Mesenchymal stem cell-derived extracellular vesicles: Pioneering the next generation of biomedical applications

Abstract

Mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) represent the next generation of biomedical applications, offering advantages over MSCs such as higher stability and lower immunogenicity. As cell-free nanoparticles MSC-EVs have demonstrated both efficacy and safety in the treatment of a range of diseases. This article discussed the applications of MSC-EVs in hair regeneration, immunomodulation, and the treatment of acute kidney injury. MSC-EVs promote hair regeneration by enhancing dermal papilla cell proliferation and migration. They also modulate immune responses and mitigate inflammation through immune-related signaling pathways. Additionally, MSC-EVs contribute to improved renal function by modulating multiple signaling pathways. Despite these promising applications challenges remain in the clinical translation of MSC-EVs. Overcoming these challenges requires extensive research to fully optimize the therapeutic potential of MSC-EVs and advance their translation into clinical practice.

Key Words: Mesenchymal stem cells; Extracellular vesicles; Nanoparticles; Hair regeneration; Immunomodulation; Acute kidney injury

Core Tip: Mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) are cell-free nanoparticles that offer several advantages over MSCs, including greater stability and lower immunogenicity. These vesicles have shown significant potential in the treatment of various diseases. This article explored the applications of MSC-EVs in hair regeneration, immunomodulation, and the treatment of acute kidney injury. It also highlighted the challenges associated with MSC-EV-based therapies, underscoring the need for continued research and innovation to address these obstacles and advance MSC-EV development and clinical translation.

TO THE EDITOR

Although mesenchymal stem cells (MSCs) are among the most widely used stem cells in clinical applications, they have notable limitations, including the risk of immune rejection, tumorigenicity, pulmonary capillary blockage, and regulatory challenges associated with live-cell transplantation[1]. The therapeutic effects of MSCs are primarily mediated through paracrine mechanisms, such as the release of exosomes[2]. Extracellular vesicles (EVs) were first identified in the 1960s as small vesicles released by platelets[3] and were imaged by Crawford[4] in 1971. In the 1980s, further research revealed that these vesicles were actively secreted by cells and defined as exosomes[5,6].

EVs are membrane-enclosed nanovesicles (approximately 40-160 nm in diameter) that carry a variety of bioactive molecules, including nucleic acids, proteins, amino acids, lipids, and metabolites[7]. As cell-free nanoparticles MSC-derived EVs (MSC-EVs) have demonstrated both efficacy and safety in the treatment of a wide range of conditions, including applications in regenerative medicine, neuroprotection, cardiovascular disease, cancer therapy, and vaccine development[7,8].

MSC-EVs carry a diverse array of bioactive molecules, including proteins, microRNAs (miRNAs), long non-coding RNAs, and circular RNAs. These molecules play crucial roles in modulating key signaling pathways involved in tissue repair, immune regulation, and angiogenesis by facilitating intercellular communication and the dynamic exchange of biological signals.

Androgenetic alopecia, commonly known as male or female pattern baldness, is a multifactorial condition that imposes a significant financial burden and psychological effects. MSC-EVs have shown potential in promoting hair follicle regeneration without causing major adverse effects. Fu et al[9] showed that MSC-EVs promote hair regeneration by enhancing the proliferation and migration of dermal papilla cells. They exert these effects by inhibiting the expression of glycogen synthase kinase-3β, thereby activating the Wnt/β-catenin signaling pathway.

MSCs are known to have immunosuppressive properties, capable of regulating immune responses through multiple mechanisms. Similarly, MSC-EVs demonstrate considerable potential for immunotherapeutic applications due to their ability to modulate immune responses and deliver immunoregulatory molecules. Yi et al[10] reviewed the mechanisms of immune regulation and therapeutic applications of MSC-EVs. MSC-EVs regulate immune responses and mitigate inflammation by delivering miRNAs, proteins, and other bioactive molecules that modulate diverse immune cell populations. They suppress T cell proliferation through the p27kip1/cyclin-dependent kinase 2 pathway[11] and inhibit B cell proliferation, differentiation, and antibody production through the phosphatidylinositol 3-kinase/protein kinase B (AKT) signaling pathway, thereby mitigating pathological immune responses. This immunomodulatory effect is mediated by bioactive molecules such as MOES, galectin-3-binding protein, pentraxin 3, and S10A6 proteins, along with miR-155-5p and miR-497-5p[12]. Additionally, MSC-EVs reduce the cytotoxic activity of natural killer cells through transforming growth factor (TGF)-β signaling, involving molecules such as latency associated peptide, TGF-β, and thrombospondin 1[13]. They also regulate macrophage polarization and cytokine secretion by modulating the AKT/Forkhead box other 1 signaling pathway, primarily through TGF-β activity[14], ultimately contributing to the suppression of inflammatory responses.

