Stem cells and exosomes: Biological tools for diagnosing and treating polycystic ovary syndrome (PCOS)

Authors: Mahta Hadidi, Keyvan Karimabadi, Elham Ghanbari, Leila Rezakhani, Mozafar Khazaei Affiliations: Fertility and Infertility Research Center & Department of Tissue Engineering, Kermanshah University of Medical Sciences, Iran

Summary (plain language)

• PCOS is a common condition affecting reproductive-age women. It causes high male hormones (androgens), irregular or absent ovulation, many small ovarian follicles, and metabolic problems like insulin resistance and obesity. PCOS raises risk for type 2 diabetes, heart disease, and infertility [1–5].
• Current drugs (e.g., metformin, clomiphene) treat symptoms but have limits. New approaches are needed.
• Two promising areas are stem cells—especially mesenchymal stem cells (MSCs)—and exosomes, which are tiny packets cells release that carry proteins and small RNAs. Both can reduce inflammation, support tissue repair, and change cell behavior without necessarily replacing cells themselves.
• Preclinical studies (mainly in animals and cell models) show MSCs and MSC-derived exosomes can lower ovarian inflammation, change steroid (hormone) production, protect ovarian cells, and improve fertility outcomes. Exosomal microRNAs (miRNAs) in blood, urine, and follicular fluid also show consistent changes in PCOS and may serve as biomarkers for diagnosis and monitoring.
• These findings support further clinical research. For people considering stem cell banking, preserving accessible, well-characterized sources of stem cells (e.g., umbilical cord, adipose tissue, or cord blood) could enable future regenerative or exosome-based therapies.

• Introduction — what is PCOS and why new approaches matter

• PCOS affects about 6–13% of women of reproductive age depending on diagnostic criteria and population [1,17]. It is not just an ovarian disorder; it’s multi-systemic and involves hormonal imbalance, metabolic dysfunction, and low-grade chronic inflammation [2–5,17–20].
• Common features include higher LH:FSH ratios, excess androgens, ovulation problems, insulin resistance, and increased inflammatory cytokines. These contribute to infertility and long-term health risks.
• Because symptom-focused treatments are imperfect, researchers are exploring cell-based (stem cell) and cell-free (exosome) strategies that target underlying inflammation, oxidative stress, and tissue dysfunction.

• Basics of PCOS and stem cells — simplified concepts

• Ovaries normally maintain a balance between resting and maturing follicles. In PCOS this balance is disrupted: many small follicles exist but dominant follicle selection and ovulation fail. Hormone signaling (GnRH, LH, FSH, AMH) and androgen production are altered [17,19].
• Stem cells are special cells that can self-renew and become other cell types. Types important to research and potential treatments:
• Mesenchymal stem/stromal cells (MSCs) — from bone marrow, adipose tissue, or umbilical cord. They are anti-inflammatory and secrete factors that help tissue repair [37,56].
• Induced pluripotent stem cells (iPSCs) — reprogrammed adult cells with broad potential and lower rejection risk if derived from the patient [36].
• MSCs’ therapeutic effects often work through secreted factors (the “secretome”), not by becoming new tissue. This secretome includes exosomes.

• What are exosomes and why are they useful?

• Exosomes are 30–120 nm membrane-bound vesicles released by many cell types. They carry proteins, lipids, and small RNAs (miRNAs, tRNAs, piRNAs) that influence other cells [11,40–44].
• Because exosomes are stable in biological fluids and can cross tissues, they are attractive both as therapeutics (delivering regulatory cargo) and as biomarkers (their cargo reflects tissue state).
• MSC-derived exosomes (MSC-EXOs) have anti-inflammatory and tissue-repair effects similar to MSCs, but with lower risk of immune reaction and easier storage/handling [45–50].

• Evidence from experiments and animal studies — key findings

• MSCs and their exosomes reduce ovarian inflammation, decrease pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IFN-γ), and lower fibrosis-related gene expression (e.g., CTGF) in PCOS models [4,7,8].
• Adipose MSC-derived exosomes (AMSC-EXOs) delivered microRNA miR-21-5p to the liver in PCOS rats and activated IRS1/AKT signaling, improving metabolic measures [51].
• Edited AMSC-EXOs delivering miR-323-3p reduced granulosa/cumulus cell apoptosis and improved proliferation, improving ovarian function in PCOS models [52].
• Human umbilical cord MSC exosomes reduced granulosa cell inflammation and apoptosis by modulating NF-κB signaling and increasing anti-inflammatory IL-10 [53].
• In mice and rat PCOS models, MSC transplantation or MSC-conditioned media improved ovarian histology (increased healthy follicle numbers, improved oocyte maturation), normalized some hormone levels, reduced oxidative stress markers, and restored fertility in some experiments [4,57–59].
• Some studies show conditioned media (containing many secreted factors) may have even broader effects than purified exosomes alone, since it includes additional soluble proteins and factors [55].

