Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder associated with chronic low-grade inflammation of the ovary. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that can reduce the weight and hyperglycemia of type 2 diabetes patients. Dapagliflozin is a highly selective, orally active and reversible inhibitor of the human SGLT2. However, the role of dapagliflozin in regulating PCOS remains unclear.

In this study, 24 six-week-old female Sprague Dawley (SD) rats were randomly divided into control, letrozole, and letrozole + dapagliflozin groups. PCOS model rats were produced by gavage administration of letrozole for 21 days. The intervention was conducted after the gavage administration of dapagliflozin for 14 days to evaluate the estrous cycle and ovarian imaging changes of the rats in each group. We observed changes in the weight, ovarian weight, and ovarian morphology of the rats in each group. Pathological changes in the ovaries were examined by H&E staining, changes in ovarian tissue cell apoptosis were identified using TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and changes in inflammation-related factors were detected using immunohistochemistry and Western blotting analysis. Network pharmacology was used to predict the inflammatory targets and pathways affected by dapagliflozin in treating PCOS, and the potential interactions between dapagliflozin and inflammation-related target proteins were evaluated through molecular docking.

Our results demonstrated that dapagliflozin treatment significantly improved PCOS symptoms, recovered ovarian morphology and physiological functions, and reduced the apoptosis of ovarian cells after drug intervention. Dapagliflozin treatment also reduced the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, indicating its anti-inflammatory properties. Furthermore, network pharmacology identified 26 intersecting target genes relevant to inflammation in PCOS, with subsequent molecular docking simulations revealing strong binding affinities of dapagliflozin to key targets, including AKT1 and TP53.

These findings suggest that dapagliflozin exerts beneficial effects on PCOS by ameliorating ovarian dysfunction and reducing inflammation. Dapagliflozin represents a promising therapeutic candidate for managing PCOS, warranting further clinical investigation to explore its full potential in treating this multifaceted disorder.

Premature ovarian insufficiency (POI) is a female reproductive disorder characterized by impaired ovarian function. Protein tyrosine kinase 2 beta (PTK2B), a non-receptor tyrosine kinase, has been implicated in folliculogenesis, but its role in POI remains unknown. In this study, a rat POI model was established by intraperitoneal injection of cyclophosphamide (Cy) for 14 days. Electroacupuncture (EA) has been elicited to effectively improve ovarian function in POI. Here, mRNA sequencing (mRNA-seq) analysis found that PTK2B expression in ovarian tissues was upregulated by Cy treatment but downregulated by EA. To investigate PTK2B's role, primary rat ovarian granulosa cells (GCs) were co-treated with Cy (250 μM) and a PTK2B inhibitor PF-431396 (10 μM) for 48 h. PF-431396 inhibited Cy-induced inflammatory response and apoptosis in GCs. Further, PTK2B binds to AKT1 in GCs. PF-431396 facilitated AKT1 phosphorylation, and the inhibitory effects of PF-431396 on GC inflammatory response and apoptosis were reversed by an AKT1 inhibitor LY294002. In vivo, rats were given PF-431396 (10 mg/kg/d) by gavage for 7 days following Cy induction for 14 days. Treatment with PF-431396 increased ovarian weight, serum E2, and AMH levels, while decreased FSH and LH levels. Additionally, it could improve Cy-induced ovarian tissue injury, inhibit inflammation and apoptosis, and elevate p-AKT1 level in ovarian tissues. Together, our results unveil that PF-431396, a PTK2B inhibitor, ameliorates ovarian dysfunction in POI through promoting AKT1 phosphorylation, suggesting that PTK2B may be a therapeutic target for POI.

The potential of low-intensity pulsed ultrasound (LIPUS) in regulating ovarian function has been demonstrated; however, there is a lack of scientific evidence regarding the long-term efficacy of LIPUS in treating ovarian injury and understanding its regulatory mechanisms. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to induce ovarian injury in rats, and LIPUS was applied to target the damaged ovarian tissues. The research aimed to investigate the long-term protective effect of LIPUS against ovum toxicity induced by VCD and elucidate the associated molecular mechanisms. During the experiment, HE staining was employed for observing the morphology and structure of the ovary, while protein sequencing was utilized for identifying and confirming the molecular mechanism through which LIPUS restores the damaged ovarian structure. The long-term effectiveness of LIPUS in protecting against ovarian injury was evaluated through ELISA, estrous cycle monitoring, fertility testing, and behavioral analysis. The results indicated that LIPUS effectively restored the structure of damaged ovaries. Both in vivo and in vitro studies revealed that this protective effect may be attributed to LIPUS inhibiting apoptosis of ovarian granulosa cells (GCs) by regulating Daxx-mediated ASK1/JNK signaling pathway. Subsequent functional tests demonstrated significant improvements in sex hormone secretion and regulation of estrous cycle within 6 cycles following LIPUS treatment. Additionally, there was a notable increase in offspring numbers after mating. Behavioral analysis revealed that LIPUS effectively alleviated menopausal symptoms resulting from ovarian injury including mood fluctuations, cognitive behavior changes, and reduced muscle excitability levels. These findings suggest that beneficial effects of LIPUS may help reduce VCD-induced ovarian damage with long-term efficacy.

