SpringerLink
Log in

Reversing Uteropathies Including Cancer-Like Changes in Mice by Transplanting Mesenchymal Stromal Cells or XAR Treatment

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

Abstract

Pluripotent, very small embryonic-like stem cells (VSELs) and tissue-committed ‘progenitors’ termed endometrial stem cells (EnSCs) are reported in mouse uterus. They express gonadal and gonadotropin hormone receptors and thus are vulnerable to early-life endocrine insults. Neonatal exposure of mouse pups to endocrine disruption cause stem/progenitor cells to undergo epigenetic changes, excessive self-renewal, and blocked differentiation that results in various uteropathies including non-receptive endometrium, hyperplasia, endometriosis, adenomyosis, and cancer-like changes in adult life. Present study investigated reversal of these uteropathies, by normalizing functions of VSELs and EnSCs. Two strategies were evaluated including (i) transplanting mesenchymal stromal cells (provide paracrine support) on D60 or (ii) oral administration of XAR (epigenetic regulator) daily from days 60–100 and effects were studied later in 100 days old mice. Results show normalization of stem/progenitor cells (Oct-4, Oct-4A, Sox-2, Nanog) and Wnt signalling (Wnt-4, β-catenin, Axin-2) specific transcripts. Flow cytometry results showed reduced numbers of 2–6 µm, LIN-CD45-SCA-1 + VSELs. Hyperplasia (Ki67) of epithelial (Pax-8, Foxa-2) and myometrial (α-Sma, Tgf-β) cells was reduced, adenogenesis (differentiation of glands) was restored, endometrial receptivity and differentiation (LIF, c-KIT, SOX-9, NUMB) and stromal cells niche (CD90, VIMENTIN, Pdgfra, Vimentin) were improved, cancer stem cells markers (OCT-4, CD166) were reduced while tumor suppressor genes (PTEN, P53) and epigenetic regulators (Ezh-2, Sirt-1) were increased. To conclude, normalizing VSELs/EnSCs to manage uteropathies provides a novel basis for initiating clinical studies. The study falls under the umbrella of United Nations Sustainable Development Goal 3 to ensure healthy lives and well-being for all of all ages.

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

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data Availability

All relevant data is included in the manuscript and the supplement.

Code Availability

Not applicable.

Abbreviations

VSELs :

Very Small embryonic-like stem cells

EnSCs :

Endometrial stem progenitor cells

MSC :

Mesenchymal stem/stromal cell

DES :

Diethylstilbesterol

E2 :

Estradiol

EDCs :

Endocrine disrupting chemicals

PND :

Postnatal day

OCT-4 :

Octamer-binding transcription factor 4

SOX-2 :

Sex determining region Y-box 2

NANOG :

Homeobox transcription factor

SCA-1 :

Stem cells antigen-1

SSEA-1 :

Stage-specific embryonic antigen-1

LIF :

Leukemia inhibitory factor

c-KIT :

Receptor tyrosine kinase

CSCs :

Cancer stem cells

CD166 (ALCAM) :

Activated leukocyte cell adhesion molecule

GFP :

Green fluorescent protein

α-SMA :

Alpha-smooth muscle actin

7AAD :

7-Amino-actinomycin D

PAX-8 :

Paired-box gene 8

FOXA-2 :

Forkhead box protein A2

NUMB :

NUMB: endocytic adaptor protein

CD90 :

Cluster of Differentiation 90

Ki-67 :

Marker of proliferation

PTEN :

Phosphatase and TENsin homolog deleted on chromosome10

P53 :

Tumour suppressor protein p53

SIRT-1 :

Silent mating type information regulation 2 homolog-1

DNMTs :

DNA methyltransferases

References

  1. Skakkebæk, N. E., Lindahl-Jacobsen, R., Levine, H., Andersson, A. M., Jorgensen, N., Main, K. M., & Juul, A. (2022). Environmental factors in declining human fertility. Nature Reviews Endocrinology, 18, 139–157. https://doi.org/10.1038/s41574-021-00598-8

    Article  PubMed  Google Scholar 

  2. Murphy, A. R., Campo, H., & Kim, J. J. (2022). Strategies for modelling endometrial diseases. Nature Reviews Endocrinology, 18, 727–743. https://doi.org/10.1038/s41574-022-00725-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dutta, S., Banu, S. K., & Arosh, J. A. (2023). Endocrine disruptors and endometriosis. Reproductive Toxicology, 115, 56–73. https://doi.org/10.1016/j.reprotox.2022.11.007

