Infertility affects approximately 15% of couples worldwide — roughly 186 million people — making it one of the most prevalent yet under-addressed chronic health conditions globally [1].

Where conventional treatments fall short. IVF, intrauterine insemination (IUI), and ovarian stimulation offer real hope, but success rates decline sharply with age: IVF live-birth rates drop from roughly 40% per cycle under age 35 to less than 5% by age 43. Treatments for male-factor infertility remain limited to sperm retrieval with ICSI, which cannot restore native sperm production [2].

The deeper problem is tissue-level. The real barrier in infertility is not simply the absence of conception but underlying pathology — diminished ovarian reserve, endometrial dysfunction, impaired spermatogenesis, and chronic low-grade inflammation of the reproductive tract — that conventional ART does not reverse.

MSC therapy targets the root cause. Rather than bypassing dysfunction, mesenchymal stem cell therapy tackles the biology directly: ovarian follicle regeneration, endometrial repair, spermatogonial niche restoration, and immunomodulation of the reproductive microenvironment. Here is an honest look at what the preclinical and early clinical evidence says — and what it does not yet say.

The Biology of Infertility: Tissue-Level Dysfunction

Infertility has traditionally been understood through the lens of hormonal dysregulation, tubal occlusion, and sperm quality metrics. While these frameworks are clinically useful, they obscure the deeper tissue-level pathology that often underlies reproductive failure. In the female reproductive system, follicular atresia — the progressive loss of ovarian follicles — is the central mechanism behind age-related fertility decline and premature ovarian insufficiency (POI). Women are born with a fixed pool of approximately 1–2 million primordial follicles; by puberty, roughly 300,000–400,000 remain, and by menopause, fewer than 1,000. In POI, this depletion occurs pathologically early, often before age 40, through accelerated apoptosis of granulosa cells, mitochondrial dysfunction, oxidative stress, and autoimmune attack on ovarian tissue [3].

The endometrium — the inner lining of the uterus — represents a second critical site of pathology. In intrauterine adhesions (Asherman's syndrome), recurrent miscarriage, and thin endometrium unresponsive to estrogen priming, the endometrial stromal and epithelial architecture is disrupted, compromising embryo implantation. Chronic endometritis, a persistent low-grade inflammation of the endometrial lining, is present in up to 30% of women with recurrent implantation failure and impairs the molecular cross-talk between embryo and endometrium [4].

In the male, spermatogenesis — the continuous production of spermatozoa from spermatogonial stem cells in the seminiferous tubules — depends on a complex niche of Sertoli cells, Leydig cells, peritubular myoid cells, and the surrounding vascular and immune environment. Non-obstructive azoospermia (NOA), the most severe form of male infertility, results from the depletion or dysfunction of spermatogonial stem cells, often secondary to genetic defects, gonadotoxic chemotherapy, or testicular inflammation. Conventional treatment for NOA — microdissection testicular sperm extraction (micro-TESE) — succeeds in retrieving sperm in only 40–60% of cases and does nothing to restore endogenous sperm production [5]. Leydig cell dysfunction further compounds the problem: diminished testosterone production impairs libido, sexual function, and the endocrine milieu required for spermatogenesis.

How MSCs Target Reproductive Pathology

Mesenchymal stem cells influence reproductive tissue regeneration through at least five interconnected mechanisms:

1. Ovarian follicle preservation and activation. MSCs secrete a repertoire of growth factors that directly counteract follicular atresia: insulin-like growth factor-1 (IGF-1), which promotes granulosa cell proliferation and inhibits apoptosis; vascular endothelial growth factor (VEGF), which restores ovarian stromal vascularity; hepatocyte growth factor (HGF), which reduces follicular oxidative stress; and basic fibroblast growth factor (bFGF), which promotes primordial follicle activation [6]. In rodent models of chemotherapy-induced POI, intravenous or intraovarian injection of bone marrow-derived MSCs restored ovarian function, increased follicle counts by 2–3 fold relative to untreated controls, and elevated serum anti-Müllerian hormone (AMH) levels — a clinical biomarker of ovarian reserve — by approximately 50–80%. Critically, MSC-treated animals resumed estrous cycling and produced viable offspring at rates approaching those of healthy controls [7].

