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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 55-62

Clinical application potential of umbilical cord mesenchymal stem cells in chemotherapeutic ovarian failure

1 Department of Gynecological Endocrinology, The Fourth Hospital of Shijiazhuang, Shijiazhuang 050000, China
2 2Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
3 Department of Neonatology, The Fourth Hospital of Shijiazhuang, Shijiazhuang 050000, China

Date of Submission15-Oct-2020
Date of Decision07-Jan-2021
Date of Acceptance09-Mar-2021
Date of Web Publication16-Apr-2021

Correspondence Address:
Xue-Lei Ding
Department of Gynecological Endocrinology, The Fourth Hospital of Shijiazhuang, 206 Zhongshan East Road, Shijiazhuang 050000
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.313685

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Chemotherapy is often used for female malignancies, but it can increase the risk of premature ovarian failure in women of reproductive age through different mechanisms. Therefore, how to protect ovarian function and preserve fertility has attracted great attention of oncologists and gynecologists. Recently, umbilical cord mesenchymal stem cells (UCMSCs) have been extensively studied in the field of regenerative medicine. Compared with mesenchymal stem cells (MSCs) from other sources, UCMSCs have a broader application potential due to their properties of lower immunogenicity, fewer ethical issues, and non-invasive collection. Paracrine is one of the most important therapeutic mechanisms of UCMSCs, which can exert anti-inflammatory, anti-fibrosis, anti-oxidative stress, immune regulation, and other therapeutic effects. Studies in animal models have shown that UCMSCs can restore ovarian function after chemotherapy injury. However, most of the relevant researches are still in the preclinical stage. In this article, the mechanism of chemotherapy-induced ovarian failure will be overviewed, and the clinical application potential of UCMSCs in chemotherapeutic ovarian injury will be discussed.

Keywords: Chemotherapy; Fertility; Paracrine; Premature Ovarian Failure; Umbilical Cord Mesenchymal Stem Cells

How to cite this article:
Fu ZJ, Li XD, Wei DW, Ding XL. Clinical application potential of umbilical cord mesenchymal stem cells in chemotherapeutic ovarian failure. Reprod Dev Med 2021;5:55-62

How to cite this URL:
Fu ZJ, Li XD, Wei DW, Ding XL. Clinical application potential of umbilical cord mesenchymal stem cells in chemotherapeutic ovarian failure. Reprod Dev Med [serial online] 2021 [cited 2021 Jun 22];5:55-62. Available from: https://www.repdevmed.org/text.asp?2021/5/1/55/313685

  Introduction Top

In recent years, the incidence of female malignant cancer is increasing and the age of onset tends to be younger. By age 39 years, one in 51 women would have been diagnosed with cancer.[1] As survival rates from chemotherapy for malignant cancer or nonmalignant tumors are continuously improving, young women who received chemotherapy may have a longer life span. As a result, they may face reduced ovarian function, fertility and quality of life in the future. Therefore, to explore effective and feasible approaches to preserve fertility and ovarian function has become the focus of attention. Since different chemotherapeutic drugs act through a range of mechanisms, the ideal treatment would be to partially target these different mechanisms to protect against ovarian damage. Umbilical cord mesenchymal stem cells (UCMSCs) have shown great potential and availability in animal and human research for the treatment of a variety of diseases. With the advantages of lower oncogenicity and faster self-renewal ability, they have been proven to repair tissue damage through a variety of mechanisms such as angiogenesis, anti-inflammation, immunoregulation, and anti-apoptosis.

  Chemotherapeutic Damage on Ovarian Function Top

Chemotherapeutic ovarian damage eventually leads to decreased ovarian reserve, infertility, and even premature ovarian failure (POF). The extent of damage generally depends on drug dosage, patient age, ovarian reserve, therapy duration, and most importantly, the type of chemotherapy drugs.

The most ovarian-toxic chemotherapy drugs are the alkylating agents (cyclophosphamide [CTX], busulphan, and dacarbazine), which are often utilized effectively in combined chemotherapy protocols.[2] A study examined the pathology of ovarian tissue harvested for cryopreservation in 17 patients who had previously exposed to no-sterilizing chemotherapy treatment, 10 of them alkylating agents being used.[3] The result showed that ovarian cortical stromal blood vessel injury and focal fibrosis of the ovarian cortex can be seen in tissue samples, which might result in the loss of primordial follicles.

