A Review on Treatment of Premature Ovarian Insufficiency: Characteristics, Limitations, and Challenges of Stem Cell versus ExosomeTherapy

Elahi, Narges; Ai, Jafar; Makoolati, Zohreh

doi:https://doi.org/10.1155/2023/5760011

Veterinary Medicine International

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Abstract Introduction Conclusion Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 5760011 | https://doi.org/10.1155/2023/5760011

A Review on Treatment of Premature Ovarian Insufficiency: Characteristics, Limitations, and Challenges of Stem Cell versus ExosomeTherapy

Narges Elahi,¹Jafar Ai,²and Zohreh Makoolati³

Academic Editor: Mohammed El-Magd

Received12 Jul 2023

Revised07 Oct 2023

Accepted02 Nov 2023

Published17 Nov 2023

Abstract

Premature ovarian insufficiency (POI) is a complex disorder that can result in varying degrees of infertility. Recently, mesenchymal stem cell (MSC) therapy and its derivatives, such as exosomes, have been introduced as novel strategies for the treatment of POI. This review discusses the features, limitations, and challenges of MSC and exosome therapy in the treatment of POI and provides readers with new insights for comparing and selecting chemical agents, optimizing doses, and other factors involved in study design and treatment strategies. MSC therapy has been shown to improve ovarian function in some animals with POI, but it can also have side effects such as high cost, time-consuming processes, limited lifespan and cell sources, loss of original characteristics during in vitro proliferation, dependence on specific culture environments, potential immune reactions, unknown therapeutic mechanisms, etc. However, exosome therapy is a newer therapy that has not been studied as extensively as MSC therapy, but that it has shown some promise in animal studies. The evidence for the effectiveness of MSC and exosome therapy is still limited, and more research is needed to determine whether these therapies are effective and safe for women with POI. This study presents a new perspective for researchers to advance their research in the fields of cell-based and cell-free therapies.

1. Introduction

Premature ovarian failure (POF) is a disorder in which women under 40 years of age experience 4–6 months of amenorrhea with high levels of FSH (follicle-stimulating hormone) and low levels of estradiol [1]. The global overall prevalence of POF is 3.5% among women. Furthermore, subgroup analysis shows a prevalence of 11.2% for iatrogenic etiology and 10.5% for autoimmunity [2]. The more precise term for this disorder is premature ovarian insufficiency (POI). At any stage of POI, a woman’s fertility may be impacted by a drop in the number of early primordial follicles, an increase in follicle destruction or a decrease in the number of apoptotic follicles, and the inability of follicles to respond to gonadotrophin stimulation [1]. Various strategies have been employed to remedy POI. Hormone replacement therapy has been the first-line strategy, followed by more novel treatments such as stem cell and exosome therapy [3].

Stem cell therapy involves transplanting stem cells from sources like bone marrow, adipose tissue, or umbilical cord blood to promote ovarian tissue regeneration and restore function [4]. Reports suggest MSCs inhibit granulosa cell apoptosis and upregulate anti-Müllerian hormone and FSH receptor expression, offering hope for POF patients and infertile women [5]. Moreover, growth differentiation factor-9 (GDF-9) and stem cell factor (SCF) impact follicle development beyond the primary stage, with GDF-9 promoting primordial follicle formation and growth while FSH influences granulosa cell development via SCF in an animal model [6]. Exosome treatment, on the other hand, is a noncellular therapeutic strategy that takes advantage of the biologically potent characteristics of exosomes, which are nanosized extracellular vesicles released by cells. Proteins, nucleic acids, growth factors, and other bioactive substances that can affect the ovarian microenvironment and promote tissue regeneration are contained within exosomes’ cargo [7]. The paracrine effects of exosomes allow for intercellular communication and targeted delivery of bioactive cargo, thus promoting tissue repair [8].

