Skip to main content
SpringerLink
Log in

Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-β, Wnt/β-Catenin and Hippo Pathways

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Radiotherapy is an indispensable cancer treatment approach. However, it is associated with hazardous consequences on multiple organs characterized by insidious worsening severity over time. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) in radiation-induced premature ovarian failure (POF). Exposing female rats to 3.2 Gy whole-body ϒ-rays successfully induced POF. One week later, a single intravenous injection of BM-MSCs (2*106) cells was administered. BM-MSCs perfectly home to the damaged ovaries, enhanced ovarian follicle pool, and preserved the ovarian function manifested by restoring serum estradiol and follicle stimulating hormone levels, besides, rescuing the fertility outcomes of irradiated rats. These events have been associated with inhibiting ovarian apoptosis (Bax/Bcl2, caspase 3) and enhancing proliferation (PCNA). Interestingly, BM-MSCs reversed the inhibition of ovarian FOXO3 expression induced by radiation which resulted in increased primordial follicles stock. Moreover, BM-MSCs recovered the suppressed folliculogenesis process induced by radiation through upregulating FOXO1, GDF-9, and Fst genes expression accompanied by downregulating TGF-β which enhanced granulosa cells proliferation and secondary follicle development. Mechanistically, BM-MSCs miRNAs epigenetically upregulate Wnt/β-catenin and Hippo signaling pathways which are implicated in ovarian follicles growth and maturation. Therefore, BM-MSCs presented a ray of hope in the treatment of radiation-associated POF through genetic and epigenetic modulation of the integrated TGF-β, Wnt/β-catenin, and Hippo pathways which control apoptosis, proliferation, and differentiation of ovarian follicles.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

Code Availability

Not applicable.

Abbreviations

POF:

premature ovarian failure

MSCs:

Mesenchymal stem cells

BM-MSCs:

Bone marrow mesenchymal stem cells

CNS:

central nervous system

TGF-β:

transforming growth factor beta

Wnt:

Wingless-type MMTV integration site family

YAP:

Yes-associated protein

FSH:

Follicle stimulating hormone

PCNA:

proliferating cell nuclear antigen

LDMEM:

low-glucose Dulbecco’s modified Eagle’s medium

Tead1:

TEA domain transcription factor 1

CCN2:

cellular communication network factor 2

BIRC1:

baculoviral inhibitors of apoptosis repeat containing1

Bax:

BCL2 Associated X, Bcl2

Bcl2:

B cell lymphoma 2

FOXO:

forkhead box O

GDF9:

growth differentiation factor 9

Fst:

follistatin

References

  1. Goswami, D., & Conway, G. S. (2007). Premature Ovarian Failure. Hormone Research, 68, 196–202.

    Article  CAS  PubMed  Google Scholar 

  2. Faubion, S. S., Kuhle, C. L., Shuster, L. T., & Rocca, W. A. (2015). Long-term Health Consequences of Premature or Early Menopause and Considerations for Management. Climacteric : The Journal of the International Menopause Society, 18, 483–491.

    Article  CAS  Google Scholar 

  3. Buyuk, E., Nejat, E., & Neal-Perry, G. (2010). Determinants of Female Reproductive Senescence: Differential roles for the ovary and the neuroendocrine axis. Seminars in Reproductive Medicine, 28, 370–379.

    Article  CAS  PubMed  Google Scholar 

  4. Welt, C. K. (2008). Primary Ovarian Insufficiency: A More Accurate Term for Premature Ovarian Failure. Clinical Endocrinology, 68, 499–509.

    Article  PubMed  Google Scholar 

  5. Mao, A. S., & Mooney, D. J. (2015). Regenerative Medicine: Current Therapies and Future Directions. Proceedings of the National Academy of Sciences of the United States of America, 112, 14452–14459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cai, M., Shen, R., Song, L., Lu, M., Wang, J., Zhao, S., Tang, Y., Meng, X., Li, Z., & He, Z.-X. (2016). Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects. Scientific Reports, 6, 28250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Musiał-Wysocka, A., Kot, M., & Majka, M. (2019). The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. Cell Transplantation, 28, 801–812.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sarukhan, A., Zanotti, L., & Viola, A. (2015). Mesenchymal Stem Cells: Myths and Reality. Swiss Medical Weekly, 145, w14229.

    PubMed  Google Scholar 

  9. He, Y., Chen, D., Yang, L., Hou, Q., Ma, H., & Xu, X. (2018). The Therapeutic Potential of Bone Marrow Mesenchymal Stem Cells in Premature Ovarian Failure. Stem Cell Research & Therapy, 9, 263.