    Article  CAS  PubMed  Google Scholar 

  4. Stephens, V. R., Rumph, J. T., Ameli, S., Bruner-Tran, K. L., & Osteen, K. G. (2022). The potential relationship between environmental endocrine disruptor exposure and the development of endometriosis and adenomyosis. Frontiers in Physiology, 12, 807685. https://doi.org/10.3389/fphys.2021.807685

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhang, Y., Lu, Y., Ma, H., Xu, Q., & Wu, X. (2021). Combined exposure to multiple endocrine disruptors and uterine leiomyomata and endometriosis in US women. Frontiers in Endocrinology, 12, 726876. https://doi.org/10.3389/fendo.2021.726876

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bariani, M. V., Rangaswamy, R., Siblini, H., Yang, Q., Al-Hendy, A., & Zota, A. R. (2020). The role of endocrine-disrupting chemicals in uterine fibroid pathogenesis. Current Opinion in Endocrinology Diabetes & Obesity, 27, 380–387. https://doi.org/10.1097/MED.0000000000000578

    Article  CAS  Google Scholar 

  7. Mallozzi, M., Leone, C., Manurita, F., Bellati, F., & Caserta, D. (2017). Endocrine disrupting chemicals and endometrial cancer: An overview of recent laboratory evidence and epidemiological studies. International Journal of Environmental Research and Public Health, 14, 334. https://doi.org/10.3390/ijerph14030334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Caserta, D., Costanzi, F., Marco, M., Benedetto, L., Matteucci, E., Assorgi, C., et al. (2021). Effects of endocrine-disrupting chemicals on endometrial receptivity and embryo implantation: A systematic review of 34 mouse model studies. International Journal of Environmental Research and Public Health, 18, 6840. https://doi.org/10.3390/ijerph18136840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kyo, S., Sato, S., & Nakayama, K. (2020). Cancer-associated mutations in normal human endometrium: Surprise or expected? Cancer Science, 111, 3458–3467. https://doi.org/10.1111/cas.14571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guo, S. W. (2020). Cancer-associated mutations in endometriosis: Shedding light on the pathogenesis and pathophysiology. Human Reproduction Update, 26, 423–449. https://doi.org/10.1093/humupd/dmz047

    Article  CAS  PubMed  Google Scholar 

  11. Suda, K., Nakaoka, H., Yoshihara, K., Ishiguro, T., Tamura, R., Mori, Y., Suda, K., Nakaoka, H., Yoshihara, K., Ishiguro, T., Tamura, R., Mori, Y., Yamawaki, K., Adachi, S., Takahashi, T., Kase, H., Tanaka, K., Yamamoto, T., Motoyama, T., … Enomoto, T. (2018). Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Reports, 24, 1777–1789. https://doi.org/10.1016/j.celrep.2018.07.037

    Article  CAS  PubMed  Google Scholar 

  12. Anglesio, M. S., Papadopoulos, N., Ayhan, A., Nazeran, T. M., Noë, M., Horlings, et al. (2017). Cancer-associated mutations in endometriosis without cancer. New England Journal of Medicine, 376, 1835–1848. https://doi.org/10.1056/NEJMoa1614814

    Article  PubMed  Google Scholar 

  13. Singh, P., & Bhartiya, D. (2023). Mouse uterine stem cells are affected by endocrine disruption and initiate uteropathies. Reproduction, 165, 249–268. https://doi.org/10.1530/REP-22-0337

    Article  CAS  PubMed  Google Scholar 

  14. Cousins, F. L., Pandoy, R., **, S., & Gargett, C. E. (2021). The elusive endometrial epithelial stem/progenitor cells. Frontiers in Cell and Developmental Biology, 9, 640319. https://doi.org/10.3389/fcell.2021.640319

    Article  PubMed  PubMed Central  Google Scholar 

  15. Santamaria, X., Mas, A., Cervelló, I., Taylor, H., & Simon, C. (2018). Uterine stem cells: From basic research to advanced cell therapies. Human Reproduction Update, 24, 673–693. https://doi.org/10.1093/humupd/dmy028

    Article  CAS  PubMed  Google Scholar 

  16. Gao, S., Zhang, Y., Liang, K., Bi, R., & Du, Y. (2022). Mesenchymal stem cells (MSCs): A novel therapy for type 2 diabetes. Stem Cells International, 2022, 1–17. https://doi.org/10.1155/2022/8637493

    Article  CAS  Google Scholar 

  17. Rungsiwiwut, R., Virutamasen, P., & Pruksananonda, K. (2021). Mesenchymal stem cells for restoring endometrial function: An infertility perspective. Reproductive Medicine and Biology, 20, 13–19. https://doi.org/10.1002/rmb2.12339

