|Year : 2021 | Volume
| Issue : 1 | Page : 55-62
Clinical application potential of umbilical cord mesenchymal stem cells in chemotherapeutic ovarian failure
Zi-Jie Fu1, Xiao-Dong Li2, Da-Wei Wei3, Xue-Lei Ding1
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 Submission||15-Oct-2020|
|Date of Decision||07-Jan-2021|
|Date of Acceptance||09-Mar-2021|
|Date of Web Publication||16-Apr-2021|
Department of Gynecological Endocrinology, The Fourth Hospital of Shijiazhuang, 206 Zhongshan East Road, Shijiazhuang 050000
Source of Support: None, Conflict of Interest: None
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|| |
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. 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|| |
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. 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. 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,, 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. 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., 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. VEGF is also a multifunctional cytokine that promotes neovascularization and inhibits both apoptosis and fibrosis. 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.
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, while inhibit cell growth and induce apoptosis in human ovarian stromal cells through mitochondrial pathway activation. The CP-DNA adducts inhibit DNA replication and produce excessive free radicals, leading to increased oxidative stress. It is reported that CP caused toxicity through the activation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in ovarian tissues. 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.,
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. It also increases generation of reactive oxygen species (ROS) and decreases mitochondrial membrane potential in GCs, which leads to increased oxidative stress., 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. 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.
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.,,, 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.
| Application of Umbilical Cord Mesenchymal Stem Cells in Chemotherapeutic Premature Ovarian Failure|| |
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. Many preclinical studies using stem cell therapy for POF have been conducted. As multipotent stem cells, they can be derived from bone marrow, adipose tissue, umbilical cord blood, Wharton's jelly, peripheral blood, and other tissues, while can differentiate into a variety of cell types such as osteocytes, chondrocytes, adipocytes, cardiac cells, neuronal cells, and germ cells., 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.
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.,, Among them, Wharton's jelly is the most commonly used to harvest UCMSCs with better osteogenic and adipogenic differentiation potentials than other sources. UCMSCs have lower immunogenicity, fewer ethical issues, high safety, abundance, and shorter amplification times, which make them better for clinical use., They have the ability to differentiate into multiple cell lineages such as neural progenitors, cardiomyocytes, skeletal myocytes, hepatocytes, osteoblasts, adipocytes, and chondrocytes., 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. This may have contributed to their immunomodulatory ability and immune tolerance making them a better choice for transplantation without immunological rejection.,, 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.,, 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].
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. 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.
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. 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+CD28−T. They also found that HO-1 expressed in UCMSCs increased GCs' viability and decreased their apoptosis overtime in in vitro co-culture experiments.
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.
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.
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., 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.
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. 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. 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.,, 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.
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. 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.
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, 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.,
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.
miRNA-17-5P (miR-17-5P) is a key regulator of the G1/S phase cell cycle transition. Sirtuins, divided into 7 classes (SIRT1 to SIRT7), can regulate cell metabolism and oxidative stress. 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.
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.
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. 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.
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. 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.
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.,,,, 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.,, 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. 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., 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. 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. MSCs have also been demonstrated to inhibit tumor progression in diseases such as glioblastoma and leukemia/lymphoma., 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. 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. 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.,
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, 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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chung K, Donnez J, Ginsburg E, Meirow D. Emergency IVF versus ovarian tissue cryopreservation: Decision making in fertility preservation for female cancer patients. Fertil Steril 2013;99:1534-42. doi: 10.1016/j.fertnstert.2012.11.057.
Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 2010;53:727-39. doi: 10.1097/GRF.0b013e3181f96b54.
Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, et al
. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod 2007;22:1626-33. doi: 10.1093/humrep/dem027.
Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, et al
. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol 2010;28:77-82. doi: 10.1200/JCO.2009.22.1077.
Karolin B, Horst M, Helen G, Indra T, Angelika Diana E, Volker S, et al
. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 2013;31:231-9. doi: 10.1200/JCO.2012.44.3721.
Zhao XJ, Huang YH, Yu YC, Xin XY. GnRH antagonist cetrorelix inhibits mitochondria-dependent apoptosis triggered by chemotherapy in granulosa cells of rats. Gynecol Oncol 2010;118:69-75. doi: 10.1016/j.ygyno.2010.03.021.
Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: What's the matter? Int J Mol Sci 2016;17:836. doi: 10.3390/ijms17060836.
Zhou L, Xie Y, Li S, Liang Y, Qiu Q, Lin H, et al
. Rapamycin prevents cyclophosphamide-induced over-activation of primordial follicle pool through PI3K/Akt/mTOR signaling pathway in vivo
. J Ovarian Res 2017;10:56. doi: 10.1186/s13048-017-0350-3.
