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PloS one2014; 9(6); e97889; doi: 10.1371/journal.pone.0097889

Changes in expression pattern of selected endometrial proteins following mesenchymal stem cells infusion in mares with endometrosis.

Abstract: Mesenchymal stem cells (MSCs) due to their self-renewal potential and differentiation capacity are useful for tissue regeneration. Immunomodulatory and trophic properties of MSCs were demonstrated suggesting their use as medicinal signaling cells able to positively change local environment in injured tissue. Equine endometrosis is a progressive degenerative disease responsible for glandular alterations and endometrial fibrosis which causes infertility in mares. More precisely, this disease is characterized by phenotypic changes in the expression pattern of selected endometrial proteins. Currently, no effective treatment is available for endometrosis. Herein, we aimed at the evaluation of expression pattern of these proteins after allogeneic equine adipose tissue-derived multipotent mesenchymal stem cells (eAT-MSCs) infusion as well as at testing the capacity of these cells to promote endometrial tissue remodeling in mares with endometrosis. eAT-MSC (2 × 10(7)/animal) were transplanted into mares' uterus and control animals received only placebo. Uterine biopsies were collected before (day 0) and after (days 7, 21 and 60) cells transplantation. Conventional histopathology as well as expression analysis of such proteins as laminin, vimentin, Ki-67-antigen, α-smooth muscle actin (α-SMA) and cytokeratin 18 (CK18) have been performed before and after eAT-MSCs transplantation. We demonstrated that eAT-MSCs induced early (at day 7) remodeling of endometrial tissue microenvironment through changes observed in intra cellular and intra glandular localization of aforementioned proteins. We demonstrated that eAT-MSCs were able to positively modulate the expression pattern of studied secretory proteins as well as, to promote the induction of glandular epithelial cells proliferation suggesting local benefits to committed endometrial tissue environment after eAT-MSCs transplantation.
Publication Date: 2014-06-05 PubMed ID: 24901368PubMed Central: PMC4046935DOI: 10.1371/journal.pone.0097889Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study evaluates the impact of using mesenchymal stem cell infusion to treat endometrosis in horses, which is a condition where certain changes in the expression of proteins in the uterus lead to infertility. The researchers found that the treatment had positive effects in modulating the expression of these proteins and encouraging cell growth.

Objective of the Study

  • The primary goal of this research was to assess the effects of using adipose tissue-derived multipotent mesenchymal stem cells (eAT-MSCs) from horses to treat equine endometrosis, a degenerative disease causing infertility. This condition is characterized by changes in the expression pattern of certain endometrial proteins, and as of now, there is no effective treatment available for it.
  • The researchers were also interested in determining whether these eAT-MSCs can induce endometrial tissue remodeling in mares with endometrosis. As such, they examined the expression patterns of these proteins after the eAT-MSC infusion.

Methodology

  • The team used a transplant approach where they infused eAT-MSC into the uterus of affected mares, while the control animals received a placebo treatment.
  • This study involved taking uterine biopsy samples before and after cells transplantation. The “after” samples were collected at days 7, 21, and 60 post-transplantation for analysis.

Analysis

  • The researchers performed both conventional histopathology and expression analysis of specific proteins, such as laminin, vimentin, Ki-67-antigen, α-smooth muscle actin (α-SMA), and cytokeratin 18 (CK18) present in the endometrium, before and after the transplant.
  • By analyzing these protein expressions, researchers were looking at early signs of endometrial tissue remodeling. These are changes believed to bring about a positive transformation in the cellular and glandular constructs of the tissue affected by endometrosis.

Findings

  • The study revealed that eAT-MSCs did initiate early remodeling of endometrial tissue microenvironment. This was marked by alterations observed in the intra cellular and intra glandular localizations of the proteins under study as early as day 7.
  • More importantly, the infused eAT-MSCs were found capable of positively modulating the expression pattern of the secretory proteins being examined. These cells also promoted the induction of glandular epithelial cells proliferation. These outcomes suggest local benefits to the affected endometrial tissue environment after eAT-MSCs transplantation.

