Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility

Abstract

Premature ovarian failure (POF) is a refractory disease for clinical treatment with the goal of restoring fertility. In this study, umbilical cord mesenchymal stem cells on a collagen scaffold (collagen/UC-MSCs) can activate primordial follicles in vitro via phosphorylation of FOXO3a and FOXO1. Transplantation of collagen/UC-MSCs to the ovaries of POF patients rescued overall ovarian function, evidenced by elevated estradiol concentrations, improved follicular development, and increased number of antral follicles. Successful clinical pregnancy was achieved in women with POF after transplantation of collagen/UC-MSCs or UC-MSCs. In summary, collagen/UC-MSC transplantation may provide an effective treatment for POF.

This is a preview of subscription content, access via your institution.

References

  1. Akasaki, Y., Hasegawa, A., Saito, M., Asahara, H., Iwamoto, Y., and Lotz, M.K. (2014). Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthritis Cartilage 22, 162–170.

    Article  CAS  PubMed  Google Scholar 

  2. Brenkman, A.B., and Burgering, B.M.T. (2003). FoxO3a eggs on fertility and aging. Trends Mol Med 9, 464–467.

    Article  CAS  PubMed  Google Scholar 

  3. Carracedo, A., and Pandolfi, P.P. (2008). The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27, 5527–5541.

    Article  CAS  PubMed  Google Scholar 

  4. Castrillon, D.H., Miao, L., Kollipara, R., Horner, J.W., and DePinho, R.A. (2003). Suppression of Ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301, 215–218.

    Article  CAS  PubMed  Google Scholar 

  5. David, A., Van Langendonckt, A., Gilliaux, S., Dolmans, M.M., Donnez, J., and Amorim, C.A. (2012). Effect of cryopreservation and transplantation on the expression of kit ligand and anti-Mullerian hormone in human ovarian tissue. Hum Reprod 27, 1088–1095.

    Article  CAS  PubMed  Google Scholar 

  6. De Vos, M., Devroey, P., and Fauser, B.C. (2010). Primary ovarian insufficiency. Lancet 376, 911–921.

    Article  PubMed  Google Scholar 

  7. 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 Cell 48, 370–382.

    Article  CAS  PubMed  Google Scholar 

  8. Esmaielzadeh, F., Hosseini, S.M., Nasiri, Z., Hajian, M., Chamani, M., Gourabi, H., Shahverdi, A.H., Vosough, A.D., and Nasr-Esfahani, M.H. (2013). Kit ligand and glial-derived neurotrophic factor as alternative supplements for activation and development of ovine preantral follicles in vitro. Mol Reproduct Dev 80, 35–47.

    Article  CAS  Google Scholar 

  9. Ezzati, M.M., Baker, M.D., Saatcioglu, H.D., Aloisio, G.M., Pena, C.G., Nakada, Y., Cuevas, I., Carr, B.R., and Castrillon, D.H. (2015). Regulation of FOXO3 subcellular localization by Kit ligand in the neonatal mouse ovary. J Assist Reprod Genet 32, 1741–1747.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Guan, J., Zhu, Z., Zhao, R.C., Xiao, Z., Wu, C., Han, Q., Chen, L., Tong, W., Zhang, J., Han, Q., et al. (2013). Transplantation of human mesenchymal stem cells loaded on collagen scaffolds for the treatment of traumatic brain injury in rats. Biomaterials 34, 5937–5946.

    Article  CAS  PubMed  Google Scholar 

  11. Hoogland, H.J., and Skouby, S.O. (1993). Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 47, 583–590.

    Article  CAS  PubMed  Google Scholar 

  12. Hsueh, A.J.W., Kawamura, K., Cheng, Y., and Fauser, B.C.J.M. (2015). Intraovarian control of early folliculogenesis. Endocr Rev 36, 1–24.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang, Y., Jiang, R., Cheng, X., Zhang, Q., Hu, Y., Zhang, H., Cao, Y., Zhang, M., Wang, J., Ding, L., et al. (2016). Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization. Mol Hum Reprod 22, 655–668.