Ling L, Feng X, Wei T, Wang Y, Wang Y, Zhang W, et al
. Effects of low-intensity pulsed ultrasound (LIPUS)-pretreated human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation on primary ovarian insufficiency in rats. Stem Cell Res Ther 2017;8:283. doi: 10.1186/s13287-017-0739-3.
Wang L, Ying YF, Ouyang YL, Wang JF, Xu J. VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model. J Assist Reprod Genet 2013;30:1301-11. doi: 10.1007/s10815-013-0043-9.
Morarji K, McArdle O, Hui K, Gingras-Hill G, Ahmed S, Greenblatt EM, et al
. Ovarian function after chemotherapy in young breast cancer survivors. Curr Oncol 2017;24:e494-502. doi: 10.3747/co.24.3335.
Gonzalez VM, Fuertes MA, Alonso C, Perez JM. Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 2001;59:657-63. doi: 10.1124/mol.59.4.657.
Fabbri R, Macciocca M, Vicenti R, Paradisi R, Klinger FG, Pasquinelli G, et al
. Doxorubicin and cisplatin induce apoptosis in ovarian stromal cells obtained from cryopreserved human ovarian tissue. Future Oncol 2016;12:1699-711. doi: 10.2217/fon-2016-0032.
Li X, Yang S, Lv X, Sun H, Weng J, Liang Y, et al
. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats. J Gynecol Oncol 2013;24:177-85. doi: 10.3802/jgo. 2013.24.2.177.
Kaygusuzoglu E, Caglayan C, Kandemir FM, Yıldırım S, Kucukler S, Kılınc MA, et al
. Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacother 2018;102:517-30. doi: 10.1016/j.biopha.2018.03.119.
Tangir J, Zelterman D, Ma W, Schwartz PE. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol 2003;101:251-7. doi: 10.1016/s0029-7844(02)02508-5.
Meirow D. Reproduction post-chemotherapy in young cancer patients. Mol Cell Endocrinol 2000;169:123-31. doi: 10.1016/s0303-7207(00)00365-8.
Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: Double strand DNA breaks and microvascular compromise. Aging (Albany NY) 2011;3:782-93. doi: 10.18632/aging.100363.
Nishi K, Gunasekaran VP, Arunachalam J, Ganeshan M. Doxorubicin-induced female reproductive toxicity: An assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats. Drug Chem Toxicol 2018;41:72-81. doi: 10.1080/01480545.2017.1307851.
Zhang T, He WH, Feng LL, Huang HG. Effect of doxorubicin-induced ovarian toxicity on mouse ovarian granulosa cells. Regul Toxicol Pharmacol 2017;86:1-10. doi: 10.1016/j.yrtph.2017.02.012.
Stringer JM, Swindells EOK, Zerafa N, Liew SH, Hutt KJ. Multidose 5-fluorouracil is highly toxic to growing ovarian follicles in mice. Toxicol Sci 2018;166:97-107. doi: 10.1093/toxsci/kfy189.
Yuksel A, Bildik G, Senbabaoglu F, Akin N, Arvas M, Unal F, et al
. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Hum Reprod 2015;30:2926-35. doi: 10.1093/humrep/dev256.
Ibrahim U, Onur Umut Y, Cenk G, Ibrahim G, Buket K, Merih HH, et al
. Effect of single-dose methotrexate on ovarian reserve in women with ectopic pregnancy. Fertil Steril 2013;100:1310-3. doi: 10.1016/j.fertnstert.2013.06.040.
Hill MJ, Cooper JC, Levy G, Alford C, Richter KS, DeCherney AH, et al
. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril 2014;101:413-9. doi: 10.1016/j.fertnstert.2013.10.027.
Sahin C, Taylan E, Akdemir A, Ozgurel B, Taskıran D, Ergenoglu AM. The impact of salpingectomy and single-dose systemic methotrexate treatments on ovarian reserve in ectopic pregnancy. Eur J Obstet Gynecol Reprod Biol 2016;205:150-2. doi: 10.1016/j.ejogrb.2016.08.028.
Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J, et al
. Fertility after ectopic pregnancy: The DEMETER randomized trial. Hum Reprod 2013;28:1247-53. doi: 10.1093/humrep/det037.
Ohannessian A, Loundou A, Courbière B, Cravello L, Agostini A. Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: A systematic review and meta-analysis. Hum Reprod 2014;29:1949-56. doi: 10.1093/humrep/deu174.