    Article  CAS  Google Scholar 

  10. Steinberg, G. K., Kondziolka, D., Wechsler, L. R., Lunsford, L. D., Coburn, M. L., Billigen, J. B., Kim, A. S., Johnson, J. N., Bates, D., King, B., Case, C., McGrogan, M., Yankee, E. W., & Schwartz, N. E. (2016). Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke, 47, 1817–1824.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Prockop, D. J. (2009). Repair of Tissues by Adult Stem/Progenitor Cells (MSCs): Controversies, Myths, and Changing Paradigms. Molecular Therapy, 17, 939–946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Attisano, L., & Wrana, J. L. (2013). Signal integration in TGF-beta, WNT, and Hippo pathways. F1000Prime Reports, 5, 17.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., Porrello, E. R., Mahmoud, A. I., Tan, W., Shelton, J. M., Richardson, J. A., Sadek, H. A., Bassel-Duby, R., & Olson, E. N. (2013). Hippo Pathway Effector Yap Promotes Cardiac Regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110, 13839–13844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu, X., Chen, Y., Wang, X., & Mu, X. (2019). Role of Hippo/YAP Signaling in Irradiation-Induced Glioma Cell Apoptosis. Cancer Management and Research, 11, 7577–7585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kawamura, K., Cheng, Y., Suzuki, N., Deguchi, M., Sato, Y., Takae, S., Ho, C. H., Kawamura, N., Tamura, M., Hashimoto, S., Sugishita, Y., Morimoto, Y., Hosoi, Y., Yoshioka, N., Ishizuka, B., & Hsueh, A. J. (2013). Hippo Signaling Disruption and Akt Stimulation of Ovarian Follicles for Infertility Treatment. Proceedings of the National Academy of Sciences of the United States of America, 110, 17474–17479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Said, R. S., El-Demerdash, E., Nada, A. S., & Kamal, M. M. (2016). Resveratrol Inhibits Inflammatory Signaling Implicated in Ionizing Radiation-Induced Premature Ovarian Failure through Antagonistic Crosstalk between Silencing Information Regulator 1 (SIRT1) and Poly(ADP-ribose) Polymerase 1 (PARP-1). Biochemical Pharmacology, 103, 140–150.

    Article  CAS  PubMed  Google Scholar 

  17. Gabr, H., Rateb, M. A., El Sissy, M. H., Ahmed Seddiek, H., & Ali Abdelhameed Gouda, S. (2016). The effect of Bone Marrow-Derived Mesenchymal Stem Cells on Chemotherapy Induced Ovarian Failure in Albino Rats. Microscopy Research and Technique, 79, 938–947.

    Article  CAS  PubMed  Google Scholar 

  18. Myers, M., Britt, K. L., Wreford, N. G., Ebling, F. J., & Kerr, J. B. (2004). Methods for Quantifying Follicular Numbers within the Mouse Ovary. Reproduction (Cambridge, England), 127, 569–580.

    Article  CAS  Google Scholar 

  19. Griffiths-Jones, S. (2004). The microRNA Registry. Nucleic Acids Research, 32, D109–D111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fu, X. Y., Chen, H. H., Zhang, N., Ding, M. X., Qiu, Y. E., Pan, X. M., Fang, Y. S., Lin, Y. P., Zheng, Q., & Wang, W. Q. (2018). Effects of Chronic Unpredictable Mild Stress on Ovarian Reserve in Female Rats: Feasibility Analysis of a Rat Model of Premature Ovarian Failure. Molecular Medicine Reports, 18, 532–540.

    CAS  PubMed  Google Scholar 

  21. Cora, M. C., Kooistra, L., & Travlos, G. (2015). Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle using Stained Vaginal Smears. Toxicologic Pathology, 43, 776–793.

    Article  CAS  PubMed  Google Scholar 

  22. Brenkman, A. B., & Burgering, B. M. (2003). FoxO3a Eggs on Fertility and Aging. Trends in Molecular Medicine, 9, 464–467.

    Article  CAS  PubMed  Google Scholar 

  23. Yamamoto, H., Yamashita, Y., Saito, N., Hayashi, A., Hayashi, M., Terai, Y., & Ohmichi, M. (2017). Lower FOXO3 mRNA Expression in Granulosa Cells is Involved in Unexplained Infertility. The Journal of Obstetrics and Gynaecology Research, 43, 1021–1028.

    Article  CAS  PubMed  Google Scholar 

  24. Knight, P. G., & Glister, C. (2006). TGF-beta Superfamily Members and Ovarian Follicle Development. Reproduction (Cambridge, England), 132, 191–206.