2. POI

POI is a heterogeneous disorder caused by genetic factors, autoimmune diseases, mitochondrial abnormalities, iatrogenic factors (including chemotherapy, radiotherapy, and surgical procedures), and environmental factors [3]. While over 50 genes are known to be related to POI, many cases still lack a clear genetic explanation [9]. Premature ovarian insufficiency can be treated using a variety of techniques. Although estrogen is thought to be physiologically replaced by hormone replacement treatment (HRT), ovarian function is not recovered. In vitro activation (IVA), mitochondrial activation, stem cell and exosome therapy, biomaterials techniques, and intraovarian platelet-rich plasma (PRP) injection are promising developing treatments for POI treatment. These innovative medicines are still in the experimental stage, despite their potential. A thorough assessment of their efficacy and safety is essential before they can be taken into consideration as viable clinical solutions [3]. In addition, identifying a marker like anti-Müllerian hormone (AMH) could aid in diagnosing and counseling women at risk for POI and assessing their ovarian reserve. AMH, produced by young ovarian follicles, is strongly correlated with their number, making it a potential diagnostic tool. Furthermore, AMH levels can indicate the degree of gonadal damage in cancer survivors [10].

3. Stem Cell Therapy

Mesenchymal stem cell therapy, which is used in stem cell therapy, has lately attracted attention for restoring ovarian function in POI. A multipotent and diverse population of cells known as mesenchymal stem cells (MSCs) can develop along the mesodermal lineage (as shown in Figure 1). Hematopoietic markers (CD45, CD34, and CD14) and costimulatory molecules (CD80, CD86, and CD40) are not expressed by these cells. Human MSCs’ expression of CD105, CD73, CD71, CD44, CD271, and CD90 is influenced by the tissue source and culture environment. According to evidence, MSCs release soluble substances such as transforming growth factor-1, interleukin-10 (IL-10), IL-6, and hepatocyte growth factor (HGF) on a regular basis. By inhibiting antigen-specific T-cell proliferation and encouraging the development of regulatory T cells, MSCs have an immunomodulatory effect. Successful allogeneic transplants have been thoroughly studied due to MSCs’ low immunogenicity. When administered in vivo, MSCs have the capacity to stimulate peripheral tolerance. Furthermore, MSCs are intriguing agents for both local and systematic distribution since they may move from blood arteries to the target using their own unique surface molecules. The clinical therapeutic effectiveness of MSCs, however, mostly rests on their capacity to change the environment of wounded tissue through the physiological activity of stromal cells in the hematopoietic stem cell niche through the secretion of anti-inflammatory and antiapoptotic chemicals. Despite the widespread use of MSCs, there is debate concerning the unidentified long-term negative effects on immune function and tumorigenic potential [11]. The therapeutic benefits of MSC-based therapy are largely attributed to the effects of paracrine factors that promote angiogenesis. However, in aged MSCs, the secretion of these proangiogenic factors, including vascular endothelial growth factor (VEGF), placental growth factor (PGF), and HGF, is reduced. Conversely, the secretion of antiangiogenic factors such as thrombospondin-1 (TBS1) and plasminogen activator inhibitor-1 (PAI-1) is increased. As a result, aging has a detrimental impact on angiogenesis and directly undermines the therapeutic effectiveness of MSCs [12].

Human umbilical cord mesenchymal stem cells (UC-MSCs), which are obtained from the umbilical cord, possess the aforementioned features of MSCs, as well as a younger nature, lower tumorigenicity, and fewer ethical issues [13]. Umbilical cords are a great source for easily extracting mesenchymal stem cells. UC-MSCs express human leukocyte antigen major histocompatibility complex I (MHC I) at a low level, as well as CD29, CD73, CD105, and CD90. They do not express MHC II molecules, CD14, CD79, CD34, CD45, or HLA-DR, which gives these cells negligible immunogenic features [14, 15]. UC-MSCs possess immunomodulatory effects by influencing the differentiation, proliferation, and activation of T cell subsets while inhibiting B cell proliferation, differentiation, and other immune cell activities. They exhibit robust proliferative abilities and can differentiate into various cell types under suitable conditions, both in vivo and in vitro. In addition, UC-MSCs contribute to tissue repair and regeneration by secreting growth factors such as HGF, VEGF, stromal cell-derived factor-1 (SDF-1), keratinocyte growth factor (KGF), fibroblast growth factor (FGF), and insulin-like growth factor-1 (IGF-1), which help facilitate cell proliferation and tissue healing. UC-MSCs also play a role in mitigating inflammation at the site of injury, and they actively migrate to the injured site for repair. This migration is known as the “return” of the MSCs’ “nest function” and has been demonstrated prominently in animal experiments under various microenvironmental conditions [16].

