EFFECT OF MESENCHYMAL STEM CELLS ON OVARIUM TISSUE IN EXPEREMENTAL OVARIAN FAILURE CASES

Year 2023, Volume: 24 Issue: 2, 249 - 253, 05.04.2023

Gizem Kabasakal , Emine Tural , Murat Serkant Ünal

https://doi.org/10.18229/kocatepetip.849512

Abstract

Premature ovarian failure (POF) is defined as the cessation of regular menstrual cycles for more than 4-6 months in woman under 40 years of age, accompanied by high follicle stimulating hormone (FSH) levels (40 IU/I and above). There can be found various etiologies of POF such as; genetic causes, toxic agents, surgical interventions, autoimmune causes, infections and hereditary problems. Chemotherapy agents used by female patients in the reproductive period for cancer treatment are cytotoxic. Chemotherapy agents cause damage to both the oocyte and the granulosa cells surrounding the oocyte, resulting in follicle loss and consequently premature ovarian failure. An irregularity in primordial follicle activation may lead to loss of ovarian reserve and premature menopause. In the transition from the primordial follicle to the primary follicle, the signaling pathways that play a controlled activating and suppressor role in protecting the follicle pool work independently but in a balanced way. In cases where the balance is disturbed, mass activation of the follicles and prematüre depletion of the follicle pool occurs. In the evaluation of ovarian reserve, serum FSH, anti-Müllerian hormone (AMH), inhibin B measurements and ovarian volume measurement by ultrasonography, antral follicle count (AFS) are performed. POF is one of the common causes of anovulation. Many treatment methods are being investigated to reduce the chemotherapy-induced POF in women, to regenerate ovarian tissue and to restore both endocrine and exocrine functions. Mesenchymal stem cells (MSCs), which have been the subject of many studies recently, are adult stem cells of stromal origin with multi-potential properties. MSCs can be isolated from many tissues such as umbilical cord, adipose tissue, placenta, bone marrow, ovarian tissue, amniotic fluid, endometrial tissue, liver. MSCs have properties like that of antiapoptotic, angiogenic, antifibrotic. They are also uncommon to create an immune response in the tissues they are administered. Through these properties, they act an important role in tissue damage repair and renewal. In experimental studies, it has been shown that MSCs obtained from various sources improve ovarian failure follicular development and ovarian functions. The results obtained may shed light on future clinical studies of MSCs in the treatment of some POF cases that are currently unsolved. Our aim in this review is to investigate the properties of MSCs isolated from different sources on ovarian tissue in POF patients.