    Article  CAS  Google Scholar 

  25. Juengel, J. L., & McNatty, K. P. (2005). The Role of Proteins of the Transforming Growth Factor-Beta Superfamily in the Intraovarian Regulation of Follicular Development. Human Reproduction Update, 11, 143–160.

    Article  CAS  PubMed  Google Scholar 

  26. Kawamura, K., Kawamura, N., & Hsueh, A. J. (2016). Activation of Dormant Follicles: A new Treatment for Premature Ovarian Failure? Current Opinion in Obstetrics & Gynecology, 28, 217–222.

    Article  Google Scholar 

  27. Conway, G. S. (2000). Premature Ovarian Failure. British Medical Bulletin, 56, 643–649.

    Article  CAS  PubMed  Google Scholar 

  28. Hunter, M. G., Robinson, R. S., Mann, G. E., & Webb, R. (2004). Endocrine and Paracrine Control of Follicular Development and Ovulation rate in Farm Species. Animal Reproduction Science, 82-83, 461–477.

    Article  CAS  PubMed  Google Scholar 

  29. Kimler, B. F., Briley, S. M., Johnson, B. W., Armstrong, A. G., Jasti, S., & Duncan, F. E. (2018). Radiation-Induced Ovarian Follicle Loss Occurs without Overt Stromal Changes. Reproduction (Cambridge, England), 155(6), 553–562.

    Article  CAS  Google Scholar 

  30. Wang, S., Sun, M., Yu, L., Wang, Y., Yao, Y., & Wang, D. (2018). Niacin Inhibits Apoptosis and Rescues Premature Ovarian Failure. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 50, 2060–2070.

    Article  CAS  Google Scholar 

  31. Rinaldi, V., Hsieh, K., Munroe, R., Bolcun-Filas, E., & Schimenti, J. (2017). Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death. Genetics, 206, 1823–1828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. John, G. B., Gallardo, T. D., Shirley, L. J., & Castrillon, D. H. (2008). Foxo3 is a PI3K-Dependent Molecular Switch Controlling the Initiation of Oocyte Growth. Developmental Biology, 321, 197–204.

    Article  CAS  PubMed  Google Scholar 

  33. Picut, C. A., Swanson, C. L., Scully, K. L., Roseman, V. C., Parker, R. F., & Remick, A. K. (2008). Ovarian Follicle Counts using Proliferating Cell Nuclear Antigen (PCNA) and Semi-Automated Image Analysis in Rats. Toxicologic Pathology, 36, 674–679.

    Article  PubMed  Google Scholar 

  34. Melo, R. M. C., Martins, Y. S., Luz, R. K., Rizzo, E., & Bazzoli, N. (2015). PCNA and Apoptosis during Post-Spawning Ovarian Remodeling in the Teleost Oreochromis Niloticus. Tissue and Cell, 47, 541–549.

    Article  CAS  PubMed  Google Scholar 

  35. Said, R. S., Nada, A. S., & El-Demerdash, E. (2012). Sodium Selenite Improves Folliculogenesis in Radiation-Induced Ovarian Failure: a Mechanistic Approach. PLoS One, 7, e50928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guo, J. Q., Gao, X., Lin, Z. J., Wu, W. Z., Huang, L. H., Dong, H. Y., Chen, J., Lu, J., Fu, Y. F., Wang, J., Ma, Y. J., Chen, X. W., Wu, Z. X., He, F. Q., Yang, S. L., Liao, L. M., Zheng, F., & Tan, J. M. (2013). BMSCs Reduce Rat Granulosa Cell Apoptosis Induced by Cisplatin and Perimenopause. BMC Cell Biology, 14, 18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jones, A. S. K., & Shikanov, A. (2019). Follicle Development as an Orchestrated Signaling Network in a 3D organoid. Journal of Biological Engineering, 13, 2.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Elvin, J. A., & Matzuk, M. M. (1998). Mouse Models of Ovarian Failure. Reviews of Reproduction, 3, 183–195.

    Article  CAS  PubMed  Google Scholar 

  39. Liu, Z., Castrillon, D. H., Zhou, W., & Richards, J. S. (2013). FOXO1/3 depletion in granulosa cells alters follicle growth, death and regulation of pituitary FSH. Molecular Endocrinology (Baltimore, Md.), 27, 238–252.