    Article  CAS  PubMed  Google Scholar 

  14. John, G.B., Gallardo, T.D., Shirley, L.J., and Castrillon, D.H. (2008). Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth. Dev Biol 321, 197–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kawamura, K., Cheng, Y., Sun, Y.P., Zhai, J., Diaz-Garcia, C., Simon, C., Pellicer, A., and Hsueh, A.J. (2015). Ovary transplantation: to activate or not to activate. Hum Reprod 30, 2457–2460.

    Article  PubMed  Google Scholar 

  16. Knapczyk-Stwora, K., Grzesiak, M., Duda, M., Koziorowski, M., and Slomczynska, M. (2013). Effect of flutamide on folliculogenesis in the fetal porcine ovary—Regulation by Kit ligand/c-Kit and IGF1/IGF1R systems. Animal Reprod Sci 142, 160–167.

    Article  CAS  Google Scholar 

  17. Lai, D., Wang, F., Yao, X., Zhang, Q., Wu, X., and Xiang, C. (2015). Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med 13, 155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, J., Kawamura, K., Cheng, Y., Liu, S., Klein, C., Liu, S., Duan, E.K., and Hsueh, A.J.W. (2010). Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci USA 107, 10280–10284.

    Article  PubMed  Google Scholar 

  19. Li, L., Fu, Y., Xu, J., Lin, X., Chen, X., Zhang, X., and Luo, L. (2015). Caloric restriction promotes the reserve of follicle pool in adult female rats by inhibiting the activation of mammalian target of rapamycin signaling. Reprod Sci 22, 60–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Luisi, S., Orlandini, C., Regini, C., Pizzo, A., Vellucci, F., and Petraglia, F. (2015). Premature ovarian insufficiency: from pathogenesis to clinical management. J Endocrinol Invest 38, 597–603.

    Article  CAS  PubMed  Google Scholar 

  21. Park, C.W., Kim, K.S., Bae, S., Son, H.K., Myung, P.K., Hong, H.J., and Kim, H. (2009). Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells 2, 59–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seli, E., Babayev, E., Collins, S.C., Nemeth, G., and Horvath, T.L. (2014). Minireview: metabolism of female reproduction: regulatory mechanisms and clinical implications. Mol Endocrinol 28, 790–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shelling, A.N. (2010). Premature ovarian failure. Reproduction 140, 633–641.

    Article  CAS  PubMed  Google Scholar 

  24. Su, J., Ding, L., Cheng, J., Yang, J., Li, X., Yan, G., Sun, H., Dai, J., and Hu, Y. (2016). Transplantation of adipose-derived stem cells combined with collagen scaffolds restores ovarian function in a rat model of premature ovarian insufficiency. Hum Reprod 31, 1075–1086.

    Article  CAS  PubMed  Google Scholar 

  25. Suzuki, N., Yoshioka, N., Takae, S., Sugishita, Y., Tamura, M., Hashimoto, S., Morimoto, Y., and Kawamura, K. (2015). Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod 30, 608–615.

    Article  PubMed  Google Scholar 

  26. Terraciano, P., Garcez, T., Ayres, L., Durli, I., Baggio, M., Kuhl, C.P., Laurino, C., Passos, E., Paz, A.H., and Cirne-Lima, E. (2014). Cell therapy for chemically induced ovarian failure in mice. Stem Cells Int 2014, 1–8.

    Article  Google Scholar 

  27. Wang, N., Luo, L.L., Xu, J.J., Xu, M.Y., Zhang, X.M., Zhou, X.L., Liu, W. J., and Fu, Y.C. (2014). Obesity accelerates ovarian follicle development and follicle loss in rats. Metabolism 63, 94–103.