Viganò M, Sansone V, d'Agostino MC, Romeo P, Perucca Orfei C, de Girolamo L. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. J Orthop Surg Res 2016;11:163. doi: 10.1186/s13018-016-0496-5.
Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration 2013;85:3-10. doi: 10.1159/000345615.
Augello A, Kurth TB, De Bari C. Mesenchymal stem cells: A perspective from in vitro
cultures to in vivo
migration and niches. Eur Cell Mater 2010;20:121-33. doi: 10.22203/ecm.v020a11.
Fazeli Z, Omrani MD, Ghaderian SM. CD29/CD184 expression analysis provides a signature for identification of neuronal like cells differentiated from PBMSCs. Neurosci Lett 2016;630:189-93. doi: 10.1016/j.neulet.2016.07.056.
Patel DM, Shah J, Srivastava AS. Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int 2013;2013:496218. doi: 10.1155/2013/496218.
Mennan C, Wright K, Bhattacharjee A, Balain B, Richardson J, Roberts S. Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord. Biomed Res Int 2013;2013:916136. doi: 10.1155/2013/916136.
Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2015;109:235-42. doi: 10.1046/j.1365-2141.2000.01986.x.
Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: A source of mesenchymal progenitors. Stem Cells 2005;23:220-9. doi: 10.1634/stemcells. 2004-0166.
Tuca AC, Ertl J, Hingerl K, Pichlsberger M, Fuchs J, Wurzer P, et al
. Comparison of Matrigel and Matriderm as a carrier for human amnion-derived mesenchymal stem cells in wound healing. Placenta 2016;48:99-103. doi: 10.1016/j.placenta.2016.10.015.
Sriramulu S, Banerjee A, Di Liddo R, Jothimani G, Gopinath M, Murugesan R, et al
. Concise review on clinical applications of conditioned medium derived from human umbilical cord-mesenchymal stem cells (UC-MSCs). Int J Hematol Oncol Stem Cell Res 2018;12:230-4.
Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2010;24:1294-301. doi: 10.1634/stemcells. 2005-0342.
Dae-Won K, Meaghan S, Kazutaka S, Paolina P, Sung-Don K, Borlongan CV. Wharton's jelly-derived mesenchymal stem cells: Phenotypic characterization and optimizing their therapeutic potential for clinical applications. Int J Mol Sci 2013;14:11692-712. doi: 10.3390/ijms140611692.
Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, Vanderwerff I, et al
. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells 2010;26:2865-74. doi: 10.1634/stemcells.2007-1028.
Liu S, Yuan M, Hou K, Zhang L, Zheng X, Zhao B, et al
. Immune characterization of mesenchymal stem cells in human umbilical cord Wharton's jelly and derived cartilage cells. Cell Immunol 2012;278:35-44. doi: 10.1016/j.cellimm.2012.06.010.
Gong W, Han Z, Zhao H, Wang Y, Wang J, Zhong J, et al
. Banking human umbilical cord-derived mesenchymal stromal cells for clinical use. Cell Transplant 2012;21:207-16. doi: 10.3727/096368911X586756.
Chui-Yee F, Li-Ling C, Arijit B, Jee-Hian T, Kalamegam G, Woon-Khiong C, et al
. Human Wharton's jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev Rep 2011;7:1-16. doi: 10.1007/s12015-010-9166-x.
Troyer DL, Weiss ML. Wharton's jelly-derived cells are a primitive stromal cell population. Stem Cells 2008;26:591-9. doi: 10.1634/stemcells.2007-0439.
Bi S, Nie Q, Wang WQ, Zhu YL, Ma XM, Wang CM, et al
. Human umbilical cord mesenchymal stem cells therapy for insulin resistance: A novel strategy in clinical implication. Curr Stem Cell Res Ther 2018;13:658-64. doi: 10.2174/1574888X13666180810154048.
Kim ES, Chang YS, Choi SJ, Kim JK, Yoo HS, Ahn SY, et al
. Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli
-induced acute lung injury in mice. Respir Res 2011;12:108. doi: 10.1186/1465-9921-12-108.
Park SE, Lee NK, Lee J, Hwang JW, Choi SJ, Hwang H, et al
. Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer's disease transgenic mouse after a single intravenous injection. Neuroreport 2016;27:235-41. doi: 10.1097/WNR.0000000000000526.
Song D, Zhong Y, Qian C, Zou Q, Ou J, Shi Y, et al
. Human umbilical cord mesenchymal stem cells therapy in cyclophosphamide-induced premature ovarian failure rat model. Biomed Res Int 2016;2016:2517514. doi: 10.1155/2016/2517514.