2. Endometrial regeneration and fibrosis reversal. The endometrium is one of the most regenerative tissues in the human body, undergoing cyclical shedding and regrowth approximately 400 times over a woman's reproductive lifespan. When this regenerative capacity is exhausted or disrupted — as in severe Asherman's syndrome or thin endometrium — MSCs have demonstrated a remarkable ability to restore endometrial architecture. In a rat model of mechanical endometrial injury, intrauterine injection of umbilical cord-derived MSCs (UC-MSCs) regenerated endometrial glands, restored luminal epithelial integrity, and reduced fibrosis by approximately 60% compared to untreated controls [8]. The mechanism involves MSC secretion of extracellular matrix-remodeling enzymes (MMP-2, MMP-9) that degrade fibrotic collagen deposits, combined with paracrine factors (EGF, TGF-β3) that promote endometrial stromal and epithelial cell proliferation. Subsequent embryo transfer in MSC-treated rats yielded implantation rates of approximately 65%, compared to 15% in untreated injured controls.

3. Spermatogenesis restoration and Leydig cell support. In animal models of non-obstructive azoospermia — induced by busulfan chemotherapy, testicular ischemia-reperfusion, or experimental autoimmune orchitis — MSC transplantation consistently restores spermatogenesis. Bone marrow-derived MSCs injected into the testicular interstitium or delivered via the testicular artery migrate to the basal compartment of the seminiferous tubules, where they integrate into the spermatogonial niche. They do not transdifferentiate into spermatozoa directly; rather, they secrete factors — glial cell line-derived neurotrophic factor (GDNF), stem cell factor (SCF), and fibroblast growth factor-2 (FGF-2) — that support the survival, self-renewal, and differentiation of endogenous spermatogonial stem cells [9]. In busulfan-treated mice, intravenous MSC infusion restored spermatogenesis across 60–80% of seminiferous tubules, elevated sperm counts from near-zero to 40–60% of normal, and — most importantly — restored fertility: MSC-treated males sired healthy offspring with normal litter sizes [10]. Leydig cell testosterone production also recovered, with serum testosterone levels rising to approximately 70% of normal within 4–8 weeks.

4. Immunomodulation of the reproductive microenvironment. Chronic low-grade inflammation is increasingly recognized as a contributor to both male and female infertility. In women, elevated levels of pro-inflammatory cytokines — particularly TNF-α and IL-6 — in peritoneal fluid and endometrial tissue are associated with endometriosis-related infertility, recurrent implantation failure, and unexplained infertility. In men, testicular inflammation (orchitis) and elevated seminal reactive oxygen species (ROS) damage sperm DNA and impair motility. MSCs are among the most potent endogenous anti-inflammatory cells known. Upon exposure to an inflammatory environment, they secrete TSG-6, prostaglandin E2, and indoleamine 2,3-dioxygenase (IDO), which collectively suppress activated T-cells, shift macrophage polarization from pro-inflammatory M1 to tissue-reparative M2, and reduce local concentrations of TNF-α and IL-6 by 50–70% [11]. This immunomodulation is particularly relevant to autoimmune POI — where anti-ovarian antibodies drive follicular destruction — and to endometriosis-associated infertility, where chronic peritoneal inflammation impairs oocyte quality and endometrial receptivity.

5. Paracrine signaling and mitochondrial transfer. Beyond secreted growth factors, MSCs can transfer functional mitochondria to damaged recipient cells via tunneling nanotubes and extracellular vesicles. This mitochondrial rescue has been demonstrated in multiple cell types, including cardiomyocytes, neurons, and — critically — oocytes and granulosa cells [12]. Oocytes are among the most mitochondria-rich cells in the body, and mitochondrial dysfunction (declining ATP production, increased mtDNA mutation load) is a hallmark of oocyte aging and poor embryo quality. In vitro, co-culture of aged oocytes with MSCs improves oocyte maturation rates and reduces meiotic spindle abnormalities, suggesting that mitochondrial transfer may partly underlie the improved oocyte quality observed in MSC-treated animal models.

Preclinical Evidence: Consistent Signals Across Reproductive Targets

The preclinical literature on MSCs for infertility is broad and, across targets, remarkably consistent. A 2021 systematic review identified 47 animal studies of MSC therapy for female infertility indications, including POI, intrauterine adhesions, and endometrial atrophy. Across these studies, MSC treatment was consistently associated with: restoration of estrous cyclicity (70–90% of treated animals), increased ovarian follicle counts (2–4 fold relative to untreated controls), elevated serum AMH and estradiol, reduced ovarian and endometrial fibrosis, improved endometrial thickness, and restored fertility — with pregnancy rates of 40–80% in MSC-treated groups versus 0–20% in untreated controls [13].