    Article  CAS  PubMed  Google Scholar 

  28. Wimmer, R.J., Liu, Y., Schachter, T.N., Stonko, D.P., Peercy, B.E., and Schneider, M.F. (2014). Mathematical modeling reveals modulation of both nuclear influx and efflux of Foxo1 by the IGF-I/PI3K/Akt pathway in skeletal muscle fibers. Am J Physiol Cell Physiol 306, C570–C584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu, L., Ding, L., Wang, L., Cao, Y., Zhu, H., Lu, J., Li, X., Song, T., Hu, Y., and Dai, J. (2017). Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars. Stem Cell Res Ther 8, 4.

    Article  CAS  Google Scholar 

  30. Xu, Y., Shi, T., Xu, A., and Zhang, L. (2016). 3D spheroid culture enhances survival and therapeutic capacities of MSCs injected into ischemic kidney. J Cell Mol Med 20, 1203–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yin, O., Cayton, K., and Segars, J.H. (2016). In vitro activation: a dip into the primordial follicle pool? J Clin Endocrinol Metab 101, 3568–3570.

    Article  CAS  PubMed  Google Scholar 

  32. Zhai, J., Yao, G., Dong, F., Bu, Z., Cheng, Y., Sato, Y., Hu, L., Zhang, Y., Wang, J., Dai, S., et al. (2016). In vitro activation of follicles and fresh tissue auto-transplantation in primary ovarian insufficiency patients. J Clin Endocrinol Metab 101, 4405–4412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, H., and Liu, K. (2015). Cellular and molecular regulation of the activation of mammalian primordial follicles: somatic cells initiate follicle activation in adulthood. Hum Reprod Update 21, 779–786.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, H., Risal, S., Gorre, N., Busayavalasa, K., Li, X., Shen, Y., Bosbach, B., Brännström, M., and Liu, K. (2014). Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice. Curr Biol 24, 2501–2508.

    Article  CAS  PubMed  Google Scholar 

  35. Zhu, S.F., Hu, H.B., Xu, H.Y., Fu, X.F., Peng, D.X., Su, W.Y., and He, Y.L. (2015). Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med 19, 2108–2117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Xiaoling Sun, Yong Liu and Fangfang He for their technical assistance in TVUS-guided transplantation, flow cytometry and repeated transvaginal ultrasonographic examinations, respectively. This work was supported by Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01030501 to Haixiang Sun), National Natural Science Foundation of China (31571189, 81571391, 30900847 to Lijun Ding), Jiangsu Provincial Medical Youth Talent (QNRC2016006) and Nanjing Medical Science Development Project (JQX14004, ZKX16042).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Yali Hu or Jianwu Dai or Haixiang Sun.

Electronic supplementary material

Figure S1

AKT1 expression in ovaries co-cultured with collagen/UC-MSCs.

Figure S2

Quantitative analyses of nuclear export of FOXO3a in oocytes of primordial follicles co-cultured with collagen/eSF or collagen/UC-MSCs.

Figure S3

Treatment with collagen/UC-MSCs had no effect on the expression of p-AKT1, FOXO3a and p-FOXO1 at 48 h. A—J, The expression of p-AKT1, FOXO3a and p-FOXO1 was determined using IHC.

Figure S4

The expression of Ki67 and C-caspase 3 in ovaries.

Figure S5

An illustration of ovary co-cultured with collagen/UC-MSCs in a culture dish.

Figure S6

Flow chart of the overall clinical study.

Figure S7

GMP grade UC-MSCs documents.

Figure S8

Procedure used for transplantation of collagen/UC-MSCs to ovaries of POF patients.

Table S1

Antibodies information

Table S2 Primers sequences

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ding, L., Yan, G., Wang, B. 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. 61, 1554–1565 (2018). https://doi.org/10.1007/s11427-017-9272-2

Download citation

Keywords

  • premature ovarian failure
  • collagen scaffold
  • UC-MSCs
  • primordial follicle activation
  • granulosa cells
  • FOXO3a
  • FOXO1