Premature ovarian insufficiency (POI) is a prevalent gynecological disorder. Cyclophosphamide (CP), as a chemotherapeutic drug, particularly plays an important role in inducing POI. Protocatechualdehyde (PCA) is a major phenolic acid in Chinese herb Danshen, and has been reported to have beneficial effects on anti-inflammatory, anti-apoptotic, and anti-oxidant functions. We aimed to investigate the effect of different doses of PCA on ovarian function and the underlying molecular mechanisms. PCA administration reduced estrous cycle disorders, increased ovarian weight, promoted the secretion of serum hormone levels, and improved the CP-damaged ovarian microenvironment. Importantly, the administration of PCA contributed to the recovery of ovarian function with POI by inhibiting the senescence and apoptosis of granulosa cells. In vitro assay further confirmed the protective effect of PCA on CP-induced senescence and apoptosis of granulosa cells. Mechanistically, both in vivo and in vitro experiments proved that PCA administration promoted activation of the Sirt1/p53 signaling cascade, ultimately improving ovarian function. In conclusion, PCA might protect against ovarian damage in CP-induced POI that might be related to its activity on senescence and apoptosis of granulosa cells by the Sirt1/p53 pathway.

Zishen Yutai Pill (ZYP) is a widely used Chinese patent medicine in the clinical treatment of diminished ovarian reserve (DOR) induced infertility in China. However, the pharmacological actions and underlying mechanisms of ZYP in treating DOR remain poorly understood. This study aimed to evaluate the therapeutic effects of ZYP on DOR and elucidate its potential mechanisms. Two models including tripterygium glycosides (TGs)-induced DOR rat model and pZP3-induced DOR mouse model were selected to assess the effectiveness of ZYP in treating DOR. The intervention lasted for 4 weeks in both models. ZYP administration significantly increased the primordial follicles and the serum levels of AMH both in DOR rat and mouse model. Further, ZYP regulated the apoptosis pathway and apoptosis-related molecules including PI3K-Akt signaling pathway, Bcl6 and Abtb2 in ovary of DOR rat. The ovarian apoptosis level was significantly downregulated in a dose-depended manner in ZYP groups. Thus, we demonstrate that ZYP improved the ovarian reserve in DOR models. The mechanisms of ZYP on DOR may be mediated through decreasing the apoptosis level by the regulation of PI3K-Akt signaling pathway and apoptosis molecules (Bcl6, Abtb2) in ovary.

Jiawei Shoutai Pill is a traditional Chinese medicine formulation used clinically by physicians to treat diminished ovarian reserve (DOR) with positive outcomes. This study aimed to explore the potential pharmacological mechanisms of Jiawei Shoutai Pill in treating DOR by using network pharmacology methods. The effective compounds from traditional Chinese medicine were collected from the TCMSP, SYMmap, and PubChem, and the corresponding targets were retrieved from PubChem, Swiss Target Prediction, and DrugBank. Additionally, targets for DOR were obtained from GeneCards and Online Mendelian Inheritance in Man databases. Subsequently, multiple networks were constructed and gene enrichment analysis was performed using Cytoscape3.9.0 software. Molecular docking and molecular dynamics simulations were conducted based on previous research results. After screening, 72 active compounds and 292 target genes of Jiawei Shoutai Pill (excluding duplicate target genes) were identified, resulting in 1371 target genes related to the disease. A total of 149 cross-target genes were identified between the drug and disease targets. Kyoto encyclopedia of genes and genomes and gene ontology analyses emphasized the various gene functions and signaling pathways involved in treating DOR. Further molecular docking and dynamics simulations partially confirmed the practicality of the action Jiawei Shoutai Pill in vivo. The pharmacological effect of the Jiawei Shoutai Pill on DOR may be related to the PI3K-AKT, TNF, and lipopolysaccharide pathways. This study paves the way for further research on the mechanism of action of the Jiawei Shoutai Pill.

Premature ovarian failure (POF) is a common female reproductive disorder, with oxidative damage playing a significant role in its development. Studies had demonstrated the beneficial antioxidant, anti-aging, and other biological properties of swim bladder collagen (peptide). In this study, acid extraction, water extraction, and enzymatic hydrolysis methods were used to extract collagen (peptide) from sturgeon (Acipenser sinensis) swim bladder, all of which exhibited significant antioxidant activity. Moreover, the effects observed in POF mice were enhanced, including an increasing in the number of growing ovarian follicles, regulation of serum hormone levels, and alterations in signaling pathways, as evidenced by the up-regulation of Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) and B cell lymphoma-2/ Bcl-associated x protein (Bcl-2/Bax) pathways, alongside the down-regulation of the mitogen-activated protein kinases (MAPK) signaling pathway. Sturgeon swim bladder collagen (peptide) could protect against cyclophosphamide-induced POF in mice, which could be very beneficial in the future advancement of health products.

In this chapter, we explore the multifaceted roles of extracellular vesicles (EVs) in ovarian biology, focusing on their contributions to folliculogenesis, oocyte competence, corpus luteum function, and immune response regulation. EVs, particularly those derived from follicular fluid (ffEVs), are crucial mediators of cell-to-cell communication within the ovarian follicle, influencing processes such as meiotic progression, stress response, and hormonal regulation. We review preexisting literature, highlighting key findings on the molecular cargo of EVs, such as miRNAs and proteins, and their involvement in regulating the function of the follicle cells. Additionally, the influence of EVs on the immune responses within the ovary was also addressed. Some attention is given to the potential of EVs as non-invasive biomarkers and therapeutic tools, particularly in addressing conditions like premature ovarian insufficiency and polycystic ovary syndrome. By discussing the existing challenges and emerging research, we hope that this chapter will provide a deeper understanding of EVs' therapeutic potential and offer insights or suggestions for advancing assisted reproductive technologies.