CTX, commonly used in the treatment of malignant tumors such as Hodgkin's disease and breast cancer,[4],[5] has a detrimental effect on female reproductive organs. It can create DNA cross-links, which in turn cause DNA breaks and ultimately trigger cell apoptosis. In addition to decreased sex hormone levels and ultrastructure changes in granulosa cells (GCs), it also causes imbalance of pro-apoptotic protein and anti-apoptotic protein in rat model.[6] CTX induces primordial follicle loss and accelerates growing follicle apoptosis mediated by the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in female mice.[7],[8] Another study reported that CTX, used to establish rat models of primary ovarian insufficiency (POI), not only caused follicular atresia and GCs apoptosis, but also induced ovarian inflammation by increasing pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and decreasing vascular endothelial growth factor (VEGF) levels.[9] VEGF is also a multifunctional cytokine that promotes neovascularization and inhibits both apoptosis and fibrosis.[10] Morarji et al. showed that the average serum AMH in young breast cancer survivors dropped to the same level as in a normal population 12 years older, 96% of whom received a CTX-containing regimen in previous chemotherapy treatment.[11]

Platinum-based chemotherapy drugs (including carboplatin and cisplatin [CP]), with doxorubicin (DOX), have moderate damage to the ovarian function. CP is a DNA cross-linking anticancer medication commonly used in the treatment of sarcomas and germ cell tumors. It is known to intercalate with DNA strands causing cross-links and adduct formation,[12] while inhibit cell growth and induce apoptosis in human ovarian stromal cells through mitochondrial pathway activation.[13] The CP-DNA adducts inhibit DNA replication and produce excessive free radicals, leading to increased oxidative stress.[14] It is reported that CP caused toxicity through the activation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in ovarian tissues.[15] However, the precise mechanism of its action remains elusive. For reproductive age, CP-induced gonadotoxicity causes primordial follicles loss by apoptosis, leading to the decrease of the ovarian reserve, menstrual cycle changes, and consequent POF.[16],[17]

DOX is widely used in the treatment of malignant tumors such as breast, ovarian, and endometrial cancers as well as lymphomas, acute leukemias. It causes double-strand-DNA-breaks in primordial follicles of human ovarian cortical tissue, oocytes and GCs isolated from DOX-treated mice in a dose-dependent fashion inducing apoptotic death of ovarian follicle as well as damage on microvascular and ovarian stroma.[18] It also increases generation of reactive oxygen species (ROS) and decreases mitochondrial membrane potential in GCs, which leads to increased oxidative stress.[19],[20] Molecular action mechanism of DOX still needs to be elucidated.

5-Fluorouracil (5FU) and methotrexate (MTX) are anti-metabolic chemotherapy drugs that target the S phase of the cell cycle, inhibit DNA synthesis, and cause relatively lower damage on ovarian function. Stringer et al. used mouse models to assess the cumulative effect of 5FU treatments three times per week on the ovary. They found that multidose 5FU treatments resulted in progressive atresia of growing follicles and a significant decrease in ovarian volume, while the number of primordial follicles was not affected.[21] This indicated that 5FU was unlikely to cause permanent infertility when used in women of pre or reproductive age. Clinical reports also showed lower amenorrhea rates in women treated with anti-metabolic drugs compared with that of those receiving alkylating agents or platinum chemotherapy.[22]

MTX is an effective chemotherapeutic agent that acts as a folic acid antagonist targeting actively proliferating cells. However, several studies have shown that MTX treatment for ectopic gestation (EP) did not adversely affect ovarian reserve and future fertility.[23],[24],[25],[26] Ohannessian et al. evaluated whether previous MTX treatment for EP affected ovarian responsiveness in in vitro fertilization cycles. They found that the mean number of oocytes retrieved during the cycles, basal plasma FSH level, and the duration of stimulation before and after the MTX treatment did not differ significantly.[27]

  Application of Umbilical Cord Mesenchymal Stem Cells in Chemotherapeutic Premature Ovarian Failure Top

How to effectively preserve the reproductive function of ovaries and restore fertility is the key to the treatment of chemotherapeutic POF. Currently, the treatment methods mainly include hormone replacement therapy, embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, in vitro maturation, and hormonal ovarian suppression. However, to date, there has been no widely used and effective cure for chemotherapy-induced POF.