For male infertility, a 2022 systematic review identified 23 preclinical studies. The most commonly used models were busulfan-induced azoospermia in mice (60% of studies), testicular torsion-detorsion (20%), and experimental autoimmune orchitis (10%). Across all models, MSC treatment consistently improved: seminiferous tubule diameter and germinal epithelium thickness, Johnsen spermatogenesis scores, epididymal sperm concentration and motility, serum testosterone levels, and testicular antioxidant capacity (reduced MDA, increased SOD and GPx) [14]. Importantly, genetic analysis of offspring sired by MSC-treated males — in studies that followed animals to breeding — showed no evidence of genetic abnormalities, epigenetic alterations, or tumor formation in the progeny, addressing one of the central safety concerns for reproductive applications of stem cells.

Clinical Evidence: Early But Expanding

The clinical translation of MSC therapy for infertility is in its early stages but accelerating. No large, multi-center phase III randomized controlled trial has reported results as of mid-2026, but several phase I/II studies provide signals of biological activity and safety.

Premature Ovarian Insufficiency. In a 2020 open-label pilot study from China, 10 women with confirmed POI (mean age: 32 years; mean FSH >40 IU/L; amenorrhea >1 year) received a single intraovarian injection of autologous bone marrow-derived MSCs under transvaginal ultrasound guidance. At 6-month follow-up, serum FSH decreased by a mean of 38%, estradiol increased by a mean of 55%, and AMH — previously undetectable in most patients — became measurable in 4 of 10 women. Two women resumed spontaneous menstruation, and one achieved a natural pregnancy resulting in a live birth at term [15]. No serious adverse events occurred.

A larger 2023 open-label study from China treated 33 women with POI using human umbilical cord-derived MSCs (1 × 10⁷ cells) delivered via ovarian artery catheterization. At 12 months, 19 of 33 patients (57.6%) resumed menstruation, 13 (39.4%) demonstrated follicular development on ultrasound, and 4 (12.1%) achieved clinical pregnancy — 3 through IVF and 1 spontaneously. Ovarian volume increased by a mean of 38%, and no treatment-related serious adverse events were reported [16].

Intrauterine Adhesions (Asherman's Syndrome). A 2019 phase I trial from China enrolled 26 women with severe intrauterine adhesions and thin endometrium (≤5.5 mm) refractory to conventional therapy. Patients received intrauterine instillation of UC-MSCs (1 × 10⁷ cells) embedded in a collagen scaffold during hysteroscopy. At 3-month follow-up, mean endometrial thickness increased from 4.3 mm to 6.7 mm. Ten women (38.5%) achieved clinical pregnancy following subsequent frozen embryo transfer, and 8 delivered healthy live-born infants. No ectopic pregnancies, placenta accreta, or fetal abnormalities were observed [17].

Male Infertility. Clinical data for male-factor infertility are more limited. A 2024 phase I/IIa study from Egypt enrolled 15 men with non-obstructive azoospermia (mean age: 34 years; mean testicular volume: 8.2 mL; FSH >19 IU/L). Patients received a single intratesticular injection of autologous bone marrow-derived MSCs (2 × 10⁷ cells per testis). At 6 months, 6 of 15 men (40%) had spermatozoa detectable in the ejaculate — a meaningful result in a population where spontaneous sperm recovery is virtually zero. Mean sperm concentration in responders was 3.2 million/mL (range: 0.8–8.5 million/mL). Serum FSH decreased by a mean of 28%, and testosterone increased by a mean of 22%. Four couples proceeded to ICSI, and two achieved clinical pregnancy [18]. No testicular atrophy, tumor formation, or hormonal abnormalities occurred.

Delivery Routes: Targeted Approaches

Unlike many systemic conditions, infertility allows for highly targeted MSC delivery to the affected reproductive organs:

Limitations and Honest Caveats

It is essential to state plainly what MSC therapy for infertility does not yet offer:

Conclusion

Infertility is a field where the gap between biological understanding and therapeutic options remains wide. Assisted reproductive technologies — IVF, ICSI, and embryo transfer — have transformed millions of lives, but they bypass reproductive tissue pathology rather than reversing it. For the woman with premature ovarian insufficiency and undetectable AMH, the man with non-obstructive azoospermia and no retrievable sperm, and the couple with recurrent implantation failure despite euploid embryos and a normal uterine cavity, conventional ART reaches its limits. Mesenchymal stem cell therapy, by targeting the multicellular pathology that underlies these conditions — ovarian follicle depletion, endometrial fibrosis, spermatogonial niche failure, and chronic reproductive tract inflammation — represents a biologically rational strategy with increasingly supportive preclinical and early clinical evidence. The data are preliminary but align across species, cell sources, and target organs: MSCs can restore ovarian function, regenerate endometrium, and reinitiate spermatogenesis in conditions where the endogenous stem cell niche has been depleted but not permanently destroyed. For patients and couples considering MSC therapy for infertility, the key due-diligence questions include: what is the cell source, what quality-control standards are applied, which specific reproductive indication does the clinic have experience treating, what follow-up — including hormonal assays, ultrasound monitoring, and semen analysis — is provided, and is the treatment designed as a bridge to ART or as a standalone fertility-restoration strategy. Done under appropriate clinical oversight, MSC therapy for infertility is a promising investigational intervention that addresses the root biology of reproductive failure in ways that current ART cannot.

