Letter to the Editor: Mesenchymal stromal cell-derived extracellular vesicles as a promising therapeutic candidate for attenuating cellular senescence

Abstract

Cellular senescence, characterized by an irreversible growth arrest, plays a pivotal role in aging and age-related pathologies. The study published in the World Journal of Stem Cells by Yang et al investigated the therapeutic potential of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in mitigating cellular senescence, providing comprehensive evidence from both in vitro and in vivo experiments. A clinical-grade production process for MSC-EVs was established, along with defined release criteria for human application. Functional assays revealed that MSC-EVs significantly reduced senescence-associated markers, including β-galactosidase, matrix metallopeptidase 1, P21, and interleukin-1β, while enhancing collagen I expression in aged human dermal fibroblasts. In a D-gal-induced aging mouse model, MSC-EVs ameliorated histopathological alterations, oxidative stress, and aging-related gene expression. Collectively, these findings underscore MSC-EVs as a promising anti-aging therapeutic strategy. Future research should focus on identifying the critical quality attributes of anti-senescent MSC-EVs and validating their efficacy in large animal models and clinical trials.

Key Words: Mesenchymal stromal cells; Extracellular vesicles; Exosomes; Cellular senescence; Aging

Core Tip: This study by Yang et al provided evidence that clinically produced mesenchymal stromal cell-derived extracellular vesicles effectively counteract cellular senescence. They reduce senescence markers and restore collagen expression in aged human dermal fibroblasts, while mitigating oxidative stress and aging-related gene expression in a D-gal-induced aging mouse model. These results highlight the potential of mesenchymal stromal cell-derived extracellular vesicles as a ready-to-use biologic strategy against aging and aging-associated tissue damage, paving the way for their further clinical development.

TO THE EDITOR

Cellular senescence, defined as a state of irreversible growth arrest, is a major contributor to aging and age-related pathologies[1]. Emerging evidence highlights that mesenchymal stromal cell (MSC)-derived extracellular vesicles represent a potent, cell-free therapeutic modality for anti-aging interventions[2]. MSC-derived extracellular vesicles (MSC-EVs) are lipid bilayer-enclosed nanoparticles enriched with bioactive molecules - including proteins, lipids, and nucleic acids - which mediate intercellular communication[3]. Several studies have demonstrated that MSC-EVs can attenuate senescence in various cell types, including fibroblasts, endothelial cells, and chondrocytes[4,5].

We read with great interest the recent article by Yang et al[6] entitled “Efficacy of extracellular vesicles derived from mesenchymal stromal cells in regulating senescence: In vitro and in vivo insights” published in the World Journal of Stem Cells. The authors utilized umbilical cord-derived MSCs with the passage number for extracellular vesicle (EV) production limited to within 4 generations. They provided compelling evidence for the anti-senescence effects of MSC-EVs, supported by robust experimental data from both cellular and animal models.

The study convincingly demonstrated that MSC-EVs suppressed key senescence-associated markers in aged human dermal fibroblasts, including β-galactosidase, matrix metallopeptidase 1, P21, and interleukin-1β, while restoring collagen I expression. These in vitro findings were further validated in a D-galactose-induced aging mouse model, where MSC-EV treatment ameliorated histopathological alterations, oxidative stress, and the expression of aging-related genes.

Metabolomic and transcriptomic analyses revealed that MSC-EVs modulate amino acid metabolism (e.g., upregulating methionine to enhance antioxidative capacity) and mitochondrial function. We hypothesize that MSC-EVs restore redox homeostasis through amino acid metabolic pathways and enhance mitochondrial energy, thereby inhibiting senescence-associated pathways and reducing the levels of β-galactosidase, matrix metallopeptidase 1, P21, and interleukin-1β, while restoring collagen I expression.

