Stem cell-derived exosomes modulate the inflammatory microenvironment and enhance regenerative capacity of oligodendrocytes

Abstract

BACKGROUND: The dynamic interplay between the inflammatory microenvironment and oligodendrocytes following neural injury constitutes a central pathological feature in neurodegenerative and demyelinating diseases. Stem cell-derived exosomes, leveraging their inherent low immunogenicity, efficient barrier-penetrating capacity, and targeted delivery of diverse pro-repair factors, play a pivotal role in modulating oligodendrocyte differentiation and the inflammatory microenvironment, thereby facilitating neural repair and regeneration. OBJECTIVE: To investigate the mechanisms by which stem cell-derived exosomes regulate the inflammatory microenvironment to enhance oligodendrocyte survival, differentiation, and myelin repair. It seeks to establish a novel "cell-free therapy" paradigm, utilizing exosome-mediated multi-component synergy (miRNAs, proteins, and metabolites) and microenvironmental adaptation for treating neurological disorders. METHODS: Literature searches were conducted in the China National Knowledge Infrastructure, PubMed, and WanFang databases, covering publications from 2010 to 2025. Chinese search terms included "exosomes, stem cells, engineered, diagnosis, inflammatory microenvironment, oligodendrocytes, signaling pathways," while English terms comprised "stem cell-derived exosomes, oligodendrocytes, inflammatory microenvironment, signaling pathway, regulatory mechanisms." Irrelevant studies were excluded, and 65 articles meeting inclusion criteria were systematically reviewed according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION: (1) The biological characteristics of exosomes and their roles in the central nervous system were summarized, analyzing the impact of the inflammatory microenvironment on oligodendrocytes and the regulatory mechanisms of exosomes, including miRNA-mediated signaling pathway regulation, anti-inflammatory factor secretion, and immune cell function modulation. (2) The regulatory mechanisms of the inflammatory microenvironment on oligodendrocyte biological behavior and their roles in disease pathogenesis were elaborated. (3) An engineered exosome delivery system based on targeting peptide modification and functional molecule loading, combined with traditional Chinese medicine active ingredient regulation strategies, was proposed to construct a novel cell-free therapy paradigm. (4) The deep interaction between the exosome functional network and myelin homeostasis was explained at the molecular level, providing new therapeutic directions for the development of exosome-targeted delivery systems to intervene in central nervous system demyelinating diseases.

1. Introduction

In recent years, stem cell-derived exosomes have become a research hotspot in the field of neural repair due to their unique biological properties, especially the mechanism by which they enhance the regenerative capacity of oligodendrocytes by modulating the inflammatory microenvironment. The inflammatory microenvironment is a common feature of various neurological diseases, composed of microglia, astrocytes, infiltrating immune cells, and inflammatory factors [1-2]. Traditional anti-inflammatory treatments (such as glucocorticoids) have issues of significant side effects and poor targeting. In contrast, stem cell-derived exosomes, as important mediators of intercellular communication, not only retain the therapeutic properties of parent cells but also possess advantages such as low immunogenicity, high stability, and good tissue tropism, playing a key role in neuroinflammation and myelin repair.

Studies have shown that stem cell-derived exosomes can deliver bioactive molecules such as miRNAs, proteins, and lipids to regulate microglia/macrophage polarization, inhibit the release of pro-inflammatory factors, promote oligodendrocyte precursor cell differentiation and myelin repair, providing new therapeutic strategies for central nervous system injury repair [3-5]. This article explores how stem cell-derived exosomes regulate the inflammatory microenvironment to promote oligodendrocyte survival, differentiation, and myelin repair, as well as the mechanisms by which they enhance the regenerative capacity of oligodendrocytes, providing a novel "cell-free therapy" paradigm for treating neurological diseases through multi-component synergy (miRNA, protein, metabolites) and microenvironmental adaptation (inflammation suppression, vascular support).