Premature ovarian failure (POF)is defined as the loss of normal ovarian function before the age of 40 and is characterized by increased gonadotropin levels and decreased estradiol levels and ovarian reserve, often leading to infertility. The incomplete understanding of the pathogenesis of POF is a major impediment to the development of effective treatments for this disease, so the use of animal models is a promising option for investigating and identifying the molecular mechanisms involved in POF patients and developing therapeutic agents. As mice and rats are the most commonly used models in animal research, this review article considers studies that used murine POF models. In this review based on the most recent studies, first, we introduce 10 different methods for inducing murine POF models, then we demonstrate the advantages and disadvantages of each one, and finally, we suggest the most practical method for inducing a POF model in these animals. This may help researchers find the method of creating a POF model that is most appropriate for their type of study and suits the purpose of their research.

Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment.

Restoring the function of the ovary is important for chemotherapy-induced ovarian failure (COF) patients. Stem cell and extracellular vesicles (EVs) therapy show promise but need further improvement.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) were primarily cultured and further three-dimensional (3D) cultured using an ultra-low attachment surface method. The expression levels of nutritional cytokines and immunomodulatory and stemness-related genes of 3D-cultured hUC-MSCs were analyzed. EVs were isolated by ultracentrifugation and characterized. Ovaries were decellularized with sodium dodecyl sulfate to obtain extracellular matrix (ECM). Lyophilized EVs from three-dimensional (2D) or 3D hUC-MSCs were mixed with ECM to prepare the 2D/3D-MSC-EVs-ECM gels. The therapeutic effect of the MSC-EVs-ECM gel on cyclophosphamide (CTX) -treated rats was analyzed through various tests. RNA sequencing was used to analyze the expression changes of genes before and after treatment.

After culturing in ultra-low attachment dishes, hUC-MSCs aggregated into spheroids and significantly upregulated the expression levels of immunomodulatory and stemness-related genes. The total EVs yield was also upregulated (5.6-fold) after 3D culture. The cell viability of CTX-treated ovarian granulosa cells (OGCs) was significantly rescued by coculture with the 3D-MSC-EVs-ECM gel. Hormones indicative of ovarian function, AMH, E2, and FSH, were recovered in both the CTX + 2D-MSC-EVs-ECM gel group and the CTX + 3D-MSC-EVs-ECM gel group, while the apoptosis-related protein Bax was significantly downregulated. The 3D-MSC-EVs-ECM gel was more effective than the 2D-MSC-EVs-ECM gel. Significantly differentially expressed genes, such as Hbb-b1, Gpd1, and Sirpa, were detected by RNA sequencing. Hbb-b1 was increased in the ovaries of CTX-treated rats, and this increase was attenuated by injecting the 2D/3D-MSC-EVs-ECM gel. Gpd1 was increased after CTX treatment, and this increase was reversed by the 3D-MSC-EVs-ECM gel. Sirpa was decreased in the ovaries of CTX-treated rats, and this decrease was attenuated by injecting the 3D-MSC-EVs-ECM gel.

Our study demonstrated that the 3D-MSC-EVs-ECM gel is an efficient strategy for the recovery of ovarian function in CTX-induced ovarian failure.

Premature ovarian failure (POF), is a condition characterized by the early decline of ovulation function. POF is a complex disorder that can be caused by various factors, and the idiopathic form represents a significant proportion of POF patients. Hormone replacement therapy (HRT) is currently considered the first-line treatment for POF. This review aims to provide a comprehensive overview of recent advancements in platelet-rich plasma (PRP), in vitro activation (IVA), stem cell therapy, exosome therapy, microRNAs, and mitochondrial targeting therapies as a promising cell-free therapeutic approach in reproductive medicine. PLT-Exos, a new generation of cells, has been used to treat POF for more than a decade and has been shown to attenuate oocyte morphology and promote the differentiation of theca cells through the upregulation of PI3K/Akt and Bcl2, as well as the downregulation of the Smad and Bax signaling pathways. This review summarizes the current state of the art in the field of PLT-Exos and discusses the advantages and limitations of their potential clinical applications.

Ovarian transplantation presents significant advantages for the preservation of female fertility. Nonetheless, a substantial number of follicles are apoptosis during the process of ovarian tissue transplantation as a result of ischemic conditions. This study aimed to assess whether adipose-derived mesenchymal stem cells combined with urinary bladder matrix (ADSC/UBM) confer a greater therapeutic benefit compared to ADSCs alone. To achieve this, ADSC/UBM was applied during the autotransplantation of rat ovaries. Thirty rats were divided into five sets of six: the untreated control group (Normal), the oophorectomy group, the autograft group, the autograft + ADSCs group (ADSC), and the autograft + ADSC/UBM group (ADSC/UBM). After transplantation, the number of follicles in the ADSC/UBM group was significantly higher than that in the autograft group. Angiogenesis was enhanced following ADSC/UBM transplantation. Follicle-stimulating hormone (FSH) levels were significantly lower, and Anti-Müllerian hormone (AMH) levels were significantly higher in rats in the ADSC/UBM group than in the Autograft group. The apoptosis rate in the ADSC/UBM group decreased. The estrous cycle in the ADSC/UBM group recovered more quickly than the ADSC group. The data indicate that UBM improves ADSC retention in graft ovaries and aids in permanently restoring ovarian function, making ADSC/UBM a promising option for ovarian transplantation.