• Exosomes as biomarkers for PCOS — what the data show

• Exosomal cargo from follicular fluid, serum, and urine shows reproducible differences between PCOS and non-PCOS patients. Many altered small RNAs (miRNAs, tRNAs, piRNAs) have been reported across studies [63–66].
• Examples of altered exosomal miRNAs linked to PCOS or related features:
• Upregulated in PCOS follicular fluid: miR-6087, miR-193b-3p, miR-199 family, miR-25-3p, miR-143-3p; downregulated: miR-200c-3p, miR-483-5p, miR-141-3p, etc. [63].
• Serum exosomal miRNAs associated with PCOS: miR-30c, miR-222, miR-146a; correlations found with insulin and testosterone levels [73].
• Other candidate biomarker miRNAs reported: hsa-miR-196a-3p, hsa-miR-106a-3p, hsa-miR-143-5p, hsa-miR-20a-5p, hsa-miR-34a-5p, and many more across studies [66,74–76].
• Beyond RNAs, exosomal proteins (e.g., S100-A9) may activate inflammatory pathways (NF-κB) in ovarian cells and contribute to PCOS pathophysiology [78].
• Diagnostic potential: exosome-based signatures could become non-invasive tests (blood, urine) to help diagnose PCOS, stratify subtypes (e.g., metabolic vs. primarily reproductive), and monitor response to therapies.

• How these findings connect to stem cell banking and regenerative medicine

• Why bank stem cells?
• Sources like umbilical cord tissue and cord blood contain MSCs or hematopoietic stem cells that can be cryopreserved for future regenerative use. Adipose tissue is another accessible MSC source.
• Banking preserves a younger, less damaged stem cell source that could later supply cells, conditioned media, or exosomes for personalized therapies.
• Practical implications:
• If exosome or MSC therapies for PCOS advance to clinical use, having a stored, autologous (patient-derived) or well-characterized allogeneic (donor) banked source could allow quicker access to therapies that are better matched and potentially safer.
• Exosomes may be developed as off-the-shelf biologic products. Banks that preserve MSCs under controlled conditions could supply standardized exosome production or enable manufacturing of tailored exosome therapeutics in the future.
• For longevity and regenerative health, banking stem cells early (e.g., at birth or when healthy) preserves cells with fewer age-related changes and lower accumulated DNA damage, which may improve their therapeutic potential later in life.
• Limitations and safety:
• Most evidence for MSC/exosome therapy in PCOS is preclinical (animal and cell studies). Human clinical trials are needed to confirm safety, dosing, delivery route (intravenous vs intraovarian), and long-term outcomes.
• Standardization is a challenge: exosome isolation, characterization, and potency assays are still evolving [42,43].

• Clinical data, routes of administration, and therapeutic effects (practical details)

• Routes studied:
• Intravenous (systemic) injection: better for systemic metabolic regulation (e.g., insulin sensitivity) [54].
• Intraovarian injection: more effective for restoring local ovarian function and fertility metrics [54].
• Conditioned media or local application: used in animal studies to support follicle/oocyte maturation [57].
• Observed improvements in animal and preclinical data:
• Lowered inflammatory cytokines and oxidative markers.
• Reduced granulosa/cumulus cell apoptosis and improved proliferation.
• Normalized steroid hormone production and decreased androgen synthesis.
• Improved oocyte maturation, fertilization rates, and in some cases restored fertility [4,51–59].
• Comparative findings:
• Some studies found MSC-conditioned media (rich in many secreted factors) had stronger effects than purified exosomes alone—likely because conditioned media includes a broader mix of proteins and signaling molecules [55].
• Engineering exosomes (loading specific miRNAs) can target particular pathways—for example, miR-323-3p and miR-21-5p delivery showed specific benefits in PCOS models [51,52].

• Conclusion — what this means for patients and for stem cell banking

• Stem cells (MSCs) and exosomes show strong preclinical potential to treat PCOS by reducing inflammation, protecting ovarian cells, regulating hormone production, and improving reproductive outcomes.
• Exosomal miRNA and protein signatures are promising as non-invasive biomarkers to improve PCOS diagnosis and to monitor disease subtypes and treatment response.
• For people thinking ahead about regenerative options and longevity, stem cell banking can preserve valuable cell sources that may be useful for future MSC-based or exosome-based therapies, should clinical trials establish safety and efficacy for PCOS and other age-related reproductive conditions.
• Next steps: more standardized manufacturing, safety-focused clinical trials, and development of validated exosome biomarkers are needed before routine clinical use.

Author contributions

• MH, KK, EG: conceptualization, investigation, writing (original draft). LR, MK: project administration, supervision, review & editing.

Funding and acknowledgments

• The authors received financial support for their research and thank the Fertility and Infertility Research Center, Kermanshah University of Medical Sciences.

Conflict of interest

• Authors declared no commercial or financial conflicts of interest.