In recent years, MSCs have drawn much attention in the field of regenerative medicine due to their proliferation and differentiation potential as well as their immunomodulatory and anti-inflammatory ability.[28] Many preclinical studies using stem cell therapy for POF have been conducted. As multipotent stem cells,[29] they can be derived from bone marrow, adipose tissue, umbilical cord blood, Wharton's jelly, peripheral blood, and other tissues,[30] while can differentiate into a variety of cell types such as osteocytes, chondrocytes, adipocytes, cardiac cells, neuronal cells, and germ cells.[31],[32] Among them, bone marrow (BM) is previously considered as the preferred source of MSCs. However, the quantity and differentiation ability of bone marrow-derived MSCs (BMSCs) significantly decreases with age, and the harvesting process of them is painfully invasive. In contrast, human umbilical cord tissue is a novel source of MSCs with easy access, no invasive process, and no risk for the donor.[33]

Umbilical cord mesenchymal stem cells

UCMSCs can be obtained from four sources: human Wharton's jelly of umbilical cord, human umbilical cord blood, human umbilical cord blood vessels, and human umbilical cord amnion.[34],[35],[36] Among them, Wharton's jelly is the most commonly used to harvest UCMSCs with better osteogenic and adipogenic differentiation potentials than other sources.[33] UCMSCs have lower immunogenicity, fewer ethical issues, high safety, abundance, and shorter amplification times, which make them better for clinical use.[37],[38] They have the ability to differentiate into multiple cell lineages such as neural progenitors, cardiomyocytes, skeletal myocytes, hepatocytes, osteoblasts, adipocytes, and chondrocytes.[39],[40] Furthermore, UCMSCs do not express the major histocompatibility complex (MHC-II) or co-stimulatory ligands such as CD40, CD80, and CD86, but instead produce MHC-I.[41] This may have contributed to their immunomodulatory ability and immune tolerance making them a better choice for transplantation without immunological rejection.[42],[43],[44] All these attractive advantages give UCMSCs a broader application prospect. Many studies have explored UCMSCs' effects on various diseases, such as acute lung injury, insulin resistance, and Alzheimer's disease.[45],[46],[47] In addition, preclinical trials using UCMSCs to restore chemotherapy-damaged ovarian function through different mechanisms have shown encouraging signs, among which CTX-induced POF models being the most studied [Table 1].
Table 1: Umbilical cord mesenchymal stem cells and paracrine action

Click here to view

Jalalie et al. were the first to report the quantitative distribution of MSCs in different regions of ovarian tissue in the POF mice models. They transplanted CM-Dil-labeled human umbilical cord vein MSCs (hUCV-MSCs) into the ovarian tissue injured by CTX, and found that the distribution of the transplanted hUCV-MSCs in medulla was greater than that in cortex and germinal epithelium.[56] Song et al. reported that UCMSCs transplanted into CTX-induced POF rat models improved the disturbed endocrine secretion system by decreasing serum FSH level and recovering serum E2 level. They also reduced ovarian cell apoptosis and improved the folliculogenesis.[48]

As mentioned above, busulfan is an alkylating antineoplastic agent that has been in use since the 1950s. The FDA approved indication for busulfan is for use with CTX as part of the regimen before allogeneic hematopoietic progenitor cell transplantation, specifically for patients with chronic myelogenous leukemia. Heme oxygenase-1 (HO-1) is expressed in most cells and has potent anti-inflammatory, antioxidant, and immunomodulatory properties.[57] Yin et al. investigated the mechanisms of HO-1 expressed in UCMSCs to restore the ovarian function and discovered that it could help recover the ovarian function of POF mice models induced by CTX and busulfan through activating the c-Jun N-terminal kinase/B cell lymphoma 2 protein (JNK/Bcl-2) signal pathway-regulated autophagy and upregulating the circulating of CD8+CD28T. They also found that HO-1 expressed in UCMSCs increased GCs' viability and decreased their apoptosis overtime in in vitro co-culture experiments.[49]

