Potential of mesenchymal stem cell-derived exosomes in the treatment of androgenetic alopecia

Abstract

Exosomes are derived from various cell types, including mesenchymal stem cells (MSCs), and play a crucial role in cellular communication, significantly influencing tissue repair and regeneration and facilitating the healing process. Thus, insights into the functions of exosomes present novel opportunities in regenerative therapy. This article aims to discuss the promising potential of exosomes derived from human adipose-derived MSCs in treating androgenetic alopecia. This study aims to highlight how exosomes derived from human adipose-derived MSCs enhance dermal papilla cell proliferation through the Wnt/β-catenin pathway, counteracting the effects of excessive dihydrotestosterone and offering a novel approach for treating androgenetic alopecia.

Key Words: Exosome; Mesenchymal stem cells; Hair regrowth; Dermal papilla cell; Wnt/β-catenin

Core Tip: Alopecia areata is an autoimmune disorder that promotes hair loss. Fu et al have demonstrated that exosomes derived from human adipose-derived mesenchymal stem cells stimulate hair follicle regeneration by activating the Wnt/β-catenin signaling pathway through cell division cycle protein 42. The study by Fu et al underscores the potential of exosome-based therapies as a promising, cell-free approach for treating androgenetic alopecia, thereby advancing regenerative medicine in hair restoration.

TO THE EDITOR

Alopecia areata (AA) is a prevalent autoimmune condition that affects approximately 2% of the population, leading to unpredictable hair loss. This hair loss can vary from small bald patches to complete hair loss on the scalp or even throughout the entire body[1]. In a recent World Journal of Stem Cells issue, Fu et al[2] conducted a study that investigated the potential of exosomes originating from human adipose-derived mesenchymal stem cells (hADSC-Exos) and human umbilical cord-derived mesenchymal stem cells (hUCMSC-Exos), both known for their regenerative and anti-inflammatory potentials[3]. Indeed, AA necessitates treatments with both regenerative and anti-inflammatory properties, such as via exosomes derived from mesenchymal stem cells (MSCs), which can promote hair follicle regeneration while modulating immune responses.

Exosomes are a class of extracellular vesicles that are secreted by almost all types of cells; moreover, exosomes carry bioactive molecules, including RNAs, DNAs, lipids, and proteins. Exosomes play a vital role in intercellular communication by transferring their molecular cargo to recipient cells and modulating various biological processes[4]. Subsequently, through this mechanism, exosomes can regulate essential cellular processes, including proliferation, differentiation, and migration, thereby affecting tissue homeostasis, regeneration, and the progression of diseases[3,4]. In the context of AA, exosomes derived from MSCs can modulate the function of cells, such as dermal papilla cells (DPCs), which are essential for maintaining hair follicle growth and cycling[5]. Therefore, this study compared the protein composition of hADSC-Exos and hUCMSC-Exos using liquid chromatography-mass spectrometry (LC-MS) proteome analysis and found differential protein expression in exosomes with different cell origins. The author also extensively studied the potential of hADSC-Exos in promoting DPC proliferation and hair follicle development.

Exosomal proteomic analysis revealed 232 conserved proteins across different culture systems associated with metabolism, extracellular matrix organization, and cell cycle regulation. hADSC-Exos enhanced hair follicle regeneration in the AA mouse model, demonstrating comparable efficacy to minoxidil. Immunofluorescence and gene expression analyses also confirmed that hADSC-Exos reversed dihydrotestosterone-induced inhibition of Wnt signaling. hADSC-Exos significantly promoted DPC proliferation and migration by inhibiting glycogen synthase kinase-3β and activating the Wnt/β-catenin signaling pathway via cell division cycle protein 42, especially through Wnt3a in DPCs. This makes them highly promising candidates for therapeutic intervention in treating AA.

Methods

In this study, the authors isolated the exosomes through differential ultracentrifugation. The exosomes were then characterized using transmission electron microscopy, nanoparticle tracking analysis, and western immunoblotting. The authors conducted a comprehensive proteomic analysis using LC-MS to compare the exosomal protein composition between hADSC-Exos and hUCMSC-Exos. An androgenetic alopecia mouse model was established by subcutaneously injecting testosterone propionate. Mice were treated with minoxidil (positive control) or hADSC-Exos via microneedle administration. Hair follicle development was assessed through macroscopic scoring and histological analysis. DPCs were evaluated for proliferation and migration using CCK-8 and Transwell assays, respectively. The Wnt/β-catenin signaling pathway was examined through quantitative polymerase chain reaction and immunofluorescence staining.

Major findings

These approaches by the authors to systematically analyze exosomal protein composition using LC-MS proteomics provide valuable insights into the molecular mechanisms underpinning exosome-mediated hair follicle regeneration. This study presents compelling evidence of hADSC-Exos inhibiting glycogen synthase kinase-3β expression through the Wnt/β-catenin signaling pathway, a significant advancement in regenerative medicine and hair restoration.

Emerging directions

The study by Fu et al[2] provides an initial understanding of the involvement of hADSC-Exos cargo proteins in enhanced hair restoration. Investigating exosome-derived bioactive molecules, including microRNAs (miRNAs), could further refine therapeutic applications, as most previous studies with various exosomes/extracellular vesicles/nanovesicles focused primarily on hair-promoting miRNAs[5]. Thus, personalized strategies utilizing patient-derived exosomes derived from MSCs may improve treatment results by avoiding immune-related adverse events. Moreover, combining exosome therapy with existing hair restoration techniques, such as platelet-rich plasma and microneedling, could improve outcomes.

Obstacles in clinical implementation

Exosome-based treatments have gained traction in regenerative medicine, with clinical trials exploring their efficacy as biomarkers, drug delivery carriers, and therapeutic agents[6]. Several studies have demonstrated the ability of MSC-derived exosomes to promote angiogenesis and cellular regeneration[7]. However, several hurdles must be addressed before exosome therapy can be widely adopted in clinical settings: (1) Scalability: Efficient production and purification methods are needed to meet clinical demands; (2) Standardization: Variability in exosome content necessitates robust quality control measures; (3) Regulatory approval: Guidelines for exosome-based products must be established to ensure safety and efficacy; and (4) Delivery mechanisms: Optimal administration routes and dosages require further investigation.

Exosome-driven interventions

Exosome-based therapies offer a cell-free alternative to traditional stem cell treatments, reducing immunogenicity and tumorigenic risks[8]. hADSC-Exos contain miRNAs and proteins that enhance cellular proliferation and tissue regeneration. Therefore, the ability of hADSC-Exos to penetrate biological barriers makes them ideal candidates for treating hair loss disorders. Ongoing research aims to engineer exosomes with targeted cargo for enhanced therapeutic efficacy.

Future research directions

Research by Fu et al[2] has expanded several avenues for future exploration and clinical application, particularly in hair restoration. However, future studies should focus on optimizing exosome production or development of artificial nanovesicles, establishing standardized culture conditions, and evolving scalable manufacturing protocols. Meanwhile, further exploration of exosome-mediated signaling pathways in hair follicle regeneration and large-scale randomized trials are required to validate efficacy/safety. In addition, the development of exosome-infused scaffolds for enhanced hair follicle regeneration is likewise needed. Additionally, research should explore the long-term impact of therapeutic protein/miRNA modulation on tissue health and function while also assessing potential off-target effects.

CONCLUSIONS

The study by Fu et al[2] provides valuable insights into the role of hADSC-Exos in hair restoration via regulating DPCs. The therapeutic success of exosomes derived from MSCs relies on their ability to regulate DPCs through key factors. This study highlights the promising future of exosomes derived from MSCs-based therapies for hair restoration.