence pathogen clearance through the secretion of antimicrobial peptides, extracellular vesicles, iron-sequestration mechanisms, and modulation of both innate and adaptive immune responses. Knowledge gap: Despite extensive preclinical investigations, MSC responses are highly pathogen-dependent, with outcomes that can be beneficial, neutral, or even detrimental depending on the infectious context. The heterogeneity in MSC efficacy across different pathogens underscores the need for a nuanced understanding of their mechanisms of action and the development of strategies to optimize therapeutic outcomes. Key findings: In bacterial infections, MSCs generally promote pathogen clearance and attenuate inflammation. Conversely, antiviral effects are often indirect, primarily involving the regulation of cytokine-driven immunopathology rather than direct inhibition of viral replication. Fungal and parasitic infections exhibit more complex interactions, with some pathogens exploiting MSCs as protective niches or reprogramming their immunological functions. Emerging strategies, including priming, genetic engineering, and cell-free secretome approaches, show promise in enhancing MSC efficacy. However, heterogeneity in cell source, manufacturing processes, potency, dosing, and timing remains a significant translational barrier. Conclusion: Future development of MSC-based therapies should shift from a universal, one-size-fits-all approach toward pathogen-specific, tailored cellular or cell-free products. This transition requires the establishment of standardized potency assays, optimized dosing protocols, and clinically meaningful endpoints. Adopting a pathogen-oriented framework will be essential for advancing MSCs as effective anti-infective agents, especially in the face of rising antimicrobial resistance.