Shen et al. compared placebo (model group), hUCMSCs transplantation (hUCMSC group), an oestradiol valerate solution and a medroxyprogesterone acetate solution injection (positive control group) in the treatment of POF mouse model induced by CTX. They found that compared with the model group, the hUCMSC groups experienced a decrease in ovarian weight followed by a gradual increase, a slight increase in oestradiol and a decrease in follicle-stimulating hormone, as well as an improvement in ovarian tissue apoptosis.[58]

Paclitaxel, a chemotherapeutic agent, is routinely administered for the treatment of various solid organ malignancies. Elfayomy et al. concluded that human umbilical cord blood-MSCs could repair ovarian injury induced by paclitaxel injection by regulating tissue expression of cytokeratin 8/18, transforming growth factor-β (TGF-β) and proliferating cell nuclear antigen, which were crucial in regulating folliculogenesis and suppressing caspase-3-induced apoptosis.[50]

Ovarian tissue fibrosis is a basic pathological change of POI. The TGF-β1 signaling pathway mediated by Smad protein plays an important role in the development of tissue fibrosis, which has been shown to be involved in fibrosis of many organs in recent studies.[59],[60] TGF-β1 causes fibroblasts in the stroma to transform into myofibroblast. Myofibroblast can synthesize and secrete extracellular matrix, which may lead to organ fibrosis when there is too much extracellular matrix. Cui et al. revealed that the TGF-β1/Smad3 signaling pathway was involved in the inhibition of ovarian tissue fibrosis, which contributed to the restoration of ovarian function in CP-induced POI rats following UCMSCs transplantation.[51]

Paracrine action of umbilical cord mesenchymal stem cells

Preclinical studies have shown that UCMSCs play a therapeutic role mainly through paracrine, cell replacement and cell to cell contact.[61] Paracrine action is one of the key mechanisms of MSC-induced therapeutic effects.

UCMSCs can secrete a variety of bioactive molecules with specific physiological functions such as IL, TNF, interferon, colony stimulating factor (CSF), growth factor, and chemokines.[62] These cytokines may be involved in several repair mechanisms of UCMSCs including anti-apoptosis, anti-inflammation, pro-angiogenesis, migration, and homing. Many studies have demonstrated that UCMSCs could repair damaged ovarian function by secreting cytokines and other factors associated with the growth and development of tissues.[48],[63],[64] Research revealed that UCMSCs reduced the apoptosis of GCs and restore ovarian function in POF mouse model, while no differentiation of UCMSCs into follicle components had been observed, and they were more likely to play a repair role through paracrine action.[65]

Extracellular vesicles

In recent years, extracellular vesicles (EVs) derived from MSCs have become an intense study subject of paracrine function, which are important in several vital cellular processes including cell-to-cell communication and immune response modulation. They can be broadly classified into three main groups: exosomes, microvesicles (MVs)/ectosomes, and apoptotic bodies.[66] EVs contain a variety of molecules including proteins (cytokines, receptors, or their ligands), DNA, mRNA, miRNA, and lipids. The mechanisms by which they repair tissues have been studied in a variety of diseases.

The latest study showed that UCMSCs-derived EVS(UCMSCs-EVs) could be absorbed by CP-damaged GCs of rats. They can increase the number of living cells, and play an important role in promoting resistance to CP-induced GCs apoptosis as well as restoring synthesis and secretion of steroid hormone in GCs. This study provided a theoretical basis for the use of MSC-derived EVs as a cell-free therapeutic strategy for POI/POF patients.[67]

Exosomes and microvesicles

Exosomes, as a kind of EVs, ranging approximately from 40 to 100 nm, are released by multi-vesicular bodies while fusing with the plasma membrane. Containing CD9, CD63, CD81 protein markers,[66] they have been described as a new mechanism for the paracrine effects of MSCs and studied separately from EVs. MVs are formed by external budding of the cell membrane with a diameter of 100–1000 nm. Carried with a large number of proteins, lipids and mRNAs, they can interact with the receptor cells through specific receptor-ligands. Several studies have shown that exosomes derived from MSCs have positive effects on cell proliferation, tissue repairment, anti-inflammation, and inhibition of apoptosis.[68],[69]

