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Can mesenchymal stem cells derived from adipose tissue and their conditioned medium improve ovarian functions? A mini-review

Published online by Cambridge University Press:  22 June 2022

Tayebe Pouryousefi-koodehi ,
Shika Shayegan ,
Soheyla Hashemi ,
Reza Arefnezhad ,
Hossein Roghani-Shahraki ,
Hossein Motedayyen ,
Neda Taghizabet  and
Fatemeh Rezaei-Tazangi Open the ORCID record for Fatemeh Rezaei-Tazangi [Opens in a new window]
Tayebe Pouryousefi-koodehi
Affiliation:
Department of Emergency, Milad Hospital, Tehran, Iran
Shika Shayegan
Affiliation:
Cyprus University of Health and Social Sciences, Faculty of Pharmacy, Kutlu Adali Boulevard, Guzelyurt, Cyprus
Soheyla Hashemi
Affiliation:
Stem Cell and Regenerative Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Reza Arefnezhad*
Affiliation:
Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Hossein Roghani-Shahraki
Affiliation:
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
Hossein Motedayyen
Affiliation:
Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
Neda Taghizabet
Affiliation:
Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Fatemeh Rezaei-Tazangi
Affiliation:
Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
*
Author for correspondence: Reza Arefnezhad. Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. E-mail: Arefnezhad@sums.ac.ir
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Summary

Stable ovarian function is a key factor in the performance of the reproductive system. In contrast, some ovarian function-related diseases, such as polycystic ovarian syndrome, premature ovarian failure (POF), and ovarian cancer, are the main cause of infertility and death of women around the world. Despite multiple attempts, there are no effective tools against these conditions; however, mesenchymal stem cell-based therapy, especially using adipose tissue, has attracted much attention in medicine in light of its advantages such as easy isolation and accessibility. Conversely, it has been suggested that MSC-conditioned medium (CM) can restore injured tissues and has high immunocompatibility. So, here, we will summarize the effects of administration of MSCs and CM derived from adipose tissue on ovarian functions and related diseases.

Keywords

Adipose tissue-derived mesenchymal stem cellConditioned mediumOvarian function

Information

Type
Review Article
Information
Zygote , Volume 30 , Issue 5 , October 2022 , pp. 589 - 592
Copyright
© The Author(s), 2022. Published by Cambridge University Press

