Antimicrobial, immunomodulatory, and anti-fibrotic properties of stem cell secretomes: from host defense to tissue repair

The stem cell secretome, encompassing growth factors, cytokines, bioactive peptides, proteases, and extracellular vesicles (EVs), has emerged as one of the most versatile and promising tools in regenerative medicine. By delivering paracrine signals that coordinate tissue repair and immune regulation, secretome-based approaches offer the therapeutic benefits of stem cell biology in a cell-free format, circumventing concerns around immunogenicity, tumorigenicity, and logistical complexity. A growing body of evidence now identifies three core functional properties that define this field and position stem cell secretomes at the interface of immunology and regenerative medicine: antimicrobial activity, anti-fibrotic potential, and immunomodulation.The antimicrobial capacity of stem cell secretomes is rooted in their production of host defense molecules, including antimicrobial peptides (AMPs) such as defensins and cathelicidins, enabling stem cells to function as active participants in innate immunity. These factors help maintain barrier integrity, shape microbial communities, and protect host tissues from infection. Understanding the regulatory mechanisms governing AMP expression, their spectrum of activity against bacterial, fungal, and viral threats, and their interplay with the broader immune system remains a central open question with clear clinical implications.Equally significant is the anti-fibrotic potential of stem cell-derived secretomes. Pathological fibrosis, characterized by dysregulated extracellular matrix deposition and progressive organ dysfunction, underlies chronic disease across multiple systems, including renal, hepatic, pulmonary, and cutaneous pathologies. Secretome-derived factors such as hepatocyte growth factor (HGF), prostaglandin E2, and EV-associated miRNAs have demonstrated capacity to attenuate fibroblast activation, reduce collagen accumulation, and resolve fibrotic signaling cascades, positioning the secretome as a promising therapeutic candidate across fibrotic disease contexts.Underpinning both of these properties is immunomodulation. Stem cell secretomes are potent regulators of innate and adaptive immune responses, with well-documented anti-inflammatory activity, including attenuation of pro-inflammatory cytokine cascades, resolution of acute inflammation, and suppression of aberrant immune activation, that underpins both the antimicrobial and anti-fibrotic outcomes described above. Beyond this, immunomodulatory stem cells are capable of polarizing macrophages toward reparative phenotypes, modulating dendritic cell function, promoting regulatory T and B cell activity, which in turn promotes secretome's broader therapeutic relevance in inflammatory and autoimmune conditions.This Research Topic welcomes original research articles, systematic reviews, and perspectives spanning the following themes:Antimicrobial properties and host defense• AMP expression, regulation, and mechanisms of action in stem cell secretomes• Secretome-mediated protection at mucosal and barrier tissues• Interaction between stem cell-derived factors and the host microbiome• Preclinical and translational models of secretome antimicrobial functionAnti-fibrotic mechanisms and tissue repair• Secretome-driven regulation of fibroblast activation and extracellular matrix remodeling• EV cargo in organ-specific fibrosis: kidney, liver, lung, and skin• Crosstalk between anti-fibrotic and pro-regenerative secretome pathways• Wound healing: cellular chemotaxis, angiogenesis, and tissue remodelingImmunomodulatory functions• Innate immune regulation: macrophage polarization and AMP-immune crosstalk• Adaptive immune modulation and regulatory T cell induction• Comparative immunomodulatory profiles across secretome sources (MSCs, placental cells, renal progenitors, skin-derived stem cells)• Secretome-based strategies in autoimmune and chronic inflammatory diseaseTranslational outlook• Standardization, GMP-compatible production, and potency assays for secretome-based therapies• Preclinical-to-clinical translation: lessons and remaining challenges• Novel delivery systems for secretome components and EVs-Topic Editor Roberto Gramignoli is the founder of Tandem Biotherapeutics, Inc., a company specializing in placenta-derived epithelial cells from the amnion membrane. The other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Fabio Sallustio, Darius Widera, Roberto Gramignoli Source: https://www.frontiersin.org/research-topics/81587/antimicrobial-immunomodulatory-and-anti-fibrotic-properties-of-stem-cell-secretomes-from-host-defense-to-tissue-repair