Yin N, Wu C, Qiu J, Zhang Y, Bo L, Xu Y, et al
. Protective properties of heme oxygenase-1 expressed in umbilical cord mesenchymal stem cells help restore the ovarian function of premature ovarian failure mice through activating the JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8+
T cells. Stem Cell Res Ther 2020;11:49. doi: 10.1186/s13287-019-1537-x.
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: Possible direct and indirect effects. Tissue Cell 2016;48:370-82. doi: 10.1016/j.tice.2016.05.001.
Cui L, Bao H, Liu Z, Man X, Liu H, Hou Y, et al
. hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β(1)/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats. Stem Cell Res Ther 2020;11:386. doi: 10.1186/s13287-020-01904-3.
Sun L, Li D, Song K, Wei J, Yao S, Li Z, et al
. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro
. Sci Rep 2017;7:2552. doi: 10.1038/s41598-017-02786-x.
Ding C, Zhu L, Shen H, Lu J, Zou Q, Huang C, et al
. Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7. Stem Cells 2020;38:1137-48. doi: 10.1002/stem.3204.
Yang Z, Du X, Wang C, Zhang J, Liu C, Li Y, et al
. Therapeutic effects of human umbilical cord mesenchymal stem cell-derived microvesicles on premature ovarian insufficiency in mice. Stem Cell Res Ther 2019;10:250. doi: 10.1186/s13287-019-1327-5.
Hong L, Yan L, Xin Z, Hao J, Liu W, Wang S, et al
. Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage. J Mol Cell Biol 2020;12:372-85. doi: 10.1093/jmcb/mjz105.
Jalalie L, Rezaie MJ, Jalili A, Rezaee MA, Vahabzadeh Z, Rahmani MR, et al
. Distribution of the CM-Dil-labeled human umbilical cord vein mesenchymal stem cells migrated to the cyclophosphamide-injured ovaries in C57BL/6 Mice. Iran Biomed J 2019;23:200-8. doi: 10.29252/.23.3.200.
Kim YM, Pae HO, Park JE, Lee YC, Woo JM, Kim NH, et al
. Heme oxygenase in the regulation of vascular biology: From molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2011;14:137-67. doi: 10.1089/ars.2010.3153.
Shen J, Cao D, Sun JL. Ability of human umbilical cord mesenchymal stem cells to repair chemotherapy-induced premature ovarian failure. World J Stem Cells 2020;12:277-87. doi: 10.4252/wjsc.v12.i4.277.
Chen H, Xu Y, Yang Y, Zhou X, Dai S, Li C. Shenqiwan ameliorates renal fibrosis in rats by inhibiting TGF-β1/Smads signaling pathway. Evid Based Complement Alternat Med 2017;2017:7187038. doi: 10.1155/2017/7187038.
Zhang L, Han C, Ye F, He Y, Jin Y, Wang T, et al
. Plasma gelsolin induced glomerular fibrosis via the TGF-β1/smads signal transduction pathway in IgA nephropathy. Int J Mol Sci 2017;18. doi: 10.3390/ijms18020390.
Li T, Xia M, Gao Y, Chen Y, Xu Y. Human umbilical cord mesenchymal stem cells: An overview of their potential in cell-based therapy. Expert Opin Biol Ther 2015;15:1293-306. doi: 10.1517/14712598.2015.1051528.
Bai L, Li D, Li J, Luo Z, Yu S, Cao S, et al
. Bioactive molecules derived from umbilical cord mesenchymal stem cells. Acta Histochem 2016;118:761-9. doi: 10.1016/j.acthis.2016.09.006.
Li J, Mao Q, He J, She H, Zhang Z, Yin C. Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism. Stem Cell Res Ther 2017;8:55. doi: 10.1186/s13287-017-0514-5.
Zhu SF, Hu HB, Xu HY, Fu XF, Peng DX, Su WY, et al
. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med 2015;19:2108-17. doi: 10.1111/jcmm.12571.
Wang S, Yu L, Sun M, Mu S, Wang C, Wang D, et al
. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int 2013;2013:690491. doi: 10.1155/2013/690491.
Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, et al
. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4:27066. doi: 10.3402/jev.v4.27066.
Zhang J, Yin H, Jiang H, Du X, Yang Z. The protective effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on cisplatin-damaged granulosa cells. Taiwan J Obstet Gynecol 2020;59:527-33. doi: 10.1016/j.tjog.2020.05.010.
Huang B, Lu J, Ding C, Zou Q, Wang W, Li H. Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Res Ther 2018;9:216. doi: 10.1186/s13287-018-0953-7.