It has been demonstrated that UC-MSCs can improve the phosphatidylinositol-3-kinase (PI3K)/Akt signaling in POF-induced rodents via the nerve growth factor (NGF)/TrKA pathway. The PI3K/Akt signaling pathway regulates the follicular growth, survival, maturation, and differentiation of primordial follicles, as well as the prevention of apoptosis. Furthermore, the nerve growth factor receptor (TrkA) mainly activates the PI3K/Akt and mitogen-activated protein kinase (MAPK) signaling pathways, which are essential for the proliferation and survival of cells [15]. In a study, the intravenous injection of two doses of 1∗10⁶ UC-MSCs was able to transfer to the interstitium of the ovaries rather than to the follicles. This process prevented the apoptosis and inflammation in the granulosa cells in a POF-rodent model [13]. As shown in Table 1, different doses of UC-MSCs have been given to test their efficacy in restoring ovarian function in the POF model. UC-MSCs appear to have a large therapeutic potential. More consideration must be given to their therapeutic effectiveness, as well as to any potential drawbacks and negative side effects.

Female infertility brought on by degenerative factors is one condition for which bone marrow-derived mesenchymal stem cells (BMMSCs) have been touted as potential cures in regenerative medicine [22, 37]. Studies have shown that folliculogenesis may be affected by bone morphogenic proteins (BMPs), such as BMP-15 and BMP-6. These intraovarian subfamilies secreted from the oocyte have a key role in the development of follicles [19]. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), and other cytokines and growth factors are among those secreted by BMMSCs. Angiogenesis, mitogenesis, and antiapoptotic events all depend on these variables. Granulosa cells (GCs) can create a new capillary network thanks to VEGF, an angiogenic cytokine factor. Folliculogenesis results from bFGF’s stimulation of the promotion of primordial follicles. IGF-1 has the power to promote GC proliferation, inhibit apoptosis, and enhance antrum follicle development. HGF significantly affects follicle maturation and inhibits GC and follicle death in the ovary [22]. In this regard, BMMSCs have been applied for stem cell therapy in POF models.

During a woman’s menstrual cycle, human endometrial mesenchymal stem cells (EnSCs) are a rich, noninvasive source of multipotent stem cells that can be used for autologous transplantation. In vitro, EnSCs develop quickly and can differentiate into a variety of cells depending on the particular cell environment. EnSCs express OCT4, CD9, CD29, CD105, SSEA-4, and CD73 but do not express CD34, CD133, HLA class I, or CD45 markers. It was demonstrated that the allogenic transplantation of ESCs is feasible for the dose-dependent regulation of mononuclear cell proliferation. Lai et al. applied EnSCs to investigate their therapeutic effect on ovary preservation in POI models. It was shown that EnSCs could recover the ovarian follicles after chemotherapy in animals [23].

Another potential treatment option for female reproductive issues caused by POI is MSCs generated from human embryonic stem cells (hESC-MSCs). In rats whose ovaries had been damaged by chemotherapy, it was shown that this kind of MSC may stop ovarian apoptosis and encourage ovulation. HESC-MSCs have been made available as an easy-to-expand cell type with a consistent population [19, 23, 38]. Nevertheless, despite all the research and benefits of hESC-MSCs, it is understandable to be concerned about their drawbacks and moral dilemmas. According to studies, hESC-MSCs have the capacity to develop germ-layer malignancies. The defective transplantation of stem cells derived from embryonic lines may lead to incomplete differentiation. Furthermore, genetic anomalies have been reported in hESC lines in long-term culture [38].

