Impact of miR-214-5p and miR-21-5p from hypoxic endometrial exosomes on human umbilical cord mesenchymal stem cell function

Abstract

Exosomes derived from hypoxic endometrial epithelial cells are pivotal in cellular communication and tissue repair, offering new perspectives on reproductive health. This manuscript highlights the study by Zhang et al, which investigates the effects of miR-214-5p and miR-21-5p in hypoxic cell-derived exosomes on human umbilical cord mesenchymal stem cells. The study reveals that low levels of these microRNAs activate the signal transducer and activator of transcription 3 signaling pathway, enhancing human umbilical cord mesenchymal stem cell migration and differentiation. These findings provide novel insights into therapeutic strategies for improving endometrial health and addressing infertility linked to thin endometrium.

Key Words: MiR-214-5p; MiR-21-5p; Hypoxic endometrial epithelial cells; Exosomes; Human umbilical cord mesenchymal stem cells; Signal transducer and activator of transcription 3 signaling; Thin endometrium; Infertility

Core Tip: This manuscript examines the study by Zhang et al on the effects of miR-214-5p and miR-21-5p in hypoxic endometrial epithelial-cell-derived exosomes on human umbilical cord mesenchymal stem cells. The study highlights how low expression levels of these microRNAs activate the signal transducer and activator of transcription 3 signaling pathway, promoting human umbilical cord mesenchymal stem cell migration and differentiation - key processes in tissue repair and regeneration. These findings offer new insights into addressing thin endometrium, a common cause of infertility, by leveraging exosome-based therapies or targeted microRNA modulation. This article underscores the potential of miR-214-5p and miR-21-5p as therapeutic targets for improving endometrial health and reproductive outcomes.

TO THE EDITOR

Thin endometrium is a significant barrier to successful embryo implantation and a primary cause of repeated implantation failure and infertility, posing challenges in assisted reproductive technologies[1]. In the recent issue of the World Journal of Stem Cells, a study by Zhang et al[2] investigates the potential of exosomes derived from hypoxic endometrial epithelial cells (EECs) to modulate the function of human umbilical cord mesenchymal stem cells (HucMSCs), which are known for their regenerative capabilities[3]. Hypoxic EECs are those subjected to low oxygen conditions, leading to cellular stress and compromised tissue repair, which is relevant in conditions like thin endometrium.

Exosomes are nanosized vesicles released by cells that carry bioactive molecules such as nucleic acids, lipids, and proteins[4]. They play a crucial role in intercellular communication and can influence various cellular processes, including proliferation, differentiation, and migration[4]. In the context of endometrial health, exosomes derived from EECs can modulate the function of other cells, such as HucMSCs[5]. The study highlights the role of the signal transducer and activator of transcription 3 (STAT3) signaling pathway, a critical mediator of cellular responses to cytokines and growth factors, involved in processes such as cell growth, survival, and differentiation[6].

The authors focus on the microRNAs (miRNAs) miR-21-5p and miR-214-5p, which are small non-coding RNAs that regulate gene expression by binding to target mRNAs. These miRNAs have been implicated in various cellular processes, including proliferation and differentiation[7-10]. In the context of thin endometrium, miR-21-5p and miR-214-5p are involved in modulating the migration and differentiation of HucMSCs. By targeting the STAT3 signaling pathway, these miRNAs can enhance the regenerative potential of HucMSCs, promoting tissue repair and improving endometrial receptivity. This makes them promising therapeutic targets for addressing infertility issues related to thin endometrium.

Methods

The researchers isolated exosomes from both normal and hypoxia-damaged EECs and characterized them using techniques such as western blotting and nanoparticle-tracking analysis. HucMSCs were cocultured with these exosomes, and the expression of miR-21-5p and miR-214-5p was analyzed through sequencing and reverse transcription quantitative polymerase chain reaction. The effects of inhibiting or overexpressing these miRNAs on HucMSC migration and differentiation were assessed using transwell and wound healing assays.

Key findings

The expression levels of miR-21-5p and miR-214-5p in HucMSCs treated with hypoxic EEC-derived exosomes were found to be significantly lower compared to those treated with exosomes from normal EECs. The low expression levels of miR-21-5p and miR-214-5p in EEC-derived exosomes-pretreated HucMSCs were associated with enhanced migratory and differentiative potentials of the HucMSCs, as these miRNAs negatively regulate the STAT3 signaling pathway. The inhibition of miR-21-5p and miR-214-5p led to increased phosphorylation of STAT3, promoting HucMSC migration and differentiation into EECs. These findings suggest that miR-21-5p and miR-214-5p play a crucial role in modulating the regenerative capabilities of HucMSCs through the STAT3 pathway, offering potential therapeutic targets for improving endometrial health.