Introduction

Suitable ovarian function (OF) is critical for the maintenance of the physiological activities of organisms, particularly the reproductive system (Yu et al., Reference Yu, Zhai, Wang, Geng, Chen, Wen, Tang, Yu, Zhang and Liu2021). Ovarian function depends on various paracrine, autocrine, and endocrine agents. These factors can modulate follicular development and steroidogenesis and influence ovarian cells such as granulosa cells, theca cells, and oocytes (Nikanfar et al., Reference Nikanfar, Oghbaei, Rastgar Rezaei, Zarezadeh, Jafari-Gharabaghlou, Nejabati, Bahrami, Bleisinger, Samadi, Fattahi, Nouri and Dittrich2021). Also, it has been highlighted that the balance of primordial follicle triggering and follicle arrest has a substantial role in the preservation of ovarian performance by which primordial follicle selection from the reserve pool into the pool of growing follicle occurs. This process enables ovulation and oocyte growth (Liu et al., Reference Liu, He, Xu, Xu, Zhao, Luo, Sun, Qi and Wang2021). However, OF is decreased in some conditions such as polycystic ovarian syndrome (PCOS) (Cho et al., Reference Cho, Kim, Seok, Jun, Park, Kweon, Lim and Kim2021), premature ovarian failure (POF) (Zhou et al., Reference Zhou, Song, Liu, Zhang, Li, Hu, Huang, Ma, Song and Zhang2021), and ovarian cancer (OCa) (Rezaei-Tazangi et al., Reference Rezaei-Tazangi, Roghani-Shahraki, Khorsand Ghaffari, Abolhasani Zadeh and Boostan2021). PCOS and POF can be the main causes of infertility (Fan et al., Reference Fan, Cieri-Hutcherson and Hutcherson2021; Shareghi-Oskoue et al., Reference Shareghi-Oskoue, Aghebati-Maleki and Yousefi2021); plus, OCa is considered a main factor responsible for women’s deaths globally. Therefore, finding suitable approaches with high effectiveness and low side effects to elevate OF is an urgent need, and unfortunately, the present therapeutic options have no clear remedy for ovarian function-related disorders (Xu et al., Reference Xu, Fan, Geng, Gao, Yu and Xia2021). Recently, mesenchymal stem cell (MSC)-based therapy, using several sources such as adipose tissue (AD), bone marrow, and umbilical cord, has been proposed as a novel candidate to improve OCa, OF, or treatment of female infertility (Touboul et al., Reference Touboul, Lis, Al Farsi, Raynaud, Warfa, Althawadi, Mery, Mirshahi and Rafii2013; Yoon, Reference Yoon2019; ArefNezhad et al., Reference ArefNezhad, Motedayyen and Mohammadi2021). MSCs can decrease stromal cell and germ cell apoptosis, potentiate folliculogenesis through secretion of some cytokines and growth factors, including insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF), and microenvironment improvement (Fu et al., Reference Fu, He, Xie and Liu2008; Elfayomy et al., Reference Elfayomy, Almasry, El-Tarhouny and Eldomiaty2016). Furthermore, MSCs may suppress fibroblast proliferation and reduce extracellular matrix deposition. These stem cells stimulate neovascularization and enhance blood perfusion of injured ovarian tissues (He et al., Reference He, Chen, Yang, Hou, Ma and Xu2018; Yoon, Reference Yoon2019). Among different sources of MSCs, AD-derived MSCs have noticeable benefits, for example, easy isolation, accessibility, and the capability to differentiate into different cell lines (ArefNezhad et al., Reference ArefNezhad, Motedayyen and Mohammadi2021). Conversely, it has been stated that MSC-conditioned medium (CM) can have therapeutic effects on ovarian damage (He et al., Reference He, Chen, Yang, Hou, Ma and Xu2018; Gunawardena et al., Reference Gunawardena, Rahman, Abdullah and Abu Kasim2019). MSC-CM, as a source of diverse growth factors, promotes the recovery of damaged tissues and its main advantage is immunocompatibility for the recipient patients (Javanmard et al., Reference Javanmard, Karimipour and Pasdar2018). Therefore, in this mini-review, the current efforts regarding the possible curative influences of MSCs and CM derived from AD on ovarian functions and related disorders will be summarized.

Mesenchymal stem cells derived from human adipose tissue and their conditioned medium: Useful tools for improving ovarian function?

Adipose-originated stem cells improve chemotherapy-induced ovarian malfunction in animal models; also, they induce angiogenesis and restore the corpus luteum and ovarian follicle number in damaged ovaries (Zhao et al., Reference Zhao, Chen, Su, Huang, Shi, Shi and Lin2019). Human omental adipose-derived MSCs can increase autophagy in OCa through the STAT3 signalling pathway (Chu et al., Reference Chu, Wang, Li, Liu, Zhang, Li, Hu, Liu, Zhou, Zuo and Peng2020). However, some reports have addressed the protumour impacts of these MSCs (Zhang et al., Reference Zhang, Torres-Rojas, Yue and Zhu2021). It has been reported that adipose-derived MSCs increase the growth and metastasis of OCa by increasing the expression of Thymosin Beta 4X-Linked (Chu et al., Reference Chu, You, Zhang, Gao, Han, Luo, Liu, Zuo and Wang2019). In addition, one study implicated an increase in OCa progression through the administration of human omental adipose-derived MSC-CM as a result of the proteomic changes of cancer cells (Zhang et al., Reference Zhang, Dong, Wang, Cai and Wang2017). In another work, Takehara and colleagues revealed the positive effects of AD-derived MSCs and their CM on cyclophosphamide-induced ovarian failure. They also observed no serious side effects and no tumour formation in animal models of POF (Takehara et al., Reference Takehara, Yabuuchi, Ezoe, Kuroda, Yamadera, Sano, Murata, Aida, Nakama, Aono, Aoyama, Kato and Kato2013). Based on the work of Chugh and colleagues, MSC-CM suppresses androgen release and regulates steroidogenesis in a cellular model of PCOS (Chugh et al., Reference Chugh, Park, Esfandyari, Elsharoud, Ulin and Al-Hendy2021). Human adipose-derived MSCs and their CM can also promote embryo development and oocyte maturation through the regulation of the receptors of growth factors IGFR, FGFR, and VEGF, and the genes associated with oocyte maturation, cumulus expansion, and apoptosis, such as BMP15, GDF9, TNFAIP6, HAS2, PTGS2, and BCL2, in animal studies (Figure 1; Lee, Reference Lee2021). The enhancement of OF is related to the increase in oocyte numbers, higher oocyte quality, and an increase in Bmp15 and Gdf 9 levels (Yin et al., Reference Yin, Chang, Li and Leung2021). Therefore, it seems that AD-derived MSCs and their CM can be effective in boosting OF in some conditions such as PCOS and POF; however, regarding ovarian cancer, more investigations are required to demonstrate their exact effects.