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released outside the cell. EVs have drawn attention not only for their role in cell waste disposal, but also as additional tools for cell-to-cell communication. Their complex contents include not only lipids, but also proteins, nucleic acids (RNA, DNA), and metabolites. A large part of these molecules are involved in mediating or influencing signal transduction in target cells. In multicellular organisms, EVs have been suggested to modulate signals in cells localized either in the neighboring tissue or in distant regions of the body by interacting with the cell surface or by entering the cells via endocytosis or membrane fusion. Most of the EV-modulated cell signaling pathways have drawn considerable attention because they affect morphogenetic signaling pathways, as well as pathways activated by cytokines and growth factors. Therefore, they are implicated in relevant biological processes, such as embryonic development, cancer initiation and spreading, tissue differentiation and repair, and immune response. Furthermore, it has recently emerged that multicellular organisms interact with and receive signals through EVs released by their microbiota as well as by edible plants. This review reports studies investigating EV-mediated signaling in target mammalian cells, with a focus on key pathways for organism development, organ homeostasis, cell differentiation and immune response.

There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF.

PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14.

Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P < 0.00001; I2 = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P = 0.0001; I2 = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P < 0.00001; I2 = 69%) and counts of different types of follicles. In addition, it elevates the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P < 0.00001; I2 = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P < 0.00001; I2 = 80%) expression, while reducing FSH expression (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P < 0.00001; I2 = 90%). Subgroup analysis indicates that the source of EVs, animal species, modeling method, administration route, and test timepoint affected efficacy. Trial sequential analysis showed that there was sufficient evidence to confirm the effects of stem cell-derived EVs on birth counts, ovarian weights, and follicle counts. However, the impact of stem cell-derived EVs on pregnancy rates needs to be further demonstrated through more animal experimental evidence.

Stem cell-derived EVs demonstrate safety and efficacy in treating POF animal models, with potential improvements in fertility outcomes.

PROSPERO registration number: CRD42024509699.

What impact does dehydroepiandrosterone (DHEA) have on ovarian angiogenesis and function in a rat model of with premature ovarian insufficiency (POI), and what are the potential mechanisms of action?

DHEA was added to a culture of human microvascular endothelial cells (HMEC-1) to investigate its effects on cell proliferation, migration and tube formation. A rat model of POI was established by intraperitoneal injection of cyclophosphamide, followed by continuous oral administration of DHEA or vehicle for 28 days. Ovarian angiogenesis, follicular growth and granulosa cell survival in ovarian tissues were assessed through haematoxylin and eosin staining, immunohistochemistry and TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL). The effect of DHEA on the fertility of rats with POI was evaluated in pregnant animals. The expression levels of characteristic genes and proteins in the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway was determined using quantitative reverse transcription PCR and western blotting.

In-vitro experiments revealed that DHEA stimulated the proliferation, migration and tube formation of HMEC-1. In in-vivo studies, DHEA treatment improved the disruption of the oestrous cycle and hormone imbalances in POI rats. Key genes in the HIF-1α/VEGF pathway exhibited up-regulated expression, promoting ovarian angiogenesis in POI rats, and enhancing follicular development and granulosa cell survival, thereby restoring fertility in rats.

DHEA can potentially restore ovarian function in rats with cyclophosphamide-induced POI by up-regulating HIF-1α/VEGF signalling, which promotes the growth of blood vessels in the ovaries.

To investigate the DNA damage response (DDR) in a cyclophosphamide (CTX)-induced mouse model of premature ovarian failure (POF).

The POF model was established by injecting mice with CTX. The body, ovarian weights, the estrus cycle, and pathological changes of the ovaries were recorded. The serum levels of 17 β-estradiol (E2) and follicle-stimulating hormone (FSH) were measured. The expression of Ki67, β-galactosidase (β-gal), p21, p53, γH2AX, and pATM in ovarian tissues was detected by immunohistochemistry. The expression of β-gal, γH2AX, and pATM was analyzed by immunofluorescence staining of primary cultured granulosa cells (GCs).

The body and ovarian weights decreased, the estrus cycles were erratic, and the FSH level increased, whereas the E2 level decreased in POF mice compared to controls. The pathological consequences of POF revealed an increase in atretic follicles, corpus luteum, and primordial follicles and a decrease in the number of primary, secondary, and tertiary follicles. Ki67 expression was reduced, β-gal, p21, p53, γH2AX, and pATM expression were elevated in the ovaries of POF mice. The expression of β-gal, γH2AX, and pATM increased in GCs with the concentration in a time-dependent manner.

In total, CTX induced POF in mice, which was mediated by the DDR pathway of ATM-P53-P21.

The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) pathway plays a crucial role in the activation of primordial follicles. However, excessive activation and the loss of primordial follicles can lead to ovarian dysfunction. The alpha-soluble N-ethylmaleimide sensitive factor attachment protein (α-SNAP) protein has been implicated in PI3K/Akt/mTORCl signaling, suggesting its potential involvement in follicle activation. Thus, this study aimed to explore the role of α-SNAP in the activation of the PI3K/Akt/mTORC1 signaling pathway and its ability to mitigate the effects of cisplatin on ovarian function, using both in vitro and in vivo models.

We transfected KGN human ovarian granulosa cells (GCs) with small interfering RNA (siRNA) targeting α-SNAP to investigate the effects of α-SNAP inhibition on GC proliferation and apoptosis, as well as on the activity of the PI3K/Akt/mTORC1 pathway. In a mouse model, α-SNAP siRNA was delivered via an adeno-associated virus before treatment with cisplatin to assess its effects on follicle activation and ovarian function. Follicle counts at various growth stages, western blotting, and immunohistochemistry analyses were conducted to detect the expression of cleaved caspase-3, Ki67, α-SNAP, and p-mTOR. Additionally, the serum concentrations of anti-Müllerian hormone (AMH) were measured through an enzyme-linked immunosorbent assay.