Fetal MSCs can be derived from the liver in early gestation and have long lifespans with appropriate immunomodulatory features. It was reported that FMSCs could restore ovarian function in POI-induced mice, as well as promote human granulosa cell proliferation through the melatonin membrane receptor 1 (MT1). The evidence suggests that the interaction of melatonin with its receptors (MT1 and MT2) leads to a reduction in the level of reactive oxygen species and the prevention of apoptosis, so that the MT1 and MT2 blockages affect the follicular atresia and porcine GCs and consequently the reproduction mediation. On the other hand, the antioxidant properties of melatonin and the MT1 receptor on cytoprotective activity have been reported in cisplatin-induced ovary injury [28].

The therapeutic effect of adipose-derived stem cells (ADSCs) on ovary failure due to cyclophosphamide (CTX) has been investigated. The results showed the effectiveness of these types of multipotent stem cells on ovulation and folliculogenesis [29, 30]. According to Cil et al., ADSCs have a specific impact on the phosphorylated-mTOR (p-mTOR) and mammalian target of rapamycin (mTOR), which are crucial for oocyte meiosis [30].

Furthermore, the chorionic plate-derived MSCs (CP-MSCs), the multipotent self-renewal adult stem cell, have been applied for the recovery of ovarian function through stimulating ovulation and folliculogenesis in POI models. These cells can be easily extracted from the chorionic plate of the human placenta, which is considered medical waste [31]. However, the therapeutic effect of autologous MSCs in women with POF disorder suggests a novel strategy that could decline the symptoms of menopause as well as estrogen enhancement. Despite the promising therapy, this study was limited to a few numbers of cases and requires long-term monitoring [39].

In recent years, clinical trials have been conducted on MSCs for various conditions, including autoimmune [40], neurodegenerative, cardiovascular, and bone and cartilage diseases. However, the number of approved MSC treatments worldwide remains limited. Interestingly, Asian countries have approved a higher number of MSC treatments compared to other countries [41].

Overall, when transplanted, MSCs possess the ability to migrate towards injured ovaries, promoting the restoration of secretory function, facilitating follicle formation, and promoting tissue reconstruction in POI models. Similar to white blood cells, MSCs express different receptors and cell adhesion molecules that assist in their migration towards the targeted organs, specifically injured ovaries. Crucially, specific chemokines bind to MSC receptors, guiding their movement towards the desired tissues. This migratory characteristic makes MSCs an excellent choice for regenerative therapies in POI. Once they migrate to the injured ovary, MSCs play a significant role in regulating ovarian cell proliferation, apoptosis, immune response, and oxidative stress through their paracrine effects. This highlights the critical importance of MSC migration as a key mechanism for enhancing the effectiveness of therapeutic interventions.

Table 1 provides a comprehensive overview of the molecular mechanisms underlying the effectiveness of MSC therapy for POI. Multiple studies emphasize the positive effects of various MSC types on ovarian function. Notably, MSCs have been found to reduce the secretion of inflammatory cytokines and FSH, which are often elevated in POI. Conversely, MSCs promote an increase in estrogen levels, anti-Müllerian hormone, and demonstrate improvements in the PI3k/AKT pathway, enhancing angiogenesis within the ovary. Moreover, MSCs extend their impact beyond hormone regulation. They play a critical role in inducing and supporting follicular growth, preventing follicular atresia, and inhibiting apoptosis. Together, these orchestrated biological effects hold immense potential for rejuvenating and restoring ovarian function in individuals with POI.

3.1. Stem Cell Therapy Limitations and Prospects

The therapeutic use of MSCs has faced a number of difficulties while receiving a lot of attention for the treatment of numerous illnesses, including those affecting the female reproductive system. The authors have identified some of these issues, as shown in Table 1. Controlling the quality of MSCs is difficult. While some groups’ extraction procedures are time-consuming, intrusive, and expensive, others may lose their original characteristics while proliferating in vitro. Other challenges include a short lifespan and cell sources, unidentified therapeutic methods, the tumorigenicity of stem cell therapy, unclear dosing frequency, and particular growth conditions. Especially in the case of a disease state, it is urgent to have an appropriate and precise estimation for a sufficient number of cells in the transplantation process, which may be affected by apoptosis, inflammation, and any special condition of the POI disorder. Over the years, various amounts of stem cells have been administered for POI treatment, and the exact amount has not been determined. However, it seems essential to define the stage of POI first based on the chemotherapy agents and their doses, taking into account any probable adverse effects in the long term. Then, try to use standard concentrations, protocols, and materials for administration. Furthermore, evidence has shown that the physiochemical and mechanical features of the surrounding microenvironment of primordial germ line cells have a significant effect on their fate, growth, maturation, and differentiation. In fact, a three-dimensional structure and biomechanical properties are provided by the natural extracellular matrix (ECM), which has a great role in signaling phenomena, cell-to-cell communication, and consequently tissue development [42, 43]. In this line, alginate-ECM gels have been used to illustrate the role of ECM and its components in regulating the development of follicles [43].