Figure 1.

Adipose tissue-derived mesenchymal stem cells (MSCs) and their conditioned medium (CM): their potential for ovarian functions and some ovarian diseases such as ovarian cancer, polycystic ovarian syndrome (PCOS), and premature ovarian failure (POF).

Conclusion

Ovarian function, which is affected by paracrine, autocrine, and endocrine factors, has a substantial role in reproductive system stability. Defects in OF can influence the fertility and life span of women by causing some diseases such as POF, PCOS, and OCa. At this time, an effective therapeutic tool against these disorders has not been suggested. Recently, some studies have investigated the effectiveness of AD-derived MSCs and their CM against these illnesses. It seems that AD-derived MSCs and their CM can potentiate angiogenesis, folliculogenesis, and corpus luteum recovery, regulate steroidogenesis, and inhibit androgen secretion probably through the secretion of various cytokines and growth factors, and therefore may be effective in OF-associated conditions such as POF and PCOS. These sources can also increase embryo development and oocyte maturation through mechanisms such as regulating growth factor receptors, e.g. IGFR, FGFR, and VEGF, oocyte maturation-related genes, cumulus expansion genes, and apoptosis-associated genes, e.g. BMP15, GDF9, TNFAIP6, HAS2, PTGS2, and BCL2. Therefore, they may be therapeutic candidates for infertility in women. However, more research is needed to show their capacity to remedy disorders related to OF, particularly OCa. Regarding OCa, there is conflicting evidence. Some papers have highlighted the negative effects of AD-derived MSCs and their CM on OCa treatment through the proteomic changes of OCa cells and increment of Thymosin Beta 4X-Linked expression. In contrast, some reports have indicated the positive impact of these mesenchymal sources on disease improvement by involving the STAT3 signalling pathway.

Data availability

All data searched in this study are included in this publication.

Acknowledgements

This work was performed in a personal capacity. The figure was created using the web-based software BioRender.

Financial support

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Conflict of interest

The authors declare that they have no competing interests.

Ethical standards

This is a mini-review article that examines past studies and the references used in the text.

Consent for publication

Not applicable.