In vitro, α-SNAP depletion prevented GC proliferation by inhibiting the PI3K/Akt/mTORC1 pathway, thereby indicating its role in the regulation of cell growth. In vivo, α-SNAP knockdown attenuated the cisplatin-induced overactivation of primordial follicles by suppressing the PI3K/Akt/mTORC1 signaling pathway and partially restoring AMH levels. In addition, the expression and distribution patterns of cleaved caspase-3, Ki67, α-SNAP, and p-mTOR varied across different follicular growth stages, suggesting a protective effect against chemotherapy-induced ovarian damage.

Inhibiting α-SNAP may attenuate GC proliferation by suppressing the PI3K/Akt/mTORC1 pathway, thereby mitigating the overactivation and loss of primordial follicles induced by cisplatin. Targeting α-SNAP may emerge as a novel strategy to prevent ovarian damage resulting from chemotherapy. However, these conclusions warrant repeated testing, and the mechanistic underpinnings of α-SNAP must be further elucidated in the future.

The phosphoinositide 3-kinase (PI3K)/Akt pathway is a key signaling cascade responsible for the regulation of cell survival, proliferation, and metabolism in the ovarian microenvironment. The optimal finetuning of this pathway is essential for physiological processes concerning oogenesis, folliculogenesis, oocyte maturation, and embryo development. The dysregulation of PI3K/Akt can impair molecular and structural mechanisms that will lead to follicle atresia, or the inability of embryos to reach later stages of development. Due to its pivotal role in the control of cell proliferation, apoptosis, and survival mechanisms, the dysregulation of this molecular pathway can trigger the onset of pathological conditions. Among these, we will focus on diseases that can harm female fertility, such as polycystic ovary syndrome and premature ovarian failure, or women's general health, such as ovarian cancer. In this review, we report the functions of the PI3K/Akt pathway in both its physiological and pathological roles, and we address the existing application of inhibitors and activators for the balancing of the molecular cascade in ovarian pathological environments.

The concept of the Land of Not-Unhappiness refers to the potential achievement of eliminating the pathologies of the aging process. To inform of how close we are to settling in the land, we summarize and review the achievements of research on anti-aging interventions over the last hundred years with a specific focus on strategies that slow down metabolism, compensate for aging-related losses, and target a broad range of age-related diseases. We critically evaluate the existing interventions labeled as "anti-aging," such as calorie restriction, exercise, stem cell administration, and senolytics, to provide a down-to-earth evaluation of their current applicability in counteracting aging. Throughout the text, we have maintained a light tone to make it accessible to non-experts in biogerontology, and provide a broad overview for those considering conducting studies, research, or seeking to understand the scientific basis of anti-aging medicine.

What role does programmed cell death 4 (PDCD4) play in premature ovarian insufficiency (POI)?

A PDCD4 gene knockout (PDCD4-/-) mouse model was constructed, a POI mouse model was established similar to human POI with 4-vinylcyclohexene dioxide (VCD), a PDCD4-overexpressed adenovirus was designed and the regulatory role in POI in vitro and in vivo was investigated.

PDCD4 expression was significantly increased in the ovarian granulosa cells of patients with POI (P ≤ 0.002 protein and mRNA) and mice with VCD-induced POI (P < 0.001 protein expression in both mouse ovaries and granulosa cells). In POI-induced mice model, PDCD4 knockouts significantly increased anti-Müllerian hormone, oestrodiol and numbers of developing follicles, and the PI3K-AKT-Bcl2/Bax signalling pathway is involved in it.

The expression and regulation of PDCD4 significantly affects the POI pathology in a mouse model. This effect is closely related to the regulation of Bcl2/Bax and the activation of the PI3K-AKT signalling pathway.

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. The purpose of this study was to investigate the protective effects of Luffa cylindrica fermentation liquid (LF) on cyclophosphamide (CTX) -induced POF in mice and to preliminarily investigate the underlying mechanisms. Thirty-two Balb/c mice were divided into four groups randomly. One group served as the control, while the other three received CTX injections to establish POF models. A 14-day gavage of either 5 or 10 μL/g LF was administered to two LF pretreatment groups. To analyze the effects of LF, the ovarian index, follicle number, the levels of serum sex hormones, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), inflammatory factors, and apoptosis of the ovarian cells were measured. The effects of LF pretreatment on the expression of TLR4/NF-κB and apoptosis pathways were also evaluated. We found that LF pretreatment increased the ovarian index and the number of primordial and antral follicles while decreasing those of atretic follicles. LF pretreatment also increased the serum levels of estradiol (E2) and anti-Müllerian hormone (AMH), while decreasing those of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Furthermore, LF pretreatment increased the levels of SOD and GSH in the ovaries, while decreasing those of MDA, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). LF administration reduced the amount of TUNEL+ ovarian cells and the levels of TLR4 and NF-κB P65 protein expression. In conclusion, LF has antioxidant, anti-inflammatory as well as anti-apoptotic effects against CTX-induced POF, and the inhibition of TLR4/NF-κB and apoptosis pathways may be involved in its mechanisms.

Recent studies have shown that umbilical cord mesenchymal stem cells have an anti-aging effect in ovaries, but the cellular and molecular mechanisms of HA-MSC ovarian anti-aging remain to be studied. Therefore, we conducted a 10X Genomics single-nucleus transcriptome sequencing experiment on the ovaries of macaque monkeys after HA-MSC treatment.

The results of cell subgroup classification were visualized by 10X Genomics single nuclear transcriptome sequencing. The aging model of hGCs was established, and the migration ability of the cells was determined after coculture of HA-MSCs and aging hGCs. The genes screened by single nuclear transcriptional sequencing were verified in vitro by qPCR.