Critical appraisal

The findings of this study align with previous research indicating that exosomes play a vital role in cell communication and tissue repair. For instance, Liang et al[5] demonstrated that exosomes from HucMSCs could repair injured EECs, highlighting the therapeutic potential of stem cell-derived exosomes in reproductive health. However, the current study adds a novel dimension by specifically identifying the roles of miR-21-5p and miR-214-5p in this context, which had not been previously elucidated.

Future perspectives

The study by Zhang et al[2] provides a foundational understanding of how miR-214-5p and miR-21-5p in hypoxic endometrial epithelial-cell-derived exosomes can modulate the function of HucMSCs. This research opens several avenues for future exploration and clinical application, particularly in the field of gynecology and beyond.

Recent advances in clinical applications

In gynecology, exosome-based therapies are gaining traction as potential treatments for conditions like thin endometrium, which is a significant barrier to successful embryo implantation and pregnancy[11]. Recent studies have demonstrated the efficacy of exosome-hydrogel systems in promoting endometrial regeneration and improving fertility outcomes[1,12]. These systems protect and deliver exosomes to the target tissue, enhancing their therapeutic potential. The findings from Zhang et al[2] suggest that manipulating miR-214-5p and miR-21-5p levels could further optimize these therapies, offering a targeted approach to improve endometrial receptivity and address infertility issues.

Implications for stem cell, cancer, and immune therapies

Beyond gynecology, the modulation of miRNAs in exosomes holds promise for stem cell therapy, cancer treatment, and immune-related therapies. In stem cell therapy, miRNA manipulation can enhance the regenerative capabilities of stem cells, potentially improving outcomes in tissue repair and regeneration[13]. In cancer therapy, targeting specific miRNAs could inhibit tumor growth and metastasis by modulating key signaling pathways[14]. For immune-related therapies, exosomes can be engineered to deliver miRNAs that modulate immune responses, offering new strategies for treating autoimmune diseases and enhancing vaccine efficacy[15].

Exosome-based therapies

Exosome-based therapies offer a novel approach to delivering therapeutic agents directly to target tissues. Exosomes can be engineered to carry specific miRNAs, such as miR-214-5p and miR-21-5p, to modulate cellular functions[2]. This method leverages the natural ability of exosomes to facilitate intercellular communication and deliver bioactive molecules. However, challenges in clinical implementation include developing efficient and scalable exosome isolation and purification methods, ensuring the stability and bioavailability of exosome preparations, and addressing potential immunogenicity.

MiRNA mimics/inhibitors

The use of miRNA mimics or inhibitors represents another promising strategy. MiRNA mimics can be used to restore the function of downregulated miRNAs, while inhibitors can suppress the activity of overexpressed miRNAs[16]. These interventions can be tailored to modulate the STAT3 signaling pathway, which is crucial for HucMSC function and endometrial repair. The primary challenges in this approach include developing safe and effective delivery systems that can target specific tissues without off-target effects, as well as ensuring the stability and controlled release of miRNA therapeutics.

Challenges in clinical implementation

One of the main challenges in translating these strategies to clinical practice is the development of delivery systems that can efficiently and specifically deliver miRNA-based therapeutics to the endometrium. Nanoparticle-based delivery systems, liposomes, and viral vectors are being explored to enhance delivery efficiency and specificity. Safety considerations are paramount, as miRNA-based therapies must be carefully evaluated for potential off-target effects and long-term safety. Regulatory hurdles and the need for robust manufacturing processes also pose significant challenges.

Future research directions

Future research should focus on optimizing miRNA manipulation strategies for therapeutic use. This includes developing more efficient delivery systems for miRNA mimics and inhibitors, as well as exploring the use of CRISPR/Cas9 technology for precise miRNA editing. Preclinical studies should be conducted to assess the therapeutic potential of miRNA-based interventions in animal models of thin endometrium, providing critical data on efficacy, safety, and pharmacokinetics. Following successful preclinical evaluation, clinical trials will be necessary to determine the safety and efficacy of these interventions in humans. These trials should aim to establish optimal dosing regimens, evaluate long-term outcomes, and identify any potential adverse effects. Additionally, research should investigate the long-term effects of miRNA modulation on tissue health and function, as well as potential off-target effects.

Conclusions

The study by Zhang et al[2] provides valuable insights into the role of exosomal miRNAs in enhancing the regenerative potential of HucMSCs in the context of thin endometrium. Targeting miR-21-5p and miR-214-5p may offer a promising therapeutic strategy for improving endometrial receptivity and addressing infertility issues related to thin endometrium.