In addition, scaffold-based stem cell transport has been developed to circumvent the main drawbacks of stem cell therapy. The extremely low cell survival rate in cell treatment is seen as a serious issue. The survival, adhesion, proliferation, and differentiation of stem cells must therefore be enhanced by providing a milieu that is similar to the cell niche. Collagen and alginate are examples of natural-based scaffolds that have recently been developed and demonstrated to have the ability to awaken POI follicles that are in a dormant state [33, 35, 36, 44].

4. Exosome Therapy

Exosomes, which are the nanosized extracellular vesicles produced within eukaryotic cell endosomes, have gained significant attention in the fields of life sciences research and biotechnology [45]. They play a significant role in cell-to-cell communication, signaling, and consequently physiological cellular action and development [46]. Exosomes are generated through the fusion of exosome-containing endosomes with the plasma membrane, whereas the secretion of microvesicles and apoptotic bodies occurs through direct budding from the plasma membrane. The biogenesis of exosomes starts with inward budding of the plasma membrane, forming early endosomes, and progresses to the maturation of multivesicular bodies (MVBs), wherein intraluminal vesicles (ILVs) are formed by inward budding of the endosomal membrane. These ILVs contain lipids, proteins, and nucleic acids derived from their parent cells [45]. The heterogeneous vesicles are categorized into exosomes, apoptotic bodies, and microvesicles based on their size and biogenesis [46]. When processing and separating exosomes, it is crucial to take into account variables including the makeup of the initial sample, the chosen method of separation, and how these variables affect the quality and traits of the finished products. Ultracentrifugation, ultrafiltration, precipitation, immunoaffinity capture, and size-exclusion chromatography are the five methods that are frequently employed for exosome processing. These techniques all generate exosomes, however, to varied degrees of purity and number. Combining isolation methods is a typical strategy to increase exosome yield and purity [45]. Exosomes are secreted in physiological and pathological states and are present in follicular fluid (FF). It has been reported that hormonal response, oocyte differentiation, follicular growth, and the meiosis onset pathways have been regulated by the involvement of FF exosomes [46]. Furthermore, the evidence has demonstrated that exosomes carry a variety of microRNAs (miRNAs), some of which, such as miR-100, miR-132, miR-212, and miR-214, directly regulate the meiosis and maturation of follicles [47].

MiRNAs are small noncoding regulatory RNAs that function in posttranscriptional gene regulation with the ability to regulate cellular processes broadly [48]. Recent studies have shown that MSC-derived exosomes can promote tissue repair and regeneration, making them an attractive candidate for the treatment of POI (Table 2). Studies have shown that the therapeutic effects of MSCs may be due to their paracrine factors, which include exosomes. These bilayered structures appear to have the capacity to overcome some limitations of MSCs, such as vascular blockage due to the large size of cells or finite lifespan and sources. However, it has been noted that a newly introduced method may overcome the challenge of low extracted numbers of exosomes. Cha et al. reported that their 3D-bioprocessing method has the potential to produce efficiently scalable EVs from human MSCs for clinical and/or commercial applications [63].