Compared with the aging model group, the number of cell receptor pairs in each subgroup of the HA-MSC-treated group increased overall. Treatment with 200 μmol/L H2O2 for 48 h was used as the optimum condition for the induction of hGC senescence. After coculture of noncontact HA-MSCs with senescent hGCs, it was found that HA-MSCs can reverse the cell structure, proliferation ability, senescence condition, expression level of senescence-related genes, and expression level of key genes regulating the senescence pathway in normal hGCs.

HA-MSC therapy can improve the tissue structure and secretion function of the ovary through multiple cellular and molecular mechanisms to resist ovarian aging. In vitro validation experiments further supported the results of single-cell sequencing, which provides evidence supporting a new option for stem cell treatment of ovarian senescence.

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.

Women experiencing primary ovarian insufficiency (POI) are more likely to experience infertility, and its incidence is increasing worldwide annually. Recently, the role of alpha-lipoic acid (ALA) in the treatment of POI has been reported. However, details of the potential pharmacological targets and related molecular pathways of ALA remain unclear and need to be elucidated. Thus, this study aims to elucidate the potential therapeutic target and related molecular mechanism of ALA on POI. First, the potential targets of POI and ALA-related targets were downloaded from online public databases. Subsequently, the overlapped target genes between POI and ALA were acquired, and gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) analysis, protein-protein interaction (PPI) networks were performed and constructed. Finally, molecular docking was performed to verify protein-to-protein effect. A total of 152 potential therapeutic targets were identified. The biological processes of the intersecting targets were mainly involved in the cellular response to peptides, response to xenobiotic stimuli, and response to peptide hormones. The highly enriched pathways were the cAMP, PI3K/AKT, estrogen, progesterone mediated oocyte maturation, and apoptosis signaling pathways. The top 10 hub targets for ALA in the treatment of POI were STAT3, STAT1, CASP3, MTOR, PTGS2, CASP8, HSP90AA1, PIK3CA, MAPK1, and ESR1. The binding between ALA and all top hub targets were verified using the molecular docking analysis. In summary, using the systematic integrated pharmacology network and bioinformatics analysis, this study illustrated that ALA participates in the treatment of POI via multiple targets and multiple pathways mechanisms.

Prolonging the reproductive lifespan is beneficial for preserving the physical and psychological health of women. The transplantation of mesenchymal stem cell (MSC)‑derived exosomes (MSC‑Exos) has been reported to be a promising regenerative therapeutic strategy for restoring the function of aging ovaries. The present study thus evaluated the therapeutic efficacy of exosomes derived from human umbilical cord‑MSCs (hUCMSC‑Exos) in a mouse model of natural ovarian aging (NOA), and further investigated the role of exosomal microRNAs (miRNAs/miRs) in the mechanisms of this creative therapy. Specifically, following the administration of hUCMSC‑Exos in mice with NOA, ovarian function was found to improve, as indicated by the restoration of follicle numbers and hormone levels. These exosomes were found to exhibit the ability to inhibit PTEN expression and suppress apoptosis both in vivo and in vitro. Subsequently, miRNA sequencing of the exosomes was performed, following which bioinformatics analysis was used to identify the highly expressed miRNAs that are capable of targeting PTEN expression. Through high‑throughput sequencing and molecular analyses, miR‑21‑5p was found to be the highest in ranking in terms of expression, suggesting that hUCMSC‑Exos can preserve ovarian function by suppressing PTEN expression to inhibit apoptosis by delivering miR‑21‑5p. On the whole, the results of the present study suggest that the application of exosomes can be used to restore ovarian function in mice with NOA. These positive findings also suggest that the transplantation of exosomes derived from MSCs holds promise as an agent against ovarian aging.

Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.

The ovary is a highly susceptible organ to senescence, and granulosa cells (GCs) have a crucial role in oocyte development promotion and overall ovarian function maintenance. As age advances, GCs apoptosis and dysfunction escalate, leading to ovarian aging. However, the molecular mechanisms underpinning ovarian aging remain poorly understood. In this study, we observed a correlation between the age-related decline of fertility and elevated expression levels of miR-143-3p in female mice. Moreover, miR-143-3p was highly expressed in senescent ovarian GCs. The overexpression of miR-143-3p in GCs not only hindered their proliferation and induced senescence-associated secretory phenotype (SASP) but also impeded steroid hormone synthesis by targeting ubiquitin-conjugating enzyme E2 E3 (Ube2e3) and luteinizing hormone and human chorionic gonadotropin receptor (Lhcgr). These findings suggest that miR-143-3p plays a substantial role in senescence and steroid hormone synthesis in GCs, indicating its potential as a therapeutic target for interventions in the ovarian aging process.

Premature ovarian failure (POF) mainly refers to ovarian dysfunction in females younger than forty. Mesenchymal stem cells (MSCs) are considered an increasingly promising therapy for POF. This study intended to uncover the therapeutic effects of human umbilical cord MSC-derived extracellular vesicles (hucMSCEVs) on POF. hucMSCs were identified by observing morphology and examining differentiation capabilities. EVs were extracted from hucMSCs and later identified utilizing nanoparticle tracking analysis, transmission electron microscopy, and Western blotting. POF mouse models were established by injecting D-galactose (Dgal). The estrous cycles were assessed through vaginal cytology, and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), estradiol (E2), and progesterone (P) were measured by ELISA. The human ovarian granulosa cell line KGN was used for in vitro experiments. The uptake of hucMSC-EVs by KGN cells was detected. After D-gal treatment, cell proliferation and apoptosis were assessed via CCK-8 assay and flow cytometry. The PI3K/Akt pathway-related proteins were determined by Western blotting. Our results revealed that POF mice had prolonged estrous cycles, increased FSH and LH levels, and decreased AMH, E2, and P levels. Treatment with hucMSC-EVs partially counteracted the above changes. D-gal treatment reduced proliferation and raised apoptosis in KGN cells, while hucMSC-EV treatment annulled the changes. D-gal-treated cells exhibited downregulated p-PI3K/PI3K and p-Akt/Akt levels, while hucMSC-EVs activated the PI3K/Akt pathway. LY294002 suppressed the roles of hucMSC-EVs in promoting KGN cell proliferation and lowering apoptosis. Collectively, hucMSC-EVs facilitate proliferation and suppress apoptosis of ovarian granulosa cells by activating the PI3K/Akt pathway, thereby alleviating POF.