According to Sun et al., the use of UCMSCs-derived exosomes (UCMSCs-Ex) can ameliorate CP-induced oxidative stress and apoptosis in ovarian GCs by down-regulating the expression of pro-apoptotic Bcl-2-associated X protein (Bax), cleaved poly-ADP-ribose polymerase (PARP) and cleaved caspase-3, as well as increasing the expression of anti-apoptotic protein Bcl-2 and caspase-3.[52]

miRNA-17-5P (miR-17-5P) is a key regulator of the G1/S phase cell cycle transition.[70] Sirtuins, divided into 7 classes (SIRT1 to SIRT7), can regulate cell metabolism and oxidative stress.[71] Among them, SIRT7 deficiency can suppress apoptosis in various kinds of cells. The latest findings revealed that, UCMSCs-Ex suppressed ROS accumulation, inhibited CTX-induced apoptosis of human GCs and rescued ovarian function in a POI mouse model through downregulating the expression of SIRT7 and its downstream target genes by activating miR-17-5P.[53]

In a recent study, UCMSC-MVs were used to treat chemotherapy-induced POI mice models induced by busulfan and CTX. The results showed that UCMSC-MVs transplantation improved estrous cycle of POI mice, increased the body weight and ovarian follicles, promoted the formation of new blood vessels and induced cytokine expression (VEGF, IGF-1, and angiogenin) in the ovaries of POI mice. In addition, UCMSC-MVs might repair ovarian function by activating the PI3K-Akt signaling pathway.[54]

Human UCMSC-derived conditioned medium (UCMSC-CM) contains the secretome, microvesicles, and exosome that can promote tissue/organ repair under various conditions. The granulocyte CSF (G-CSF) is glycoprotein produced by many different cell types and has a wide range of physiological functions. It attenuates oxidative stress-induced cell apoptosis through the PI3K/Akt pathway.[72] In the latest study, UCMSC-CM could relieve CP-induced depletion of follicles and preserve fertility on a CP-induced ovarian injury model. In addition, UCMSC-CM can upregulate G-CSF expression in GCs and decrease GC apoptosis induced by CP through PI3K/Akt pathway.[55]

Clinical application potential of umbilical cord mesenchymal stem cells for chemotherapeutic premature ovarian failure

Study from Ding et al. showed that primordial follicle can be activated by collagen/UCMSCs through phosphorylation of FOXO3a and FOXO1 in mice. After co-culture with collagen/UCMSCs, it was activated into preovulatory stage in vivo. This study was also the first to use UCMSCs in POF patients, while 2 of the 14 patients successfully conceived after accepting collagen/UCMSCs or UCMSCs transplantation.[73] However, none of the patients had previously received chemotherapy or radiotherapy. In a recent study, Yan et al. assessed the clinical outcomes of POI women (n = 61) who were treated with intraovarian injections of UCMSCs (1 to 3 times). All patients received the standard hormone replacement regimen of estradiol throughout the UCMSCs treatment. After stem cells injection, different stages of follicles (antral follicle counts, dominant follicles counts, and matured follicle counts) were found to grow in the ovaries together with elevated AMH levels. Four patients successfully conceived after in vitro fertilization and embryo transfer, and the babies all developed normally.[74]

Current data from ClinicalTrials.gov indicate that there are eleven clinical trials on MSCs therapy for POI/POF patients worldwide. Four of the eleven studies involve UCMSCs transplantation. However, the studies' inclusion and exclusion criteria do not explicitly describe the chemotherapy history. It can be seen that clinical trials on UCMSCs' transplantation in POI/POF patients are still in progress, and the efficacy of UCMSCs in treating chemotherapy-induced POI/POF remains to be further studied.

Problems and prospects

Considering the clinical application of UCMSCs, several concerns remain to be addressed.