    Article  PubMed  Google Scholar 

  18. Syed, S. M., Kumar, M., Ghosh, A., Tomasetig, F., Ali, A., Whan, R. M., Syed, S. M., Kumar, M., Ghosh, A., Tomasetig, F., Ali, A., Whan, R. M., Alterman, D., & Tanwar, P. S. (2020). Endometrial Axin2 + cells drive epithelial homeostasis, regeneration, and cancer following oncogenic transformation. Cell Stem Cell, 26, 64-80e13. https://doi.org/10.1016/j.stem.2019.11.012

    Article  CAS  PubMed  Google Scholar 

  19. James, K., Bhartiya, D., Ganguly, R., Kaushik, A., Gala, K., Singh, P., & Metkari, S. M. (2018). Gonadotropin and steroid hormones regulate pluripotent very small embryonic-like stem cells in adult mouse uterine endometrium. Journal of Ovarian Research, 11, 83. https://doi.org/10.1186/s13048-018-0454-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gunjal, P., Bhartiya, D., Metkari, S., Manjramkar, D., & Patel, H. (2015). Very small embryonic-like stem cells are the elusive mouse endometrial stem cells- a pilot study. Journal of Ovarian Research, 8, 9. https://doi.org/10.1186/s13048-015-0138-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ratajczak, M. Z., Ratajczak, J., & Kucia, M. (2019). Very small embryonic-like stem cells (vsels). Circulation Research, 124, 208–210. https://doi.org/10.1161/CIRCRESAHA.118.314287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bhartiya, D., Shaikh, A., Anand, S., Patel, H., Kapoor, S., Sriraman, K., … Unni, S. (2016). Endogenous, very small embryonic-like stem cells: Critical review, therapeutic potential and a look ahead. Human Reproduction Update, 23, 1–36. https://doi.org/10.1093/humupd/dmw030

  23. Singh, P., & Bhartiya, D. (2021). Pluripotent stem (VSELs) and progenitor (EnSCs) cells exist in adult mouse uterus and show cyclic changes across estrus cycle. Reproductive Sciences, 28, 278–290. https://doi.org/10.1007/s43032-020-00250-2

    Article  CAS  PubMed  Google Scholar 

  24. Singh, P., Metkari, S., & Bhartiya, D. (2022). Additional evidence to support OCT-4 positive VSELs and EnSCs as the elusive tissue-resident stem/progenitor cells in adult mice uterus. Stem Cell Research & Therapy, 13, 60. https://doi.org/10.1186/s13287-022-02703-8

    Article  CAS  Google Scholar 

  25. Singh, P., Metkari, S. M., & Bhartiya, D. (2022). Mice uterine stem cells are affected by neonatal endocrine disruption & initiate uteropathies in adult life independent of circulatory ovarian hormones. Stem Cell Reviews and Reports, 18, 1686–1701. https://doi.org/10.1007/s12015-021-10279-8

    Article  CAS  PubMed  Google Scholar 

  26. Fernandes, G., Silva, G., Pavan, A., Chiba, D., Chin, C., & Santos, D. (2017). Epigenetic regulatory mechanisms induced by resveratrol. Nutrients, 9, 1201. https://doi.org/10.3390/nu9111201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Esfandyari, S., Chugh, R. M., Park, H., Hobeika, E., Ulin, M., & Al-Hendy, A. (2020). Mesenchymal stem cells as a bio-organ for treatment of female infertility. Cells, 9, 2253. https://doi.org/10.3390/cells9102253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pokrovskaya, L. A., Zubareva, E. V., Nadezhdin, S. V., Lysenko, A. S., & Litovkina, T. L. (2020). Biological activity of mesenchymal stem cells secretome as a basis for cell-free therapeutic approach. Research Results in Pharmacology, 6, 57–68. https://doi.org/10.3897/rrpharmacology.6.49413

    Article  CAS  Google Scholar 

  29. Abumaree, M. H., Jumah, A., Kalionis, M. A., Jawdat, B., Al Khaldi, D., AlTalabani, A., & Knawy, B. A. (2013). Phenotypic and functional characterization of mesenchymal stem cells from chorionic villi of human term placenta. Stem Cell Reviews and Reports, 9, 16–31. https://doi.org/10.1007/s12015-012-9385-4

    Article  CAS  PubMed  Google Scholar 

  30. Gao, L., Huang, Z., Lin, H., Tian, Y., Li, P., & Lin, S. (2019). Bone marrow mesenchymal stem cells (bmscs) restore functional endometrium in the rat model for severe asherman syndrome. Reproductive Sciences, 26, 436–444. https://doi.org/10.1177/1933719118799201