Zhu Z, Zhang Y, Zhang Y, Zhang H, Liu W, Zhang N, et al
. Exosomes derived from human umbilical cord mesenchymal stem cells accelerate growth of VK2 vaginal epithelial cells through MicroRNAs in vitro
. Hum Reprod 2019;34:248-60. doi: 10.1093/humrep/dey344.
Cloonan N, Brown MK, Steptoe AL, Wani S, Chan WL, Forrest AR, et al
. The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 2008;9:R127. doi: 10.1186/gb-2008-9-8-r127.
Vazquez BN, Thackray JK, Serrano L. Sirtuins and DNA damage repair: SIRT7 comes to play. Nucleus 2017;8:107-15. doi: 10.1080/19491034.2016.1264552.
Kojima H, Otani A, Oishi A, Makiyama Y, Nakagawa S, Yoshimura N. Granulocyte colony-stimulating factor attenuates oxidative stress-induced apoptosis in vascular endothelial cells and exhibits functional and morphologic protective effect in oxygen-induced retinopathy. Blood 2011;117:1091-100. doi: 10.1182/blood-2010-05-286963.
Ding L, Yan G, Wang B, Xu L, Gu Y, Ru T, et al
. Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility. Sci China Life Sci 2018;61:1554-65. doi: 10.1007/s11427-017-9272-2.
Yan L, Wu Y, Li L, Wu J, Zhao F, Gao Z, et al
. Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency. Cell Prolif 2020;53:e12938. doi: 10.1111/cpr.12938.
Torsvik A, Røsland GV, Svendsen A, Molven A, Immervoll H, McCormack E, et al
. Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: Putting the research field on track-letter. Cancer Res 2010;70:6393-6. doi: 10.1158/0008-5472.CAN-10-1305.
de la Fuente R, Bernad A, Garcia-Castro J, Martin MC, Cigudosa JC. Retraction: Spontaneous human adult stem cell transformation. Cancer Res 2010;70:6682. doi: 10.1158/0008-5472.CAN-10-2451.
Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, et al
. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 2009;69:5331-9. doi: 10.1158/0008-5472.CAN-08-4630.
Wang Y, Huso DL, Harrington J, Kellner J, Jeong DK, Turney J, et al
. Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture. Cytotherapy 2005;7:509-19. doi: 10.1080/14653240500363216.
Rubio D, Garcia-Castro J, Martín MC, de la Fuente R, Cigudosa JC, Lloyd AC, et al
. Spontaneous human adult stem cell transformation. Cancer Res 2005;65:3035-9. doi: 10.1158/0008-5472.CAN-04-4194.
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al
. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007;449:557-63. doi: 10.1038/nature06188.
Cuiffo BG, Karnoub AE. Mesenchymal stem cells in tumor development: Emerging roles and concepts. Cell Adh Migr 2012;6:220-30. doi: 10.4161/cam.20875.
Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Semin Cell Dev Biol 2015;40:82-8. doi: 10.1016/j.semcdb.2015.03.001.
Coffman LG, Choi YJ, McLean K, Allen BL, di Magliano MP, Buckanovich RJ. Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop. Oncotarget 2016;7:6916-32. doi: 10.18632/oncotarget.6870.
Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med 2013;13:856-67. doi: 10.2174/1566524011313050016.
Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, et al
. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 2009;4:e4992. doi: 10.1371/journal.pone.0004992.
Zhou X, Li T, Chen Y, Zhang N, Wang P, Liang Y, et al
. Mesenchymal stem cell-derived extracellular vesicles promote the in vitro
proliferation and migration of breast cancer cells through the activation of the ERK pathway. Int J Oncol 2019;54:1843-52. doi: 10.3892/ijo.2019.4747.
Gauthaman K, Yee FC, Cheyyatraivendran S, Biswas A, Choolani M, Bongso A. Human umbilical cord Wharton's jelly stem cell (hWJSC) extracts inhibit cancer cell growth in vitro
. J Cell Biochem 2012;113:2027-39. doi: 10.1002/jcb.24073.
Song N, Gao L, Qiu H, Huang C, Cheng H, Zhou H, et al
. Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro
and in a mouse model of allogeneic bone marrow transplant. Int J Mol Med 2015;36:139-49. doi: 10.3892/ijmm. 2015.2191.
Marofi F, Vahedi G, Biglari A, Esmaeilzadeh A, Athari SS. Mesenchymal stromal/stem cells: A new era in the cell-based targeted gene therapy of cancer. Front Immunol 2017;8:1770. doi: 10.3389/fimmu.2017.01770.
Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: A systematic review. Stem Cell Rev Rep 2018;14:1-2. doi: 10.1007/s12015-017-9765-x.