Premature ovarian insufficiency (POI) induced by chemotherapy is an intractable disorder with a considerable incidence that commonly results in insufficient fertility and concomitant complications in female patients. Due to limitations in the current progress in POI diagnosis and treatment, there is an urgent need to develop novel remedies to improve ovarian function and protect fertility. The ameliorative effect of human umbilical cord mesenchymal stem cells (hUCMSCs) and exosomes derived from them in POI treatment could be a new hope for patients. Herein, we identified exosomes from hUCMSCs (hUCMSC-Exos). Then, systematic infusion of hUCMSC-Exos was accomplished via tail intravenous injection to investigate the feasibility of the treatment of rats with chemotherapy-induced POI by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS). Ovarian functions in the indicated group were evaluated, including oestrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, proliferation and apoptosis of granulosa cells (GCs), and reproductive ability testing. Furthermore, the potential influence of hUCMSC-Exos on ovarian tissues was illuminated by conducting RNA-seq and multifaceted bioinformatics analyses. POI rats with hUCMSC-Exos transplantation exhibited a decrease in follicle-stimulating hormone (FSH) and apoptosis of GCs but an increase in oestradiol (E2), anti-Müllerian hormone (AMH), and the number of ovarian follicles and foetuses in the uterus. And the immunomodulation- and cellular vitality-associated gene sets in rats had also undergone moderate changes. Our data indicated the feasibility of hUCMSC-Exos in improving ovarian function and protecting fertility in chemotherapy-induced POI rats. HUCMSC-Exos can improve the local microenvironment of ovarian tissue in POI rats by participating in immune regulation, cellular viability, inflammation regulation, fibrosis and metabolism, and other related signal pathways.

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. This study was aimed at exploring the improving effects of miR-22-3p on the symptoms of POF in mice by inhibiting chemokine-like receptor 1 (CMKLR1) expression. Female mice were intraperitoneally injected with cyclophosphamide to construct POF mice models. Lentiviral vectors containing miR-22-3p, short hairpin RNA (sh)-CMKLR1, and overexpression (oe)-CMKLR1, respectively, or in combination, were injected into the ovaries of both sides of POF mice. miR-22-3p and CMKLR1 expression in ovarian tissues of mice was assessed, and the targeting relationship between miR-22-3p and CMKLR1 was predicted and verified. Serum estradiol (E2), anti-Mullerian hormone, and follicle-stimulating hormone levels were assessed. Ovarian weight was weighed, and pathological changes and the number of primordial follicles, primary follicles, secondary follicles, and atresia follicles were observed. Apoptosis of ovarian tissues was determined. In ovarian tissues of POF mice, miR-22-3p expression was decreased while CMKLR1 expression was increased. miR-22-3p up-regulation or CMKLR1 down-regulation restored sex hormone levels, improved ovarian weight and the number of primordial follicles, primary follicles, and secondary follicles, and reduced the number of atresia follicle and ovarian granulosa cell apoptosis in POF mice. miR-22-3p targeted CMKLR1, and overexpressing CMKLR1 reversed the ameliorative effects of miR-22-3p overexpression on POF mice. Our research highlights that overexpressed miR-22-3p down-regulates CMKLR1 to ameliorate the symptoms of POF in mice. Therefore, the miR-22-3p/CMKLR1 axis could improve the symptoms of POF.

Polycystic ovarian syndrome (PCOS) is a common disorder that leads to infertility in reproductive-aged females. HOTAIR is highly expressed in various gynecological diseases and is associated with a poor prognosis. We aimed to explore the role of HOTAIR in PCOS.

First, PCOS rats were induced using dehydroepiandrosterone and then treated with si-HOTAIR. Next, HOTAIR mRNA expression and serum hormone levels were detected. HE staining was applied to observe estrus cycle, ovarian morphology and count the number of follicles. Apoptosis in the ovary was detected by TUNEL. Thereafter, ovarian granulosa cells (GCs) were isolated from PCOS rats, transfected with si-HOTAIR and treated with LY294002 (Akt inhibitor) or IGF-1. CCK-8 and flow cytometry assays were used to evaluate cell viability and apoptosis. IGF-1, apoptosis- and PI3K/Akt pathway-associated protein expressions in ovary and GCs were also detected.

In in vivo experiments, si-HOTAIR decreased serum T, E₂ and LH levels but increased FSH level, restored estrus cycle, ovarian morphology and inhibited apoptosis of ovary in PCOS rats. Meanwhile, in vitro assays showed that si-HOTAIR upregulated the viability but inhibited the apoptosis of PCOS GCs. Furthermore, both in vivo and in vitro assays revealed that si-HOTAIR increased Bcl-2 expression but suppressed Bax, Bad, IGF-1 expressions and PI3K, AKT phosphorylation. However, the aforementioned effects of si-HOTAIR in vitro were further enhanced by LY294002 and partially reversed by IGF-1.

HOTAIR knockdown improved PCOS, and the mechanism may relate to IGF-1-mediated PI3K/Akt pathway, indicating HOTAIR may be a novel therapeutic target for PCOS.