    Article  CAS  PubMed  Google Scholar 

  31. Yi, K. W., Mamillapalli, R., Sahin, C., Song, J., Tal, R., & Taylor, H. S. (2019). Bone marrow-derived cells or C-X-C motif chemokine 12 (CXCL12) treatment improve thin endometrium in a mouse model†. Biology of Reproduction, 100, 61–70. https://doi.org/10.1093/biolre/ioy175

    Article  PubMed  Google Scholar 

  32. Santamaria, X., Cabanillas, S., Arbona, C., & Simon, C. (2015). Autologous cell therapy with CD133 + bone marrow stem cells in refractory Asherman’s syndrome and endometrial atrophy: A pilot cohort study. Fertility and Sterility, 104, e90. https://doi.org/10.1016/j.fertnstert.2015.07.278

    Article  Google Scholar 

  33. Novakovic, R., Rajkovic, J., Gostimirovic, M., Gojkovic-Bukarica, L., & Radunovic, N. (2022). Resveratrol and reproductive health. Life, 12, 294. https://doi.org/10.3390/life12020294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Amaya, S. C., Savaris, R. F., Filipovic, C. J., Wise, J. D., Hestermann, E., Young, S. L., & Lessey, B. A. (2014). Resveratrol and endometrium: A closer look at an active ingredient of red wine using in vivo and in vitro models. Reproductive Sciences, 21, 1362–1369. https://doi.org/10.1177/1933719114525271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, C., Chen, Z., Zhao, X., Lin, C., Hong, S., Lou, Y., **, Y., Wang, C., Chen, Z., Zhao, X., Lin, C., Hong, S., Lou, Y., Shi, X., Zhao, M., Yang, X., Guan, M.-X., & **, Y. (2021). Transcriptome-based analysis reveals therapeutic effects of resveratrol on endometriosis in a rat model. Drug Design Development and Therapy, Volume 15, 4141–4155. https://doi.org/10.2147/DDDT.S323790

    Article  Google Scholar 

  36. Kong, X., Xu, X., Zhou, L., Zhu, M., Yao, S., Ding, Y., … Zhou, H. (2020). MTA1, a target of resveratrol, promotes epithelial-mesenchymal transition of endometriosis via ZEB2. Molecular Therapy - Methods & Clinical Development, 19, 295–306. https://doi.org/10.1016/j.omtm.2020.09.013

  37. Kolahdouz Mohammadi, R., & Arablou, T. (2017). Resveratrol and endometriosis: In vitro and animal studies and underlying mechanisms (review). Biomedicine & Pharmacotherapy, 91, 220–228. https://doi.org/10.1016/j.biopha.2017.04.078

    Article  CAS  Google Scholar 

  38. Chen, Lin, Shih, Wang, Hong, Shieh, … Hsia. (2019). Natural antioxidant resveratrol suppresses uterine fibroid cell growth and extracellular matrix formation in vitro and in vivo. Antioxidants, 8, 99. https://doi.org/10.3390/antiox8040099

  39. Wu, C.-H., Shieh, T.-M., Wei, L.-H., Cheng, T.-F., Chen, H.-Y., Huang, T.-C., … Hsia,S.-M. (2016). Resveratrol inhibits proliferation of myometrial and leiomyoma cells and decreases extracellular matrix-associated protein expression. Journal of Functional Foods, 23, 241–252. https://doi.org/10.1016/j.jff.2016.02.038

  40. Tripathi, V., Chhabria, S., Jadhav, V., Bhartiya, D., & Tripathi, A. (2018). Stem cells and progenitors in human peripheral blood get activated by extremely active resveratrol (XAR™). Stem Cell Reviews and Reports, 14, 213–222. https://doi.org/10.1007/s12015-017-9784-7

    Article  CAS  PubMed  Google Scholar 

  41. Singh, P., & Bhartiya, D. (2022). Molecular insights into endometrial cancer in mice. Stem Cell Reviews and Reports, 18, 1702–1717. https://doi.org/10.1007/s12015-022-10367-3

    Article  CAS  PubMed  Google Scholar 

  42. Chapman, J. C., Min, S. H., Freeh, S. M., & Michael, S. D. (2009). The estrogen-injected female mouse: New insight into the etiology of PCOS. Reproductive Biology and Endocrinology, 7, 47. https://doi.org/10.1186/1477-7827-7-47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Newbold, R. R., Bullock, B. C., & McLachlan, J. A. (1990). Uterine adenocarcinoma in mice following developmental treatment with estrogens: A model for hormonal carcinogenesis. Cancer Research, 50, 7677–7681.