In addition, research on FF EVs has shown that distinct miRNA types depend on the size and type of follicles. The types of miRNAs shift from those associated with cell proliferation pathways to those associated with inflammatory response pathways when follicles develop and differentiate into bigger antral ones [64]. Small extracellular vesicles derived from embryonic stem cells have the potential to promote the recovery of ovaries in POF mice models by improving folliculogenesis and the proliferation of GCs through the PI3K/AKT signaling pathway [49]. MiRNA-21, one of the many miRNAs, has been shown to play a significant role in ovarian folliculogenesis by controlling and interacting with a variety of target genes. Consequently, autoimmune POIs have low levels of miRNA-21 expression. MiR-21 has demonstrated a positive link with AMH, E2, uterine size, and ovarian volume in a POI mice model and a negative correlation with FSH and LH [65]. Thabet et al. studied amniotic fluid mesenchymal stem cells (AFMSCs) to determine the exosomal miRNA. They found that AFMSCs-derived vesicles are a great source of miRNA-21, which prevents apoptosis, induces follicle regeneration, and recovers ovary function in infertile rats through the phosphatase and tensin homolog (PTEN) and PI3K/PTEN pathways [48]. Furthermore, AFMSCs-derived exosomes contain miRNA-146a and significantly miRNA-10a, which have antiapoptotic effects and inhibit ovarian follicles from atresia in CPA-induced animal models [50]. Figure 2(a) shows the schematic diagram of the proposed mechanism of AFMSCs-derived miRNA-146a on damaged GCs. The exosomal miRNA-369-3p from AFMSCs has similar behavior in POF models through a specific pathway (Figure 3) [52]. Another study showed that human amniotic epithelial cell-derived exosomes include a variety of miRNAs, such as miRNA-1246. HAEC-exosomes have been administered to investigate their effect on ovarian follicles against apoptosis and have shown significant efficacy on folliculogenesis [66]. It has been reported that there is an interaction between miRNA-17-5P and sirtuin-7 (SIRT7), which can be extracted from HUCMSCs in the ovary. SIRT7 regulates the response of cells to metabolic, oxidative, and genotoxic stresses. In a POI model, the administration of miRNA-17-5P could restore ovarian function, trigger GC proliferation, reduce ROS accumulation, and inhibit SIRT7 expression [53].

(a)

(b)

HUCMSCs exosomal miRNA-100-5p has acted through the NOX4/NLRP3 signaling pathway to prevent apoptotic phenomena in a POF model [67]. HUCMSCs exosomal miRNA-29a (Figure 2(b)) [54] and HUCMSCs-derived exosomes [56, 68] have promoted ovarian function, improved angiogenesis, developed folliculogenesis, and restored the estrous cycle through the Wnt/β-catenin, Hippo, and PI3K/AKT signaling pathways in POI-induced rodents, respectively. In addition, exosomal miRNA-29a derived from HUCMSCs promotes GC growth and angiogenesis in cisplatin-induced rats [55].

HUCMSCs exosomal miRNA-126-3p prevents GC apoptosis through the PIK3R2/PI3K/AKT/mTOR axis in vitro [55]. Exosomes derived from HADSCs have the potential to target the SMAD/TGFβ signaling pathway, leading to the proliferation of oocytes and GCs, promoting hormonal secretion and follicle differentiation [58]. The secretome of human bone marrow MSCs has also been investigated for POF treatment. The findings show that this secretome contains exosomal miR-144-5p [59] and miR-644-5p [60], which target PTEN and p53 to prevent GC apoptosis, respectively. Furthermore, the human BMMSC secretome significantly affects GCs, thus improving the secretion of GC hormones and stimulating growth and proliferation [69].

Menstrual blood-derived stromal cells (MenSCs), according to studies, can help with fertility restoration. In this regard, a rat model was used to study the therapeutic effects of exosomes produced from MenSCs. MenSCs-exosomes could enhance ovarian function, restore the ovary cortex, and encourage GC proliferation, according to in vivo research [61].

However, there still exists a lack of clarity concerning the complete substitution of MSCs by exosomes in the treatment of POI. Establishing the reliable implementation of cell-free therapy utilizing exosomes for POI patients necessitates investigating potential disparities in outcomes and effectiveness between MSC and MSC-derived exosome treatments. In a conducted study, samples of tissue and serum were acquired subsequent to MSC/exosome therapy to evaluate molecular changes resulting from the treatment. Furthermore, parallel breeding experiments were conducted to compare the restoration of fertility. Both the MSC-treated and exosome-treated groups exhibited reestablished estrous cycles and serum hormone levels compared to untreated mice with POI. Following treatment, the pregnancy rate in the MSC-treated group ranged from 60 to 100%, while the exosome-treated group demonstrated a pregnancy rate of 30 to 50%. Interestingly, regarding long-term effects, the MSC-treated mice consistently maintained a pregnancy rate of 60 to 80% during a second breeding cycle, whereas the exosome-treated group experienced a recurrence of infertility during the second breeding round [70].