Keywords

Mesencymal stem cell, Follicle, Ovary, Chemotherapy

DENEYSEL OVERYAN YETMEZLİKLERDE MEZENKİMAL KÖK HÜCRELERİN OVARYUM DOKUSUNA ETKİSİ

Abstract

Prematür Overyan Yetmezlik (POY), folikül stimülan hormonun (FSH) yüksek düzeylerinin (40 IU/I ve üzeri) eşliğinde, 40 yaşından küçük bir hastada menstrüel siklusların düzeninin 4-6 aydan uzun bir süre boyunca kesilmesi olarak tanımlanmaktadır. Etyolojisinde genetik nedenler, toksik ajanlar, cerrahi girişimler, otoimmün nedenler, enfeksiyonlar ve kalıtsal problemler bulunabilir. Reprodüktif dönemde kadın hastaların kanser tedavisi için kullandıkları kemoterapik ajanlar, sitotoksik etkilidir. Kemoterapik ajanlar hem oosit hem de oositi çevreleyen granüloza hücrelerinde hasara neden olarak folikül kaybı ve buna bağlı olarak da prematür over yetmezliğine sebep olmaktadır. Primordial folikül aktivasyonunda oluşabilecek bir düzensizlik over rezerv kaybına ve prematür menopoza yol açabilmektedir. Primordial folikülden primer foliküle geçişte, kontrollü aktive edici ve baskılayıcı rol oynayarak folikül havuzunun korunmasında rol alan sinyal yolakları birbirinden bağımsız ancak dengeli bir şekilde çalışır. Dengenin bozulduğu durumlarda, folliküllerin kitlesel aktivasyonu ve folikül havuzunun erkenden tükenmesi meydana gelmektedir. Overyan rezervin değerlendirilmesinde serum FSH, anti-Müllerian hormon (AMH), inhibin B ölçümleri ve ultrasonografi ile over hacmi ölçümü, antral folikül sayımı (AFS) ölçümü yapılır. POY, anovulasyonun yaygın nedenlerinden biridir. Kadınlarda kemoterapiye bağlı POY’nin azaltması, over dokusunun yenilenmesi ve hem endokrin hem de ekzokrin fonksiyonlarını geri kazanılması için birçok tedavi yöntemi araştırılmaktadır. Son zamanlarda birçok çalışmaya konu olan mezenkimal kök hücreler (MKH) stromal kökenli multipotent özellikte erişkin kök hücreleridir. Göbek kordonu, adipoz doku, plasenta, kemik iliği, ovaryum dokusu, amniyotik sıvı, endometriyal doku, karaciğer gibi birçok dokudan izole edilebilirler. MKH’lerin antiapoptotik, anjiojenik, antifibrotik özellikleri bulunmaktadır. Uyguladıkları dokularda immün yanıta neden olma ihtimalleri de düşüktür. Bu özellikleri sayesinde doku hasarı onarımında ve yenilenmesinde önemli roller üstlenirler. Yapılan deneysel çalışmalarda çeşitli kaynaklardan elde edilen MKH’lerin, overyan yetmezlikte foliküler gelişime katkısı ve overyan fonksiyonlara olumlu etkileri araştırılmıştır. Elde edilen sonuçlar, şu an için çözümsüz olan bazı POY olgularının tedavisinde MKH'ler ile ilgili gelecekteki klinik çalışmalara ışık tutabilir. Bu derlemedeki amacımız farklı kaynaklardan izole edilen MKH’lerin POY hastalarının over dokusu üzerindeki özelliklerini araştırmaktır.