    CAS  PubMed  Google Scholar 

  44. Kaushik, A., Anand, S., & Bhartiya, D. (2020). Altered biology of testicular VSELs and SSCs by neonatal endocrine disruption results in defective spermatogenesis, reduced fertility and tumor initiation in adult mice. Stem Cell Reviews and Reports, 16, 893–908. https://doi.org/10.1007/s12015-020-09996-3

    Article  CAS  PubMed  Google Scholar 

  45. Sharma, D., & Bhartiya, D. (2022). Dysfunctional ovarian stem cells due to neonatal endocrine disruption result in pcos and ovarian insufficiency in adult mice. Stem Cell Reviews and Reports, 18, 2912–2927. https://doi.org/10.1007/s12015-022-10414-z

    Article  CAS  PubMed  Google Scholar 

  46. Soleimani, M., & Nadri, S. (2009). A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nature Protocols, 4, 102–106. https://doi.org/10.1038/nprot.2008.221

    Article  CAS  PubMed  Google Scholar 

  47. Lan, T., Luo, M., & Wei, X. (2021). Mesenchymal stem/stromal cells in cancer therapy. Journal of Hematology & Oncology, 14, 195. https://doi.org/10.1186/s13045-021-01208-w

    Article  Google Scholar 

  48. Moraes, D. (2018). What the relationship between CD90 and CD44 in mesenchymal stem cells? Cytotherapy, 20, S47. https://doi.org/10.1016/j.jcyt.2018.02.124

    Article  Google Scholar 

  49. Bhartiya, D., Singh, P., Sharma, D., & Kaushik, A. (2022). Very small embryonic-like stem cells (VSELs) regenerate whereas mesenchymal stromal cells (MSCs) rejuvenate diseased reproductive tissues. Stem Cell Reviews and Reports, 18, 1718–1727. https://doi.org/10.1007/s12015-021-10243-6

    Article  CAS  PubMed  Google Scholar 

  50. Kaushik, A., Metkari, S., Ali, S., & Bhartiya, D. (2023). Preventing/reversing adverse effects of endocrine disruption on mouse testes by normalizing tissue resident VSELs. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-023-10601-6

    Article  PubMed  Google Scholar 

  51. Choi, H. Y., Seok, J., Kang, G. H., Lim, K. M., & Cho, S. G. (2021). The role of NUMB/NUMB isoforms in cancer stem cells. BMB Reports, 54, 335–343. https://doi.org/10.5483/BMBRep.2021.54.7.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brandmaier, A., Hou, S. Q., & Shen, W. H. (2017). Cell cycle control by PTEN. Journal of Molecular Biology, 429, 2265–2277. https://doi.org/10.1016/j.jmb.2017.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim, D. K., Ham, M. H., Lee, S. Y., Shin, M. J., Kim, Y. E., Song, P., … Kim, J. H.(2020). CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells. BMB Reports, 53, 622–627. https://doi.org/10.5483/BMBRep.2020.53.12.102

  54. Vannuccini, S., & Petraglia, F. (2019). Recent advances in understanding and managing adenomyosis. F1000Research, 8, 283. https://doi.org/10.12688/f1000research.17242.1

  55. Johnatty, S. E., Stewart, C. J. R., Smith, D., Nguyen, A., O’ Dwyer, J., O’Mara, T.A., … Spurdle, A. B. (2020). Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer. Scientific Reports, 10, 3621. https://doi.org/10.1038/s41598-020-59916-1

  56. Uimari, O., Nazri, H., & Tapmeier, T. (2021). Endometriosis and uterine fibroids (leiomyomata): Comorbidity, risks and implications. Frontiers in Reproductive Health, 3, 750018. https://doi.org/10.3389/frph.2021.750018

    Article  PubMed  PubMed Central  Google Scholar 

  57. McMellen, A., Woodruff, E. R., Corr, B. R., Bitler, B. G., & Moroney, M. R. (2020). Wnt signaling in gynecologic malignancies. International Journal of Molecular Sciences, 21, 4272. https://doi.org/10.3390/ijms21124272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fatima, I., Barman, S., Rai, R., Thiel, K. W., & Chandra, V. (2021). Targeting wnt signaling in endometrial cancer. Cancers, 13, 2351. https://doi.org/10.3390/cancers13102351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nees, L. K., Heublein, S., Steinmacher, S., Juhasz-Böss, I., Brucker, S., Tempfer, C. B., & Wallwiener, M. (2022). Endometrial hyperplasia as a risk factor of endometrial cancer. Archives of Gynecology and Obstetrics, 306, 407–421. https://doi.org/10.1007/s00404-021-06380-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ring, K. L., Mills, A. M., & Modesitt, S. C. (2022). Endometrial hyperplasia. Obstetrics and gynecology, 140, 1061–1075. https://doi.org/10.1097/AOG.0000000000004989