References

ArefNezhad, R., Motedayyen, H. and Mohammadi, A. (2021). Therapeutic aspects of mesenchymal stem cell-based cell therapy with a focus on human amniotic epithelial cells in multiple sclerosis: A mechanistic review. International Journal of Stem Cells, 14(3), 241–251. doi: 10.15283/ijsc21032 CrossRefGoogle ScholarPubMed
Cho, J., Kim, T. H., Seok, J., Jun, J. H., Park, H., Kweon, M., Lim, J. Y. and Kim, G. J. (2021). Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway. Laboratory Investigation; a Journal of Technical Methods and Pathology, 101(3), 304–317. doi: 10.1038/s41374-020-00513-1 CrossRefGoogle ScholarPubMed
Chu, Y., You, M., Zhang, J., Gao, G., Han, R., Luo, W., Liu, T., Zuo, J. and Wang, F. (2019). Adipose-derived mesenchymal stem cells enhance ovarian cancer growth and metastasis by increasing thymosin beta 4X-linked expression. Stem Cells International, 20, 25–38.Google Scholar
Chu, Y., Wang, Y., Li, K., Liu, M., Zhang, Y., Li, Y., Hu, X., Liu, C., Zhou, H., Zuo, J. and Peng, W. (2020). Human omental adipose-derived mesenchymal stem cells enhance autophagy in ovarian carcinoma cells through the STAT3 signalling pathway. Cellular Signalling, 69, 109549. doi: 10.1016/j.cellsig.2020.109549 CrossRefGoogle ScholarPubMed
Chugh, R. M., Park, H. S., Esfandyari, S., Elsharoud, A., Ulin, M. and Al-Hendy, A. (2021) Mesenchymal stem cell-conditioned media regulate steroidogenesis and inhibit androgen secretion in a PCOS cell model via BMP-2. International Journal of Molecular Sciences, 22(17), 9184–9195. doi: 10.3390/ijms22179184 CrossRefGoogle Scholar
Elfayomy, A. K., Almasry, S. M., El-Tarhouny, S. A. and Eldomiaty, M. A. (2016). 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 and Cell, 48(4), 370–382. doi: 10.1016/j.tice.2016.05.001 CrossRefGoogle Scholar
Fan, C. W., Cieri-Hutcherson, N. E. and Hutcherson, T. C. (2021). Systematic review of black cohosh (Cimicifuga racemosa) for management of polycystic ovary syndrome-related infertility. Journal of Pharmacy Practice, 36, 8971900211012244. doi: 10.1177/08971900211012244 Google Scholar
Fu, X. F., He, Y. L., Xie, C. H. and Liu, W. (2008). Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy, 10(4), 353–363. doi: 10.1080/14653240802035926 CrossRefGoogle ScholarPubMed
Gunawardena, T. N. A., Rahman, M. T., Abdullah, B. J. J. and Abu Kasim, N. H. (2019). Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. Journal of Tissue Engineering and Regenerative Medicine, 13(4), 569–586. doi: 10.1002/term.2806 CrossRefGoogle ScholarPubMed
He, Y., Chen, D., Yang, L., Hou, Q., Ma, H. and Xu, X. (2018). The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. Stem Cell Research and Therapy, 9(1), 263. doi: 10.1186/s13287-018-1008-9 CrossRefGoogle ScholarPubMed
Javanmard, M. Z., Karimipour, M. and Pasdar, F. A. (2018). Conditioned medium derived from mesenchymal stem cells regenerates’ defected articular cartilage. Journal of the Urmia University of Medical Sciences, 29, 7–22.Google Scholar
Lee, S. H. (2021). Human adipose-derived stem cells’ paracrine factors in conditioned medium can enhance porcine oocyte maturation and subsequent embryo development. International Journal of Molecular Sciences, 22(2), 579–588. doi: 10.3390/ijms22020579 CrossRefGoogle ScholarPubMed
Liu, Y., He, Q. K., Xu, Z. R., Xu, C. L., Zhao, S. C., Luo, Y. S., Sun, X., Qi, Z. Q. and Wang, H. L. (2021). Thiamethoxam exposure induces endoplasmic reticulum stress and affects ovarian function and oocyte development in mice. Journal of Agricultural and Food Chemistry, 69(6), 1942–1952. doi: 10.1021/acs.jafc.0c06340 CrossRefGoogle ScholarPubMed
Nikanfar, S., Oghbaei, H., Rastgar Rezaei, Y. R., Zarezadeh, R., Jafari-Gharabaghlou, D., Nejabati, H. R., Bahrami, Z., Bleisinger, N., Samadi, N., Fattahi, A., Nouri, M. and Dittrich, R. (2021). Role of adipokines in the ovarian function: Oogenesis and steroidogenesis. Journal of Steroid Biochemistry and Molecular Biology, 209, 105852. doi: 10.1016/j.jsbmb.2021.105852 CrossRefGoogle ScholarPubMed