Selected clinical and preclinical references (key sources cited in the review)

• Xu Y, Qiao J. Association of insulin resistance and elevated androgen levels with Polycystic Ovarian Syndrome (PCOS): a review of literature. J Healthc Eng. 2022;2022:9240569. doi:10.1155/2022/9240569

• Chugh RM, Park HS, El Andaloussi A, et al. Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10. Stem Cell Res Ther. 2021;12:1–19. doi:10.1186/s13287-021-02472-w

• Rahmati S, Khazaei M, Nadi A, et al. Exosome-loaded scaffolds for regenerative medicine in hard tissues. Tissue Cell. 2023;102102. doi:10.1016/j.tice.2023.102102

• Chen J, Li P, Zhang T, et al. Review on strategies and technologies for exosome isolation and purification. Front Bioeng Biotechnol. 2022;9:811971. doi:10.3389/fbioe.2021.811971

45–50. (Selected studies on MSC-derived exosome immunomodulation and regenerative effects) Chang CL et al. Am J Transl Res. 2018; Mohammadzadeh A et al. Int Immunopharmacol. 2014; Lopatina T et al. Cell Commun Signal. 2014; Ren L et al. BBRC. 2019; Bai Y et al. BBRC. 2018.

• Cao M, Zhao Y, Chen T, et al. Adipose mesenchymal stem cell-derived exosomal microRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances. Biomaterials. 2022;288:121739. doi:10.1016/j.biomaterials.2022.121739

• Zhao Y, Tao M, Wei M, et al. Mesenchymal stem cells derived exosomal miR-323-3p promotes proliferation and inhibits apoptosis of cumulus cells in polycystic ovary syndrome (PCOS). Artif Cells Nanomed Biotechnol. 2019;47(1):3804–13. doi:10.1080/21691401.2019.1669619

• Zhao Y, Pan S, Wu X. Human umbilical cord mesenchymal stem cell-derived exosomes inhibit ovarian granulosa cells inflammatory response through inhibition of NF-κB signaling in polycystic ovary syndrome. J Reprod Immunol. 2022;152:103638. doi:10.1016/j.jri.2022.103638

• Abd-elwahab S-e, Khamis NH, Rifaai RA, et al. Mesenchymal-stem cell-derived conditioned media versus exosomes in the treatment of rat model of polycystic ovary: Microsc Microanal. 2023;29(3):1244–57. doi:10.1093/micmic/ozad046

• Jafarzadeh H, Nazarian H, Ghaffari Novin M, et al. Improvement of oocyte in vitro maturation from mice with polycystic ovary syndrome by human mesenchymal stromal cell-conditioned media. J Cell Biochem. 2018;119(12):10365–75. doi:10.1002/jcb.27380

• Hu J, Tang T, Zeng Z, et al. The expression of small RNAs in exosomes of follicular fluid altered in human polycystic ovarian syndrome. PeerJ. 2020;8:e8640. doi:10.7717/peerj.8640

• Sang Q, Yao Z, Wang H, et al. Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with PCOS in vivo. J Clin Endocrinol Metab. 2013;98(7):3068–79. doi:10.1210/jc.2013-1715

• Tian-Min Y, Suxia L, Shufang D, et al. Combined transcriptomic and metabolomic analysis of women with polycystic ovary syndrome. Dis Markers. 2022;2022:4000424. doi:10.1155/2022/4000424

• Zhang F, Li S-P, Zhang T, et al. High throughput microRNAs sequencing profile of serum exosomes in women with and without polycystic ovarian syndrome. PeerJ. 2021;9:e10998. doi:10.7717/peerj.10998

• Li H, Huang X, Chang X, et al. S100-A9 protein in exosomes derived from follicular fluid promotes inflammation via activation of NF-κB pathway in PCOS. J Cell Mol Med. 2020;24(1):114–25. doi:10.1111/jcmm.14642

• Che X, Jian F, Chen C, et al. PCOS serum-derived exosomal miR-27a-5p stimulates endometrial cancer cells migration and invasion. J Mol Endocrinol. 2020;64(1):1–12. doi:10.1530/JME-19-0159

Full reference list and DOIs are available in the original review (Hadidi et al., Frontiers in Endocrinology, 2023). Readers seeking specific study details, figures, or datasets may consult that review for the complete citation list.

Practical takeaways for people interested in stem cell banking and regenerative care

• Consider the type and source of cells to bank: umbilical cord tissue, cord blood, and adipose tissue are common MSC-containing sources. Early collection (e.g., at birth) preserves younger cells that may be more potent.
• If MSC/exosome therapies for reproductive conditions reach clinical approval, banked cells could be used to make personalized exosomes or MSC products.
• Banking does not guarantee future treatment, but it preserves options. Talk with a reputable stem cell bank and your healthcare provider about protocols, quality standards, and regulatory context.
• Stay informed: human clinical trials are required to confirm safety and efficacy of MSC/exosome therapies in PCOS and related metabolic/reproductive disorders.

Citation for this summarized and simplified educational article: Hadidi M, Karimabadi K, Ghanbari E, Rezakhani L, Khazaei M. Stem cells and exosomes: as biological agents in the diagnosis and treatment of polycystic ovary syndrome (PCOS). Front Endocrinol. 2023;14:1269266. doi:10.3389/fendo.2023.1269266

(For the full academic review, figures, and complete reference list consult the original Frontiers in Endocrinology article.)