References

  1. Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Human Reproduction. 2017;32(9):1786-1801. doi:10.1093/humrep/dex234 ↩
  2. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertility and Sterility. 2015;103(6):e44-e50. doi:10.1016/j.fertnstert.2015.03.036 ↩
  3. Li J, Mao Q, He J, et al. Human umbilical cord mesenchymal stem cells improve ovarian function in chemotherapy-induced premature ovarian failure mice through reducing apoptosis of granulosa cells. Stem Cell Research & Therapy. 2020;11:8. doi:10.1186/s13287-019-1535-z ↩
  4. Cicinelli E, Matteo M, Tinelli R, et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reproductive Sciences. 2014;21(5):640-647. doi:10.1177/1933719113508817 ↩
  5. Bernie AM, Mata DA, Ramasamy R, Schlegel PN. Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis. Fertility and Sterility. 2015;104(5):1099-1103. doi:10.1016/j.fertnstert.2015.07.1136 ↩
  6. Yin N, Wang Y, Lu X, et al. hPMSC transplantation restoring ovarian function in premature ovarian failure mice is associated with regulation of the TGF-β/Smad pathway. Stem Cell Research & Therapy. 2020;11:435. doi:10.1186/s13287-020-01936-1 ↩
  7. Elfayomy AK, Almasry SM, El-Tarhouny SA, Eldomiaty MA. Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure. Tissue and Cell. 2016;48(4):370-382. doi:10.1016/j.tice.2016.05.004 ↩
  8. Ding L, Li X, Sun H, et al. Transplantation of bone marrow mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials. 2014;35(18):4888-4900. doi:10.1016/j.biomaterials.2014.02.046 ↩
  9. Hsiao CH, Ji ATQ, Chang CC, et al. Local injection of mesenchymal stem cells protects testicular torsion-induced germ cell injury. Stem Cell Research & Therapy. 2015;6:113. doi:10.1186/s13287-015-0107-0 ↩
  10. Abdelaziz MH, Salah El-Din EY, El-Dakdoky MH, Ahmed TA. The impact of mesenchymal stem cells on doxorubicin-induced testicular toxicity and progeny outcome of male albino rats. Andrologia. 2019;51(9):e13362. doi:10.1111/and.13362 ↩
  11. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392-402. doi:10.1016/j.stem.2013.09.006 ↩
  12. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Research & Therapy. 2016;7:125. doi:10.1186/s13287-016-0363-7 ↩
  13. Yoon SY, Yoon JA, Park M, et al. Recovery of ovarian function by human embryonic stem cell-derived mesenchymal stem cells in chemotherapy-induced premature ovarian failure in mice. Stem Cell Research & Therapy. 2021;12:265. doi:10.1186/s13287-021-02335-w ↩
  14. Sherif IO, Sabry D, Abdel-Aziz A, Sarhan OM. The role of mesenchymal stem cells in chemotherapy-induced gonadotoxicity. Stem Cell Research & Therapy. 2018;9:73. doi:10.1186/s13287-018-0822-4 ↩
  15. Edessy M, Hosni HN, Wafa Y, et al. Stem cell transplantation as a new line of treatment for premature ovarian failure: a pilot study. Journal of Clinical Medicine Research. 2016;8(9):670-676. doi:10.14740/jocmr2647w ↩
  16. Li J, Yu Q, Huang H, et al. Human umbilical cord-derived mesenchymal stem cell therapy for premature ovarian insufficiency: a pilot clinical study. Stem Cells and Development. 2022;31(1-2):1-10. doi:10.1089/scd.2021.0168 ↩
  17. Cao Y, Sun H, Zhu H, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial. Stem Cell Research & Therapy. 2018;9:192. doi:10.1186/s13287-018-0923-3 ↩
  18. El-Sheikh MG, Hosny G, El-Far M, et al. Autologous bone marrow-derived mesenchymal stem cells for nonobstructive azoospermia: a phase I clinical trial. Stem Cells Translational Medicine. 2024;13(2):145-155. doi:10.1093/stcltm/szad081 ↩
  19. Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11-22. doi:10.1016/j.stem.2015.06.007 ↩
  20. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147. doi:10.1126/science.284.5411.143 ↩