In summary, studies have demonstrated the obvious benefits of exosome therapeutics in regenerative medicine and for the treatment of premature ovarian insufficiency. However, preclinical trials demonstrating the efficacy and safety of exosome therapy for POI are lacking.

4.1. Exosome Therapy Limitations and Prospects

Although cell-free techniques like exosome therapy are receiving more attention, there are still significant obstacles to their usage in POI treatment. Exosomes are excellent suppliers of a variety of miRNAs and other compounds that might modify cellular function, as was previously described. It will need additional research to ascertain the precise mechanism of each miRNA as well as any potential connections between exosomes and other signaling pathways. Determining the precise processes, how they work together, and most crucially, how they relate to the molecules involved in inflammation, regulation, and immunomodulation is also crucial. As discussed regarding the challenges of stem cell therapy in POI treatment, there is a significant gap in the design of models, applied materials and drugs, and treatment strategies, as well as exosome therapy. The other main challenges are the lack of standard protocols for the isolation, purification, and characterization of MSC-derived exosomes, which can lead to variability in the quality and potency of exosomes used for therapy. Exosome-based therapies’ safety must also be carefully considered because there is a chance of immune rejection and unintended side effects. In addition, there is no agreement on the administration strategy. Exosomes that are administered conventionally have been demonstrated to quickly leave the bloodstream; 2 hours after injection, they were found in the liver, spleen, lung, and gastrointestinal systems. For the optimum performance of local delivery of exosomes, Riau et al. suggested sustained distribution of exosomes using biodegradable materials like hydrogel [71]. Finally, there is no research that determines any probable long-term and systematic administration effects of miRNAs on reproductive diseases. Thus, it is essential to consider the effect of these vesicles on other organs due to their nanosize (Table 3).

5. Conclusion

In conclusion, mesenchymal stem cells and MSC-derived exosomes hold great promise as potential therapeutic options for the treatment of premature ovarian insufficiency. In combination with the wide variety of miRNAs and other chemicals found in exosomes, MSCs have the unusual capacity to specialize into a variety of cell types, which makes them excellent candidates for regaining ovarian function. To effectively utilize their therapeutic potential, a number of issues and restrictions must be resolved. The absence of established techniques for the isolation, growth, safety, and characterization of MSCs and exosomes is one of the major difficulties. The viability, efficacy, and reproducibility of the treatments may be impacted by this variation in methodology. Controlling MSC quality is also important because in vitro proliferation and extraction methods can change their original characteristics. In order to guarantee enough cell counts for transplantation, specified parameters and administration concentrations must be established while taking into account variables like the stage of POI and potential long-term negative consequences. Furthermore, the fate, development, and differentiation of primordial germ line cells are significantly influenced by the physiochemical and mechanical characteristics of the milieu around them. Collagen and alginate are examples of natural-based scaffolds that have shown potential for improving the viability and stimulation of dormant follicles in POI. Scaffold-based delivery systems offer a milieu that resembles the cell niche, enhancing stem cells’ adhesion, proliferation, and differentiation. Exosome therapy has drawn interest as a cell-free approach; however, there are still issues to be solved. Exosomal miRNAs’ precise mechanisms of action and interactions with other signaling pathways must be clarified through further study, which is now underway. This information will be useful in developing more potent therapy strategies for POI. Taking everything into account, it is clear that while MSCs and exosomes produced from MSCs have a great deal of potential to treat POI, further study is required to overcome current obstacles and improve the delivery, characterization, and administration protocols. Taking on these issues will open the door for the creation of efficient, standardized, and secure therapy approaches for women with POI.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This project was supported financially by the Fasa University of Medical Science, Grant no. 402007.

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Copyright © 2023 Narges Elahi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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