    Article  CAS  Google Scholar 

  40. Cunningham, M. A., Zhu, Q., & Hammond, J. M. (2004). FoxO1a can Alter Cell Cycle Progression by Regulating the Nuclear Localization of p27kip in Granulosa Cells. Molecular endocrinology (Baltimore, Md.), 18, 1756–1767.

    Article  CAS  Google Scholar 

  41. Castrillon, D. H., Miao, L., Kollipara, R., Horner, J. W., & DePinho, R. A. (2003). Suppression of Ovarian Follicle Activation in Mice by the Transcription factor Foxo3a. Science (New York, N.Y.), 301, 215–218.

    Article  CAS  Google Scholar 

  42. Shen, M., Lin, F., Zhang, J., Tang, Y., Chen, W. K., & Liu, H. (2012). Involvement of the Up-Regulated FoxO1 Expression in Follicular Granulosa Cell Apoptosis Induced by Oxidative Stress. The Journal of Biological Chemistry, 287, 25727–25740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Park, Y., Maizels, E. T., Feiger, Z. J., Alam, H., Peters, C. A., Woodruff, T. K., Unterman, T. G., Lee, E. J., Jameson, J. L., & Hunzicker-Dunn, M. (2005). Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-Dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad. The Journal of Biological Chemistry, 280, 9135–9148.

    Article  CAS  PubMed  Google Scholar 

  44. Liu, L., Rajareddy, S., Reddy, P., Du, C., Jagarlamudi, K., Shen, Y., Gunnarsson, D., Selstam, G., Boman, K., & Liu, K. (2007). Infertility caused by Retardation of Follicular Development in Mice with Oocyte-Specific Expression of Foxo3a. Development (Cambridge, England), 134, 199–209.

    Article  CAS  Google Scholar 

  45. Hashimoto, O., Nakamura, T., Shoji, H., Shimasaki, S., Hayashi, Y., & Sugino, H. (1997). A Novel Role of Follistatin, an Activin-Binding Protein, in the Inhibition of Activin Action in Rat Pituitary Cells. Endocytotic Degradation of Activin and its Acceleration by Follistatin associated with Cell-Surface Heparan Sulfate. The Journal of Biological Chemistry, 272, 13835–13842.

    Article  CAS  PubMed  Google Scholar 

  46. Jorgez, C. J., Klysik, M., Jamin, S. P., Behringer, R. R., & Matzuk, M. M. (2004). Granulosa Cell-Specific Inactivation of Follistatin causes Female Fertility Defects. Molecular Endocrinology (Baltimore, Md.), 18, 953–967.

    Article  CAS  Google Scholar 

  47. Davis, A. J., Brooks, C. F., & Johnson, P. A. (2001). Follicle-Stimulating Hormone Regulation of Inhibin Alpha- and beta(B)-subunit and Follistatin Messenger Ribonucleic Acid in Cultured Avian Granulosa Cells. Biology of Reproduction, 64, 100–106.

    Article  CAS  PubMed  Google Scholar 

  48. Fazzini, M., Vallejo, G., Colman-Lerner, A., Trigo, R., Campo, S., Barañao, J. L. S., & Saragüeta, P. E. (2006). Transforming Growth Factor β1 Regulates Follistatin Mrna Expression during in vitro Bovine Granulosa Cell Differentiation. Journal of Cellular Physiology, 207, 40–48.

    Article  CAS  PubMed  Google Scholar 

  49. Mantawy, E. M., Said, R. S., & Abdel-Aziz, A. K. (2019). Mechanistic Approach of the Inhibitory Effect of Chrysin on Inflammatory and Apoptotic Events Implicated in Radiation-Induced Premature Ovarian Failure: Emphasis on TGF-β/MAPKs signaling pathway. Biomedicine & Pharmacotherapy, 109, 293–303.

    Article  CAS  Google Scholar 

  50. Rosairo, D., Kuyznierewicz, I., Findlay, J., & Drummond, A. (2008). Transforming Growth Factor-Beta: its Role in Ovarian Follicle Development. Reproduction (Cambridge, England), 136, 799–809.

    Article  CAS  Google Scholar 

  51. Elvin, J. A., Clark, A. T., Wang, P., Wolfman, N. M., & Matzuk, M. M. (1999). Paracrine Actions of Growth Differentiation Factor-9 in the Mammalian Ovary. Molecular Endocrinology, 13, 1035–1048.

    Article  CAS  PubMed  Google Scholar 

  52. Chu, Y. L., Xu, Y. R., Yang, W. X., & Sun, Y. (2018). The role of FSH and TGF-β Superfamily in Follicle Atresia. Aging, 10, 305–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, H. X., Li, T. Y., & Kidder, G. M. (2010). WNT2 Regulates DNA Synthesis in Mouse Granulosa Cells through Beta-Catenin. Biology of Reproduction, 82, 865–875.