    Article  CAS  PubMed  Google Scholar 

  61. Kim, H., Kim, H. J., & Ahn, H. S. (2023). Does endometriosis increase the risks of endometrial hyperplasia and endometrial cancer? Gynecologic Oncology, 169, 147–153. https://doi.org/10.1016/j.ygyno.2022.06.021

    Article  PubMed  Google Scholar 

  62. Kuai, D., Tang, Q., Tian, W., & Zhang, H. (2023). Rapid identification of endometrial hyperplasia and endometrial endometrioid cancer in young women. Discover Oncology, 14, 121. https://doi.org/10.1007/s12672-023-00736-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Devis, L., Moiola, C. P., Masia, N., Martinez-Garcia, E., Santacana, M., Stirbat, T. V., … Colas, E. (2017). Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion, and metastasis in early-stage endometrioid endometrial cancer. The Journal of Pathology, 24, 475–487. https://doi.org/10.1002/path.4851

  64. Liang, S., Huang, C., Jia, S., & Wang, B. (2011). Activated leukocyte cell adhesion molecule expression is up-regulated in the development of endometrioid carcinoma. International Journal of Gynecologic Cancer, 21, 523–528. https://doi.org/10.1097/IGC.0b013e31820e135a

    Article  Google Scholar 

  65. **ao, M., Wang, X., Yan, M., & Chen, W. (2016). A systematic evaluation for the potential translation of CD166-related expression as a cancer biomarker. Expert Review of Molecular Diagnostics, 16, 925–932. https://doi.org/10.1080/14737159.2016.1211932

    Article  CAS  PubMed  Google Scholar 

  66. Bhartiya, D., Sharma, N., Dutta, S., Kumar, P., Tripathi, A., & Tripathi, A. (2023). Very small embryonic-like stem cells transform into cancer stem cells and are novel candidates for detecting/monitoring cancer by a simple blood test. Stem Cells, 41, 310–318. https://doi.org/10.1093/stmcls/sxad015

    Article  PubMed  Google Scholar 

  67. Capezzuoli, T., Rossi, M., La Torre, F., Vannuccini, S., & Petraglia, F. (2022). Hormonal drugs for the treatment of endometriosis. Current Opinion in Pharmacology, 67, 102311. https://doi.org/10.1016/j.coph.2022.102311

    Article  CAS  PubMed  Google Scholar 

  68. Kailasam, A., & Langstraat, C. (2022). Contemporary use of hormonal therapy in endometrial cancer: A literature review. Current Treatment Options in Oncology, 23, 1818–1828. https://doi.org/10.1007/s11864-022-01031-6

    Article  PubMed  Google Scholar 

  69. Kaushik, A., & Bhartiya, D. (2020). Additional evidence to establish existence of two stem cell populations including VSELs and SSCs in adult mouse testes. Stem Cell Reviews and Reports, 16, 992–1004. https://doi.org/10.1007/s12015-020-09993-6

    Article  CAS  PubMed  Google Scholar 

  70. Cui, X., Zhao, X., & Liang, Y. (2022). Sex differences in normal and malignant hematopoiesis. Blood Science, 4(4), 185–191. https://doi.org/10.1097/bs9.0000000000000133

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ratajczak, M. Z. (2017). Why are hematopoietic stem cells so ‘sexy’? On a search for developmental explanation. Leukemia, 31, 1671–1677. https://doi.org/10.1038/leu.2017.148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mierzejewska, K., Borkowska, S., Suszynska, E., Suszynska, M., Poniewierska-Baran,A., Maj, M., … Ratajczak, M. Z. (2015). Hematopoietic stem/progenitor cells express several functional sex hormone receptors—novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells and Development, 24, 927–937. https://doi.org/10.1089/scd.2014.0546

  73. Squillaro, T., Peluso, G., & Galderisi, U. (2016). Clinical trials with mesenchymal stem cells: An update. Cell Transplantation, 25, 829–848. https://doi.org/10.3727/096368915X689622

    Article  PubMed  Google Scholar 

  74. Wang, Y.-J., Zhao, P., Sui, B.-D., Liu, N., Hu, C.-H., Chen, J., … **, Y. (2018).Resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates. Experimental & Molecular Medicine, 50, 1–15. https://doi.org/10.1038/s12276-018-0109-y