Keywords

Mezenkimal kök hücre, Folikül, Ovaryum, Kemoterapi

References

• 1. Rastegar F, Shenaq D, Huang J, et al. Mesenchymal stem cells: Molecular characteristics and clinical applications. World J Stem Cells. 2010;2(4):67-80.
• 2. Unal MS, Tufan AC. Mesenchymal Stem Cells and C-type Natriuretic Peptide Signaling: A Proposal for a New Treatment Approach for Skeletal Dysplasias. Current Stem Cell Research & Therapy. 2016;11:513-21.
• 3. Haynesworth SE, Baber MA, Caplan Al. Cell surface antigens on human marrow derived mesenvhymal cells are detected by monoclonal antibodies. Bone. 1992;13:69-80.
• 4. Ramazan DEMİR (Editör). Histoloji Atlası, Fonksiyonel İlişkileriyle. 11inci Baskı, Ankara: Palme Yayıncılık, 2008:375-87.
• 5. Seyhun SOLAKOĞLU, Yener AYTEKİN (Editör). Temel Histoloji. 10uncu Baskı, İstanbul: Nobel Tıp Kitabevleri, 2009:435-43.
• 6. Liu R, Zhang X, Fan Z, et al. Human amniotic mesenchymal stem cells improve the follicular microenvironment to recover ovarian function in premature ovarian failure mice. Stem Cell Res Ther. 2019;10(1):299.
• 7. Reddy P, Liu L, Adhikari D, et al. Oocyte-Specific Deletion of Pten Causes Premature Activation of the Primordial Follicle Pool. Science. 2008;319(5863):611-3.
• 8. Lai D, Wang F, Yao X, et al. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. Journal of Translational Medicine. 2015;13:155.
• 9. Kara N, Tural S, Oktena G, et al. Prematüre ovaryen yetmezlik ve 46,X,del(X)(q21). Journal of Experimental and Clinical Medicine. 2012;29:167-8.
• 10. He Y, Chen D, Yang L, et al. The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. Stem Cell Research & Therapy. 2018;9(1):263.
• 11. Zheng Q, Fu X, Jiang J, et al. Umbilical Cord Mesenchymal Stem Cell Transplantation Prevents Chemotherapy Induced Ovarian Failure via the NGF/TrkA Pathway in Rats. Biomed Res Int. 2019;1-9.
• 12. Mohamed SA, Shalaby SM, Abdelaziz M, et al. Human Mesenchymal Stem Cells Partially Reverse Infertility in Chemotherapy-Induced Ovarian Failure. Reprod Sci. 2018;25(1):51-63.
• 13. Kalich-Philosoph L, Roness H, Carmely A, et al. Cyclophosphamide triggers follicle activation and "burn out"; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5(185):185ra62.
• 14. Jang H, Lee OH, Lee Y, et al. Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary. Journal of Pineal Research. 2016;60(3):336- 47.
• 15. Afifi Noha M, Reyad Olfat N. Role of mesenchymal stem cell therapy in restoring ovarian function in a rat model of chemotherapy-induced ovarian failure: a histological and immunohistochemical study. The Egyptian Journal of Histology. 2013;36(1):114–26.
• 16. Besikcioglu HE, Sarıbas GS, Ozogul C, et al. Determination of the effects of bone marrow derived mesenchymal stem cells and ovarian stromal stem cells on follicular maturation in cyclophosphamide induced ovarian failure in rats. Taiwan J Obstet Gynecol. 2019;58(1):53-9.
• 17. Takehara Y, Yabuuchi A, Ezoe K, et al. The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function. Lab Invest. 2013;93(2):181-93.
• 18. Mohamed SA, Shalaby S, Brakta S, et al. Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency. Biomedicines. 2019;7(1):7.
• 19. Song D, Zhong Y, Qian C, et al. Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model. BioMed Research International. 2016;(6):1-13.
• 20. Zhu SF, Hu HB, Xu HY, et al. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med. 2015;19(9):2108-17.
• 21. Huang B, Qian C, Ding C, et al. Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1. Stem Cell Res Ther. 2019;10:362.
• 22. Yin N, Zhao W, Luo Q, et al. Restoring Ovarian Function With Human Placenta-Derived Mesenchymal Stem Cells in Autoimmune-Induced Premature Ovarian Failure Mice Mediated by Treg Cells and Associated Cytokines. Reprod Sci. 2018;25(7):1073-82.
• 23. Li J, Mao Q, He J, et al. Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism. Stem Cell Res Ther. 2017;8(1):55.
• 24. Yang Z, Du X, Wang C, 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(1):250.
• 25. Gorre N, Adhikari D, Lindkvist R, et al. mTORC1 Signaling in Oocytes Is Dispensable for the Survival of Primordial Follicles and for Female Fertility. PLOS One. 2014;9(10):e110491.
• 26. Liu AL, Liao HQ, Li ZL, et al. New Insights into mTOR Signal Pathways in Ovarian-Related Diseases: Polycystic Ovary Syndrome and Ovarian Cancer. Asian Pac J Cancer Prev. 2016;17(12):5087-94.
• 27. Yaba A, Demir N. The mechanism of mTOR (mammalian target of rapamycin) in a mouse model of polycystic ovary syndrome (PCOS). J Ovarian Res. 2012;5:38.
• 28. Zhou L, Xie Y, Li S, et al. Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. J Ovarian Res. 2017;16;10(1):56.
• 29. Peng J, Xiao N, Cheng L. Therapeutic potential of BMSCs for premature ovarian failure in mice. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2018;43(1):7-13.
• 30. Ding C, Zou Q, Wang F, et al. Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor. Stem Cell Res Ther. 2018;9(1):55.
• 31. Liu T, Huang Y, Guo L, et al. CD44+/CD105+ Human Amniotic Fluid Mesenchymal Stem Cells Survive and Proliferate in the Ovary Long-Term in a Mouse Model of Chemotherapy-Induced Premature Ovarian Failure. Int J Med Sci. 2012;9(7):592–602.
• 32. Huang B, Lu J, Ding C, et al. Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Res Ther. 2018;9(1):216.