Importantly, their work represents a significant advancement in MSC-EV biology and establishes a pioneering clinical - grade production process. The authors produced EVs from umbilical cord-derived MSCs in a cGMP-compliant facility, ensuring high - quality, contamination - free manufacturing. To achieve scalability, a multi-tiered cell banking system was implemented, consisting of a master cell bank (passage 2) and a post-production cell bank (passage 4), enabling large-scale and continuous supply. Reproducibility was enhanced by standardized protocols under cGMP conditions, minimizing batch variability. Moreover, cost-effectiveness is achieved through long-term savings resulting from large-batch production and a reduced rate of batch failures. Beyond standard CFU and release criteria, the integration of cGMP compliance, scalable cell banking, and cost-efficiency establishes a truly clinical-grade platform, laying a solid foundation for clinical translation. The authors defined critical quality attributes - including particle size, morphology, surface markers (CD9, CD81, TSG101), purity (> 79%), and sterility - aligning with international standards such as the “Minimal Information for Studies of Extracellular Vesicles 2023” guidelines[7] and the requirement for small EVs from human pluripotent stem cells[8]. This emphasis on standardization directly addresses one of the major bottlenecks in the field, as highlighted in a letter by Liu[9], which underscores the challenges posed by heterogeneity and poor reproducibility in EV-based therapies.

The cargo of MSC-EVs constitutes a complex mixture, and Yang et al[6] have specifically identified key functional components that potentially underpin their anti-senescent effects. These include diverse cytokines, growth factors, bioactive lipids, and notably, specific regulatory microRNAs and proteins identified through their analyses. Such components mediate intercellular cell-to-cell communication and cell signaling, modulating cellular and tissue metabolism over both short and long distances in vivo. Despite these advances, several crucial questions persist. There is a pressing need to standardize EV isolation methods, precisely characterize functional cargo - particularly the specific microRNAs and proteins identified by Yang et al[6] that may drive anti-senescent activity - and establish large-scale production processes suitable for clinical translation. As emphasized by Liu[9], elucidating the mechanistic pathways of MSC-EVs, particularly those linked to the identified bioactive components, and optimizing delivery strategies are urgent priorities. To enhance targeting and therapeutic efficacy, targeted delivery approaches such as surface modifications of MSC-EVs or peptide-mediated targeting warrant further exploration. Additionally, long-term safety assessments are essential to determine the safety profile, biodistribution, and potential off-target effects of MSC-EVs in clinical contexts. Comparative efficacy trials against other anti-aging interventions (e.g., senolytics or caloric restriction mimetics) are also needed to strengthen the translational potential of MSC-EVs[10].

Compared to whole MSC transplantation, MSC-EVs confer several notable advantages including lower immunogenicity, greater storage stability, reduced thrombosis risk, and superior biocompatibility. However, it is important to acknowledge that EV immunogenicity remains a complex and multifaceted issue, potentially influenced by both the dose and the cellular source. Further in-depth studies are warranted to fully elucidate and optimize these factors for successful clinical translation. Their work paves the way for the future clinical application of MSC-EVs, not only in aging but also in diverse age-related pathologies such as degenerative diseases, chronic inflammation, and metabolic disorders.

In conclusion, MSC-EVs hold great promise as a novel therapeutic approach for mitigating cellular senescence and its associated dysfunctions. Their ability to modulate multiple senescence pathways highlights their potential as a next-generation anti-aging therapy. To advance MSC-EVs towards clinical application, several concrete research priorities should be addressed. First, standardizing EV isolation methods, such as size-exclusion chromatography or ultrafiltration, is essential to ensure the consistency and purity of isolated EVs. Second, establishing potency assays that directly reflect the activity of their functional cargo within the EVs is crucial for accurately evaluating therapeutic efficacy. Third, the development of scalable, Good Manufacturing Practice-compatible bioreactor platforms is imperative to enable large-scale production of MSC-EVs that meet rigorous quality standards for clinical use. In addition, refining delivery strategies, conducting comprehensive safety evaluations, and exploring combinatorial approaches that compare or combine MSC-EVs with senolytics or metabolic interventions will further enhance their translational potential. Collectively, these efforts will strengthen the scientific foundation for MSC-EV research and accelerate their progression into clinical trials targeting aging and age-related diseases.