First, it is uncertain whether high doses of UCMSCs cause serious adverse effects such as malignant transformation. In the 2,000 s, it was reported that MSCs could spontaneously transform into malignancies and form tumors in vivo. However, these initial reports were later retracted as it turned out that the tumor formation observed was the result of cross-contamination with cancer cells.[75],[76],[77],[78],[79] Although there have been no reports of MSC-related tumors forming in human patients, it cannot be ruled out that there is still the risk of tumors formation after treatment with MSCs. Another issue with MSCs is their potential to promote metastasis development. MSCs' ability to home into the cancer microenvironment is a part of normal repair function, where MSCs are recruited by sites of tissue injury and inflammation. MSCs with their immunosuppressive properties in the tumor microenvironment can be influenced by tumor cells, and in return to regulate the growth, expansion, and metastasis of tumor cells through their paracrine activities and the secretion of various trophic factors.[80],[81],[82] Coffman et al. demonstrated that Hedgehog (HH) secreted by ovarian tumor cells derived the expression of CA-MSCs BMP4, which in turn increased the production of HH by ovarian tumor cells, which was associated with enhanced chemoresistance and decreased survival. This feedback loop promoted chemotherapy resistance both in vitro and in vivo.[83] MSCs can also promote ovarian cancer growth by impacting host cells in the tumor microenvironment by increasing angiogenesis and inhibiting the anti-tumor immune response.[84],[85] Zhou et al. treated the MDA-MB-231 and MCF-7 human breast cancer cell lines cells with medium containing UCMSCs-EVs, while the results revealed that UCMSCs-EVs significantly enhanced the proliferation, migration, and invasion of the cells in vitro through the induction of the epithelial-mesenchymal transition through the extracellular signal-regulated kinase pathway.[86] On the contrary, there have been reports describing a reduction in tumor growth after treatment with MSCs. Gauthaman et al. compared the effects of human Wharton's jelly stem cell (hWJSC) extracts (CM and cell lysate) on breast adenocarcinoma, ovarian carcinoma, and osteosarcoma cells. They found that hWJSC had tumor suppressive effects on all three cell lines, in which upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl-2 and SURVIVIN genes were observed.[87] MSCs have also been demonstrated to inhibit tumor progression in diseases such as glioblastoma and leukemia/lymphoma.[88],[89] UCMSC-CM can eliminate the potential side effects of MSCs on tumor cells, such as differentiation into other stromal cell types, metastasis induction, and stimulation of epithelial-mesenchymal transformation of tumor cells.[55] The safety of using MSCs in the field of cancer is worthy of attention due to their contributory role in tumor growth and inhibition.

Second, UCMSCs or UCMSCS-EVs transplantation can be performed two ways, namely locally injected into the ovarian tissue or into the blood circulation. Zhu et al. also applied UCMSCs in CTX-induced ovarian injury rat models, and compared the two methods of UCMSCs transplanting by intravenous injection and in situ ovarian injection as well as their effects on the damaged ovarian function.[64] They found that long-term effects of the two methods on ovarian function were similar by evaluating the hormone levels, estrous cycles, and reproductive performance. Intravenous injection might be a preferred method with less invasiveness and shorter recovery time. However, all the individuals included in recent clinical studies received intraovarian injections of UCMSCs and showed no serious side effects or complications relevant to the treatment.[73],[74]

On the whole, more work on the efficiency and safety of UCMSCs in clinical application needs to be done in the future work. Some technical issues, such as the dose of cell transplantation, the selection of time window of cell transplantation, the duration of curative effect, the injection rate, and the frequency of transplantation remain to be solved.

Chemotherapy cause ovarian failure in reproductive age women and its mechanisms may range from ovarian stromal fibrosis, vascular damage, oxidative stress injury, inflammation reaction, and cell apoptosis to follicular atresia. Systematic review showed that both BMSCs and UCMSCs have better ability to restore fertility than other MSCs,[90] whereas, UCMSCs may have a broader application prospect due to the properties of lower immunogenicity, fewer ethical issues, and higher safety. EVs, including exosomes, as part of paracrine action, play a repair role against the injury mechanisms mentioned above, which have been demonstrated in several studies. Furthermore, as a cell-free therapy, there might be less concern about immune rejection. Although their effects on animal models of chemotherapy-induced POF have been studied, their clinical application in the treatment of chemotherapeutic ovarian injury has not been fully studied. Nevertheless, ongoing research and promising results led us to confirm their efficacy in the repair of ovarian injury.

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Conflicts of interest

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