Rezaei-Tazangi, F., Roghani-Shahraki, H., Khorsand Ghaffari, M., Abolhasani Zadeh, F., Boostan, A., ArefNezhad, R. and Motedayyen, H. (2021). The therapeutic potential of common herbal and nano-based herbal formulations against ovarian cancer: New insight into the current evidence. Pharmaceuticals, 14(12), 1315–1325. doi: 10.3390/ph14121315 CrossRefGoogle ScholarPubMed
Shareghi-Oskoue, O., Aghebati-Maleki, L. and Yousefi, M. (2021). Transplantation of human umbilical cord mesenchymal stem cells to treat premature ovarian failure. Stem Cell Research and Therapy, 12(1), 454. doi: 10.1186/s13287-021-02529-w CrossRefGoogle ScholarPubMed
Takehara, Y., Yabuuchi, A., Ezoe, K., Kuroda, T., Yamadera, R., Sano, C., Murata, N., Aida, T., Nakama, K., Aono, F., Aoyama, N., Kato, K. and Kato, O. (2013). The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function. Laboratory Investigation; A Journal of Technical Methods and Pathology, 93(2), 181–193. doi: 10.1038/labinvest.2012.167 CrossRefGoogle ScholarPubMed
Touboul, C., Lis, R., Al Farsi, H., Raynaud, C. M., Warfa, M., Althawadi, H., Mery, E., Mirshahi, M. and Rafii, A. (2013). Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model. Journal of Translational Medicine, 11, 28. doi: 10.1186/1479-5876-11-28 CrossRefGoogle Scholar
Xu, J. Y., Fan, Y. H., Geng, J. Z., Gao, N., Yu, F. H. and Xia, T. (2021). Application progress of acupuncture in treatment of ovarian hypofunction. TMR Non-Drug Therapy, 4(3), 16–28. doi: 10.53388/TMRND20210822036 CrossRefGoogle Scholar
Yin, J., Chang, H. M., Li, R. and Leung, P. C. K. (2021). Recent progress in the treatment of women with diminished ovarian reserve. Gynecology and Obstetrics Clinical Medicine, 1(4), 186–189. doi: 10.1016/j.gocm.2021.10.004 CrossRefGoogle Scholar
Yoon, S. Y. (2019). Mesenchymal stem cells for restoration of ovarian function. Clinical and Experimental Reproductive Medicine, 46(1), 1–7. doi: 10.5653/cerm.2019.46.1.1 CrossRefGoogle ScholarPubMed
Yu, L., Zhai, J., Wang, Y., Geng, Y., Chen, X., Wen, Y., Tang, H., Yu, R., Zhang, Y. and Liu, X. (2021). Exposure to N-monoacetyl-p-phenylenediamine impaired ovarian function in mice. Journal of Applied Toxicology, 41(12), 2031–2041. doi: 10.1002/jat.4183 CrossRefGoogle ScholarPubMed
Zhang, Y., Dong, W., Wang, J., Cai, J. and Wang, Z. (2017). Human omental adipose-derived mesenchymal stem cell-conditioned medium alters the proteomic profile of epithelial ovarian cancer cell lines in vitro . OncoTargets and Therapy, 10, 1655–1663. doi: 10.2147/OTT.S129502 CrossRefGoogle ScholarPubMed
Zhang, W., Torres-Rojas, C., Yue, J. and Zhu, B. M. (2021). Adipose-derived stem cells in ovarian cancer progression, metastasis, and chemoresistance. Experimental Biology and Medicine, 246(16), 1810–1815. doi: 10.1177/15353702211023846 CrossRefGoogle Scholar
Zhao, Y. X., Chen, S. R., Su, P. P., Huang, F. H., Shi, Y. C., Shi, Q. Y. and Lin, S. (2019). Using mesenchymal stem cells to treat female infertility: An update on female reproductive diseases. Stem Cells International, 20, 19–28.Google Scholar
Zhou, F., Song, Y., Liu, X., Zhang, C., Li, F., Hu, R., Huang, Y., Ma, W., Song, K. and Zhang, M. (2021). Si-Wu-Tang facilitates ovarian function through improving ovarian microenvironment and angiogenesis in a mouse model of premature ovarian failure. Journal of Ethnopharmacology, 280, 114431. doi: 10.1016/j.jep.2021.114431 CrossRefGoogle Scholar
Figure 0

Figure 1. Adipose tissue-derived mesenchymal stem cells (MSCs) and their conditioned medium (CM): their potential for ovarian functions and some ovarian diseases such as ovarian cancer, polycystic ovarian syndrome (PCOS), and premature ovarian failure (POF).