Premature ovarian failure (POF) is an insidious cause of female infertility and a devastating condition for women. POF also has a strong familial and heterogeneous genetic background. Management of POF is complicated by the variable etiology and presentation, which are generally characterized by abnormal hormone levels, gene instability and ovarian dysgenesis. To date, abnormal regulation associated with POF has been found in a small number of genes, including autosomal and sex chromosomal genes in folliculogenesis, granulosa cells, and oocytes. Due to the complex genomic contributions, ascertaining the exact causative mechanisms has been challenging in POF, and many pathogenic genomic characteristics have yet to be elucidated. However, emerging research has provided new insights into genomic variation in POF as well as novel etiological factors, pathogenic mechanisms and therapeutic intervention approaches. Meanwhile, scattered studies of transcriptional regulation revealed that ovarian cell function also depends on specific biomarker gene expression, which can influence protein activities, thus causing POF. In this review, we summarized the latest research and issues related to the genomic basis for POF and focused on insights gained from their biological effects and pathogenic mechanisms in POF. The present integrated studies of genomic variants, gene expression and related protein abnormalities were structured to establish the role of etiological genes associated with POF. In addition, we describe the design of some ongoing clinical trials that may suggest safe, feasible and effective approaches to improve the diagnosis and therapy of POF, such as Filgrastim, goserelin, resveratrol, natural plant antitoxin, Kuntai capsule et al. Understanding the candidate genomic characteristics in POF is beneficial for the early diagnosis of POF and provides appropriate methods for prevention and drug treatment. Additional efforts to clarify the POF genetic background are necessary and are beneficial for researchers and clinicians regarding genetic counseling and clinical practice. Taken together, recent genomic explorations have shown great potential to elucidate POF management in women and are stepping from the bench to the bedside.

Primary ovarian insufficiency (POI) is an essential cause of young female fertility loss. At present, there are many treatments for primary ovarian insufficiency, but due to the complexity of the pathogenesis of primary ovarian insufficiency, the efficacy still could not be satisfactory. Stem cell transplantation is a feasible intervention protocol for primary ovarian insufficiency. However, its wide application in the clinic is limited by some defects such as tumorigenic and controversial ethical issues. Stem cell-derived extracellular vesicles (EVs) represent an important mode of intercellular communication attracting increasing interest. It is well documented that stem cell-derived extracellular vesicles for primary ovarian insufficiency with exciting therapeutic effects. Studies have found that stem cell-derived extracellular vesicles could improve ovarian reserve, increase the growth of follicles, reduce follicle atresia, and restore hormone levels of FSH and E2. Its mechanisms include inhibiting ovarian granulosa cells (GCs) apoptosis, reactive oxygen species, and inflammatory response and promoting granulosa cells proliferation and angiogenesis. Thus, stem cell-derived extracellular vesicles are a promising and potential method for primary ovarian insufficiency patients. However, stem cell-derived extracellular vesicles are still a long way from clinical translation. This review will provide an overview of the role and the mechanisms of stem cell-derived extracellular vesicles in primary ovarian insufficiency, and further elaborate on the current challenges. It may suggest new directions for future research.

Mammals represent a relevant species in worldwide cultures with significant commercial value. These animals are considered an attractive large animal model for biomedical and biotechnology research. The development of large animal experimental models may open alternative strategies for investigating stem cells (SCs) physiology and potential application in the veterinary field. The embryonic stem cells (ESCs) are known to possess natural pluripotency that confers the ability to differentiate into various tissues in vivo and in vitro. These notable characteristics can be useful for research and innovative applications, including biomedicine, agriculture and industry. Transcription factors play a crucial role in preserving stem cell self-renewal, whereas growth factors are involved in both growth and differentiation. However, to date, many questions concerning pluripotency, cellular differentiation regulator genes, and other molecules such as growth factors and their interactions in many mammalian species remain unresolved. The purpose of this review is to provide an overall review regarding the study of ESCs in mammals and briefly discuss the role of transcription and growth factors.

Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.

Premature ovarian failure (POF) is a multifactorial disease that refers to the occurrence of secondary amenorrhea, estrogen decrease, and gonadotropin increase in women under the age of 40. The prevalence of POF is increasing year by year, and the existing instances can be categorized as primary or secondary cases. This disease has adverse effects on both the physiology and psychology of women. Hormone replacement therapy is the recommended treatment for POF, and a multidisciplinary strategy is required to enhance the quality of life of patients. According to recent studies, the primary mechanism of POF is the depletion of ovarian reserve function as a result of increased primordial follicular activation or primordial follicular insufficiency. Therefore, understanding the processes of primordial follicle activation and associated pathways and exploring effective interventions are important for the treatment of POF.

Having biological children remains an unattainable dream for most couples with reproductive failure or gonadal dysgenesis. The combination of stem cells with gene editing technology and organ-on-a-chip models provides a unique opportunity for infertile patients with impaired gametogenesis caused by congenital disorders in sex development or cancer survivors. But how will these technologies overcome human infertility? This review discusses the regenerative mechanisms, applications, and advantages of different types of stem cells for restoring gametogenesis in infertile patients, as well as major challenges that must be overcome before clinical application. The importance and limitations of in vitro generation of gametes from patient-specific human-induced pluripotent stem cells (hiPSCs) will be discussed in the context of human reproduction. The potential role of organ-on-a-chip models that can direct differentiation of hiPSC-derived primordial germ cell-like cells to gametes and other reproductive organoids is also explored. These rapidly evolving technologies provide prospects for improving fertility to individuals and couples who experience reproductive failure.

Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.