Acute kidney injury (AKI) is characterized by a rapid decline in kidney function, posing serious risks to patient health and survival. Currently, there are no effective treatments available for AKI. However, MSC-EVs have shown promising therapeutic potential in its management. Wang et al[15] reviewed the role of MSC-EVs in AKI repair and the underlying mechanisms. MSC-EVs restored renal function by reducing DNA damage, apoptosis, oxidative stress, and inflammation while enhancing renal cell proliferation and survival. These therapeutic effects were mediated by MSC-EV cargo, such as proteins, miRNAs, long non-coding RNAs, and circular RNAs. Human bone marrow MSC-EVs protect against renal ischemia/reperfusion injury via miR-199a-3p, which activates the AKT and extracellular signal-regulated kinase signaling pathways[16]. Human umbilical cord MSC-EVs alleviate sepsis-associated AKI via miR-146b, which suppresses nuclear factor kappa B signaling, thereby reducing inflammation and improving renal function[17]. MSC-EVs enhance kidney function via miRNA-200a-3p, which activates the Kelch-like ECH-associated protein 1/nuclear factor-erythroid 2-related factor 2 signaling to promote antioxidant responses and mitigate renal injury[18]. They also reverse the progressive deterioration of kidney function in AKI mouse models by modulating the sirtuin 1 signaling pathway[19].

Compared with MSCs, MSC-EVs offer several significant advantages, including greater stability, lower immunogenicity, reduced risk of immune rejection, the ability to cross biological barriers such as the blood-brain barrier, and fewer complications. As such, MSC-EVs represent a safer, more scalable, and promising alternative to conventional MSC-based cell therapy.

Despite their promising potential several challenges hinder the clinical application of MSC-EVs. Key hurdles include heterogeneity and lack of standardization, insufficient characterization, limited scalability and production capacity, mechanistic uncertainty, regulatory and safety concerns, and issues with reproducibility. Due to variations in cell sources, culture conditions, and isolation methods, EVs exhibit significant heterogeneity in terms of size, cargo, cellular origin, and functional effects on recipient cells[7].

These variabilities highlight the urgent need for standardized quality control protocols. Currently, there are no universally accepted markers or methodologies for the identification and quantification of MSC-EVs, leading to inconsistencies across studies. Additionally, the precise mechanisms underlying the therapeutic effects of MSC-EVs remain poorly understood, limiting their translational potential. Large-scale production of MSC-EVs poses another challenge, as it is difficult to ensure consistent quality and potency, which restricts their clinical use. Furthermore, the absence of clear regulatory guidelines for MSC-EV-based therapies represents a significant barrier to clinical translation. Addressing these challenges is essential for advancing MSC-EV research and ensuring their standardization, reproducibility, and therapeutic efficacy in clinical applications.

As the field advances, interdisciplinary collaborations among researchers, clinicians, and industry partners will be pivotal in accelerating the translation of MSC-EVs from bench to bedside. Such partnerships will help standardize isolation, characterization, and large-scale manufacturing protocols, ensuring the consistency, safety, and efficacy of MSC-EV-based therapies. Regulatory frameworks will also play a crucial role in guiding clinical translation, necessitating rigorous preclinical and clinical evaluations to validate their therapeutic potential across diverse medical conditions. With continued progress MSC-EVs could revolutionize regenerative medicine. Their ability to promote tissue repair, modulate immune responses, and reduce inflammation makes them promising cell-free therapeutics for addressing some of the most pressing challenges in medicine, including those in regenerative medicine, autoimmune disorders, neurodegenerative diseases, and cardiovascular conditions.