  75. Suvorova, I. I., Knyazeva, A. R., Petukhov, A. V., Aksenov, N. D., & Pospelov, V. A. (2019). Resveratrol enhances pluripotency of mouse embryonic stem cells by activating AMPK/Ulk1 pathway. Cell Death Discovery, 5, 61. https://doi.org/10.1038/s41420-019-0137-y

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bhartiya, D. (2013). Are mesenchymal cells indeed pluripotent stem cells or just stromal cells? OCT-4 and VSELs biology has led to better understanding. Stem Cells International, 2013, 1–6. https://doi.org/10.1155/2013/547501

    Article  CAS  Google Scholar 

  77. Taichman, R. S., Wang, Z., Shiozawa, Y., Jung, Y., Song, J., Balduino, A., … Krebsbach,P. H. (2010). Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells and Development, 19, 1557–1570. https://doi.org/10.1089/scd.2009.0445

  78. Bhartiya, D., Mohammad, S. A., Singh, P., Sharma, D., & Kaushik, A. (2022). GFP tagged VSELs help delineate novel stem cells biology in multiple adult tissues. Stem Cell Reviews and Reports, 18, 1603–1613. https://doi.org/10.1007/s12015-022-10401-4

    Article  PubMed  Google Scholar 

  79. Ren, G., Shi, J., Huang, S., Liu, C., Ni, F., He, Y., … **e, H. (2022). The fabrication of novel zein and resveratrol covalent conjugates: Enhanced thermal stability, emulsifying and antioxidant properties. Food Chemistry, 374, 131612. https://doi.org/10.1016/j.foodchem.2021.131612

  80. Berretta, M., Bignucolo, A., Di Francia, R., Comello, F., Facchini, G., Ceccarelli,M., … Maurea, N. (2020). Resveratrol in cancer patients: from bench to bedside. International Journal of Molecular Sciences, 21, 2945. https://doi.org/10.3390/ijms21082945

  81. Bhaskara, V. K., Mittal, B., Mysorekar, V. V., Amaresh, N., & Simal-Gandara, J. (2020). Resveratrol, cancer and cancer stem cells: A review on past to future. Current Research in Food Science, 3, 284–295. https://doi.org/10.1016/j.crfs.2020.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Madanes, D., Meresman, G., Valla, S. A., Hassan, N., Kiesel, L., Greve, B., … Ricci,A. G. (2022). Resveratrol impairs cellular mechanisms associated with the pathogenesis of endometriosis. Reproductive BioMedicine Online, 44, 976–990. https://doi.org/10.1016/j.rbmo.2022.02.008

  83. Ren, B., Kwah, M. X.-Y., Liu, C., Ma, Z., Shanmugam, M. K., Ding, L., … Goh, B. C. (2021) . Resveratrol for cancer therapy: Challenges and future perspectives. Cancer Letters, 515, 63–72. https://doi.org/10.1016/j.canlet.2021.05.001

  84. Ko, J.-H., Sethi, G., Um, J.-Y., Shanmugam, M. K., Arfuso, F., Kumar, A. P., … Ahn,K. S. (2017). The role of resveratrol in cancer therapy. International Journal of Molecular Sciences, 18, 2589. https://doi.org/10.3390/ijms18122589

  85. Hmadcha, A., Martin-Montalvo, A., Gauthier, B. R., Soria, B., & Capilla-Gonzalez, V. (2020). Therapeutic potential of mesenchymal stem cells for cancer therapy. Frontiers in Bioengineering and Biotechnology, 8, 43. https://doi.org/10.3389/fbioe.2020.00043

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li, J., Qi, J., Yao, G., Zhu, Q., Li, X., Xu, R., … Sun, Y. (2021). Deficiency of Sirtuin 1 impedes endometrial decidualization in recurrent implantation failure patients. Frontiers in Cell and Developmental Biology, 9:598364. https://doi.org/10.3389/fcell.2021.598364

  87. Cummings, M. J., Yu, H., Paudel, S., Hu, G., Li, X., Hemberger, M., & Wang, X. (2022). Uterine-specific SIRT1 deficiency confers premature uterine aging and impairs invasion and spacing of blastocyst, and stromal cell decidualization, in mice. Molecular Human Reproduction, 28, gaac016. https://doi.org/10.1093/molehr/gaac016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Taguchi, A., Wada-Hiraike, O., Kawana, K., Koga, K., Yamashita, A., Shirane, A., & Fujii, T. (2014). Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: A possible role of the sirtuin 1 pathway. Journal of Obstetrics and Gynaecology Research, 40, 770–778. https://doi.org/10.1111/jog.12252