    Article  CAS  PubMed  Google Scholar 

  54. Castañon, B. I., Stapp, A. D., Gifford, C. A., Spicer, L. J., Hallford, D. M., & Hernandez Gifford, J. A. (2012). Follicle-Stimulating Hormone Regulation of Estradiol Production: Possible Involvement of WNT2 and β-catenin in Bovine Granulosa Cells. Journal of Animal Science, 90, 3789–3797.

    Article  PubMed  Google Scholar 

  55. Fan, H. Y., O'Connor, A., Shitanaka, M., Shimada, M., Liu, Z., & Richards, J. S. (2010). Beta-catenin (CTNNB1) Promotes Preovulatory Follicular Development but Represses LH-mediated Ovulation and Luteinization. Molecular Endocrinology (Baltimore, Md.), 24, 1529–1542.

    Article  CAS  Google Scholar 

  56. Hsieh, M., Johnson, M. A., Greenberg, N. M., & Richards, J. S. (2002). Regulated Expression of Wnts and Frizzleds at Specific Stages of Follicular Development in the Rodent Ovary. Endocrinology, 143, 898–908.

    Article  CAS  PubMed  Google Scholar 

  57. Hernandez Gifford, J. A. (2015). The Role of WNT Signaling in Adult Ovarian Folliculogenesis. Reproduction (Cambridge, England), 150, R137–R148.

    Article  CAS  Google Scholar 

  58. Li, L., Ji, S. Y., Yang, J. L., Li, X. X., Zhang, J., Zhang, Y., Hu, Z. Y., & Liu, Y. X. (2014). Wnt/β-catenin Signaling Regulates Follicular Development by Modulating the Expression of Foxo3a Signaling Components. Molecular and Cellular Endocrinology, 382, 915–925.

    Article  CAS  PubMed  Google Scholar 

  59. Yao, H. H., Matzuk, M. M., Jorgez, C. J., Menke, D. B., Page, D. C., Swain, A., & Capel, B. (2004). Follistatin Operates Downstream of Wnt4 in Mammalian Ovary Organogenesis. Developmental Dynamics: An Official Publication of the American Association of the Anatomists, 230, 210–215.

    Article  CAS  Google Scholar 

  60. Pan, D. (2007). Hippo Signaling in Organ Size Control. Genes & Development, 21, 886–897.

    Article  CAS  Google Scholar 

  61. Hsueh, A. J. W., & Kawamura, K. (2020). Hippo Signaling Disruption and Ovarian Follicle Activation in Infertile Patients. Fertility and Sterility, 114, 458–464.

    Article  CAS  PubMed  Google Scholar 

  62. Hu, J., Zhao, W., Huang, Y., Wang, Z., Jiang, T., & Wang, L. (2019). MiR-1180 from Bone Marrow MSCs Promotes Cell Proliferation and Glycolysis in Ovarian Cancer Cells via SFRP1/Wnt Pathway. Cancer Cell International, 19, 66. https://doi.org/10.1186/s12935-019-0751-z.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors did not receive support from any organization for the submitted work.

Author information

Author notes

  1. Marwa O. El-Derany and Riham S . Said contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt

    Marwa O. El-Derany

  2. Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt

    Riham S . Said

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt

    Ebtehal El-Demerdash

Authors
  1. Marwa O. El-Derany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riham S . Said
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ebtehal El-Demerdash
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MO: Conceptualization, Methodology, Investigation, Formal analysis, Writing-Original draft preparation and Editing, RS: Conceptualization, Methodology, Investigation, Formal analysis, Writing-Original draft preparation and Editing, ED: Conceptualization, Methodology, Supervision, Formal analysis, Writing-Original draft preparation and Editing All authors have read the journal’s authorship statement and agree to it.

Corresponding author

Correspondence to Ebtehal El-Demerdash.

Ethics declarations

Ethical Approval

The experimental protocol was carried out in accordance with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 2011) and was approved by the Research Ethics Committee, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors have read the journal’s policy on disclosure of potential conflicts of interest and they all declare no personal or financial conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PNG 1240 kb)

ESM 2

(DOCX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-Derany, M.O., Said, R.S... & El-Demerdash, E. Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-β, Wnt/β-Catenin and Hippo Pathways. Stem Cell Rev and Rep 17, 1429–1445 (2021). https://doi.org/10.1007/s12015-021-10135-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-021-10135-9

Keywords

Search

Navigation