Harnessing Adult Mesenchymal Stem Cells as Next-Generation Therapeutics to Combat Antimicrobial Resistance: A One Health Perspective

Antimicrobial resistance (AMR) is one of the most pressing current global health challenges, threatening human and animal health, food security, and environmental sustainability. The extensive use and misuse of antibiotics in human medicine and livestock production system have accelerated the emergence of multidrug-resistant (MDR) pathogens, necessitating the development of innovative alternatives to conventional antibiotics. While there are several areas of innovative alternatives are currently being pursued globally to mitigate MDR, adult mesenchymal stem cells (MSCs) have emerged as one of the most promising candidates owing to their regenerative, immunomodulatory, and especially intrinsic antimicrobial properties. Increasing evidence demonstrates that MSCs secrete a broad spectrum of antimicrobial peptides (AMPs), cytokines, chemokines, extracellular vesicles (EVs), and other bioactive molecules that directly inhibit pathogens while enhancing host immune responses. Unlike conventional antibiotics, MSC-derived products exert multifaceted actions by simultaneously promoting microbial clearance, reducing inflammation, and facilitating tissue repair, thereby minimizing the risk of resistance development. From a One Health perspective, MSC-based therapeutics offer an attractive strategy to reduce antibiotic use in livestock, improve animal health, and limit the spread of resistant pathogens across humans, animals, and the environment. Here we highlights the antimicrobial mechanisms of adult MSCs, their potential applications in veterinary medicine, and emerging opportunities for transcriptomics-guided discovery of novel MSC-derived antimicrobial peptides as well as application of artificial intelligence for sustainable animal production. Keywords: Mesenchymal stem cells, MDR pathogens, antimicrobial resistance, antimicrobial peptides (AMP), One Health. Introduction AMR has become a major global public health concern, compromising the effectiveness of antibiotics that have transformed medicine over the past century. The inappropriate use of antimicrobials in humans, food-producing animals, and agriculture has accelerated the emergence of multidrug-resistant (MDR) organisms. Resistant pathogens and resistance genes spread through direct animal contact, food products, waste-water, soil, and wildlife, emphasizing the interconnected nature of human, animal, and environmental health. Consequently, the One Health approach advocates integrated strategies to reduce antimicrobial use while developing safe and effective alternatives. Among emerging alternatives, adult mesenchymal stem cells (MSCs) have attracted considerable attention because they combine regenerative medicine with innate immune defense. Initially recognized for their ability to differentiate into mesodermal tissues, MSCs are now known to function primarily through paracrine signaling. Their secretome, comprising antimicrobial peptides (AMPs), cytokines, growth factors, extracellular vesicles, and immunomodulatory proteins, contributes significantly to tissue repair and antimicrobial defense. Antimicrobial peptides (AMPs) in combating antimicrobial resistance AMPs are evolutionary conserved gene encoded, short, positively charged host defense peptides found in all walks of life from microorganisms to humans (Zhang et al., 2016). Many AMPs are encoded in clusters in the genome and are expressed either constitutively or induced by specific external stimulators like infection or inflammatory condition. Constitutively expressed AMPs are primarily stored as inactive precursors in granules and are released locally at the site of infection or inflammation, whereas the induced expression of AMPs are stimulated by pathogen-associated molecular patterns (PAMPs) or cytokines (Hancock and Diamond, 2000). AMPs belong to the innate immune system which provides first line of protection against microbial infection. The anti microbial activity of AMP was demonstrated against gram positiv…