    Article  CAS  PubMed  Google Scholar 

  89. Shirane, A., Wada-Hiraike, O., Tanikawa, M., Seiki, T., Hiraike, H., Miyamoto, Y., Taketani, Y., Shirane, A., Wada-Hiraike, O., Tanikawa, M., Seiki, T., Hiraike, H., Miyamoto, Y., Sone, K., Hirano, M., Oishi, H., Oda, K., Kawana, K., Nakagawa, S., … Taketani, Y. (2012). Regulation of SIRT1 determines initial step of endometrial receptivity by controlling E-cadherin expression. Biochemical and Biophysical Research Communications, 424, 604–610. https://doi.org/10.1016/j.bbrc.2012.06.160

    Article  CAS  PubMed  Google Scholar 

  90. Elibol, B., & Kilic, U. (2018). High levels of SIRT1 expression as a protective mechanism against disease-related conditions. Frontiers in Endocrinology, 9, 614. https://doi.org/10.3389/fendo.2018.00614

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tatone, C., Di Emidio, G., Barbonetti, A., Carta, G., Luciano, A. M., Falone, S., & Amicarelli, F. (2018). Sirtuins in gamete biology and reproductive physiology: Emerging roles and therapeutic potential in female and male infertility. Human Reproduction Update, 24, 267–289. https://doi.org/10.1093/humupd/dmy003

    Article  CAS  PubMed  Google Scholar 

  92. Seishima, R., Leung, C., Yada, S., Murad, K. B. A., Tan, L. T., Hajamohideen, A.,… Barker, N. (2019). Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development. Nature Communications, 10, 5378. https://doi.org/10.1038/s41467-019-13363-3

  93. Chumduri, C., & Turco, M. Y. (2021). Organoids of the female reproductive tract. Journal of Molecular Medicine, 99, 531–553. https://doi.org/10.1007/s00109-020-02028-0

    Article  PubMed  Google Scholar 

  94. Lõhmussaar, K., Boretto, M., & Clevers, H. (2020). Human-derived model systems in gynecological cancer research. Trends in Cancer, 6, 1031–1043. https://doi.org/10.1016/j.trecan.2020.07.007

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Help from Confocal Microscopy; Flow Cytometry and Histology Central Facilities at NIRRCH is acknowledged. Subhan MD help is acknowledged for XAR treatment. We acknowledge all those who have published data that may be directly relevant but may not have been quoted.

Funding

The study was supported by the core support provided by Indian Council of Medical Research, Government of India, New Delhi. PS acknowledges the DST-INSPIRE fellowship (IF170144).

Author information

Author notes

  1. Deepa Bhartiya

    Present address: Epigeneres Biotech Pvt Ltd, Lower Parel, Mumbai, 400 013, India

Authors and Affiliations

  1. Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive & Child Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India

    Pushpa Singh, S. M. Metkari & Deepa Bhartiya

  2. Epigeneres Biotech Pvt Ltd, Lower Parel, Mumbai, 400 013, India

    Anish Tripathi

Authors
  1. Pushpa Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. M. Metkari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anish Tripathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deepa Bhartiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DB planned the study, arrange the funds, and helped in manuscript drafting. All authors discussed the findings, read, and approved the final version. PS helped design the study, performed all experiments, and wrote the article. SMM performed all the surgeries. AT provided XAR- a nano-formulation of Resveratrol.

Corresponding author

Correspondence to Deepa Bhartiya.

Ethics declarations

Ethics Approval

Project no-16/17 was approved on 21 December 2017.

Consent to Participate

Not applicable.

Consent for Publication

NIRRCH manuscript number RA/1420/12-2022.

Conflict of Interest

Authors declare no conflict of interest whatsoever that could be perceived as prejudicing the impartiality of the research reported. This study was completed when DB was at NIRRCH and no conflict of interest existed with Epigeneres Biotech Pvt Ltd., Mumbai which she joined after superannuation. XAR was provided as a gift by Epigeneres as an outcome of an earlier collaborative publication (https://doi.org/10.1007/s12015-017-9784-7).

Additional information

Publisher’s Note

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

All work is done at NIRRCH.

Supplementary Information

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 3.29 MB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, P., Metkari, S.M., Tripathi, A. et al. Reversing Uteropathies Including Cancer-Like Changes in Mice by Transplanting Mesenchymal Stromal Cells or XAR Treatment. Stem Cell Rev and Rep 20, 258–282 (2024). https://doi.org/10.1007/s12015-023-10632-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-023-10632-z

Keywords

Search

Navigation