The Role of m6A Modification in Regulating MSC Differentiation and Immunomodulation: Implications for Regenerative Medicine and Therapeutic Applications.

Mesenchymal stem cells (MSCs) are widely utilized in tissue repair, anti-inflammatory treatment, and cell therapy due to their remarkable multidirectional differentiation potential, immunosuppressive capabilities, and low immunogenicity. However, the regulatory mechanisms underlying their functions are intricate, and epigenetic modifications are a significant contributing factor. N6-methyladenosine (m6A) modification affects the proliferation, differentiation, and immunomodulation of MSCs by regulating the stability, transport, and translation of RNA. Studies have shown that m6A modification promotes osteogenic differentiation through the bone morphogehetic protein/small mothers against decapentaplegic (BMP/Smad) and wingless-related integration site/β-catenin (Wnt/β-catenin) pathways. It also enhances the anti-inflammatory effect of MSCs by modulating immune cell polarization and the release of inflammatory mediators. Moreover, exosomes secreted by MSCs contribute to immunomodulation and the response to cancer treatment by regulating the m6A modification of genes in target cells. "Writers" of m6A, such as methyltransferase-like 3 (METTL3) and METTL14, and "erasers", such as fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), are crucial in regulating the functions of MSCs. Targeting m6A modification via the clinical application of MSCs may represent a new cancer treatment strategy. Therefore, a comprehensive investigation of the m6A regulatory mechanism is essential. This review provides theoretical and technical support for the clinical use of MSCs, facilitating the development of more effective therapeutic strategies.