Cite This Article

APA
Mambelli LI, Mattos RC, Winter GH, Madeiro DS, Morais BP, Malschitzky E, Miglino MA, Kerkis A, Kerkis I. (2014). Changes in expression pattern of selected endometrial proteins following mesenchymal stem cells infusion in mares with endometrosis. PLoS One, 9(6), e97889. https://doi.org/10.1371/journal.pone.0097889

Publication

ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 9
Issue: 6
Pages: e97889
PII: e97889

Researcher Affiliations

Mambelli, Lisley I
  • Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brasil; Programa de Pós-Graduação em Anatomia dos Animais Domésticos e Silvestres da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, São Paulo, SP, Brasil.
Mattos, Rodrigo C
  • Reprolab, Faculdade de Medicina Veterinária, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
Winter, Gustavo H Z
  • Reprolab, Faculdade de Medicina Veterinária, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
Madeiro, Dener S
  • Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brasil.
Morais, Bruna P
  • Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brasil.
Malschitzky, Eduardo
  • Curso de Medicina Veterinária, ULBRA, Canoas, RS, Brasil.
Miglino, Maria Angélica
  • Programa de Pós-Graduação em Anatomia dos Animais Domésticos e Silvestres da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, São Paulo, SP, Brasil.
Kerkis, Alexandre
  • Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brasil.
Kerkis, Irina
  • Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brasil.

MeSH Terms

  • Animals
  • Biomarkers
  • Biopsy
  • Endometriosis / genetics
  • Endometriosis / pathology
  • Endometriosis / therapy
  • Endometrium / metabolism
  • Endometrium / pathology
  • Female
  • Gene Expression Profiling
  • Horses
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / metabolism
  • Mucous Membrane / metabolism
  • Mucous Membrane / pathology
  • Transcriptome

Conflict of Interest Statement

The authors have declared that no competing interests exist.

References

This article includes 34 references
  1. Kenney RM. The etiology, diagnosis and classification of chronic degenerative endometritis. Equine Vet J 25: 186.
  2. Schoon HA, Schoon D, Klug E. Uterusbiopsien als Hilfsmittel fur Diagnose und Prognose von Fertilitatsstorungen der Stute. Pferdeheilkunde 8: 355–362.
  3. Kenney RM. Cyclic and pathologic changes of the mare endometrium as detected by biopsy, with a note on early embryonic death.. J Am Vet Med Assoc 1978 Feb 1;172(3):241-62.
    pubmed: 621166
  4. Brunckhorst D, Shoon HA, Bader H, Sieme H. Morphologische, enzym-und immunohistochemische charakteristika des endometrialen yklus der stute. Fertilität 7: 44–51.
  5. Gerstenberg C, Allen WR, Stewart F. Factors controlling epidermal growth factor (EGF) gene expression in the endometrium of the mare.. Mol Reprod Dev 1999 Jul;53(3):255-65.
  6. Aupperle H, Ozgen SSchoon HA, Schoon D, Hoppen HO, Sieme H, Tannapfel A. Cyclical endometrial steroid hormone receptor expression and proliferation intensity in the mare.. Equine Vet J 2000 May;32(3):228-32.
    pubmed: 10836478doi: 10.2746/042516400776563554google scholar: lookup
  7. Walter I, Handler J, Reifinger M, Aurich C. Association of endometriosis in horses with differentiation of periglandular myofibroblasts and changes of extracellular matrix proteins.. Reproduction 2001 Apr;121(4):581-6.
    pubmed: 11277878
  8. Hoffmann C, Ellenberger C, Mattos RC, Aupperle H, Dhein S, Stief B, Schoon HA. The equine endometrosis: new insights into the pathogenesis.. Anim Reprod Sci 2009 Apr;111(2-4):261-78.
  9. Lehmann J, Ellenberger C, Hoffmann C, Bazer FW, Klug J, Allen WR, Sieme H, Schoon HA. Morpho-functional studies regarding the fertility prognosis of mares suffering from equine endometrosis.. Theriogenology 2011 Oct 15;76(7):1326-36.
  10. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses.. Blood 2005 Feb 15;105(4):1815-22.
    pubmed: 15494428doi: 10.1182/blood-2004-04-1559google scholar: lookup
  11. Uccelli A, Prockop DJ. Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?. Curr Opin Immunol 2010 Dec;22(6):768-74.
    pubmed: 21093239doi: 10.1016/j.coi.2010.10.012google scholar: lookup
  12. Caplan AI. What's in a name?. Tissue Eng Part A 2010 Aug;16(8):2415-7.
    pubmed: 20412005doi: 10.1089/ten.tea.2010.0216google scholar: lookup
  13. Caplan AI, Correa D. The MSC: an injury drugstore.. Cell Stem Cell 2011 Jul 8;9(1):11-5.
    pmc: PMC3144500pubmed: 21726829doi: 10.1016/j.stem.2011.06.008google scholar: lookup
  14. Sorrell JM, Baber MA, Caplan AI. Influence of adult mesenchymal stem cells on in vitro vascular formation.. Tissue Eng Part A 2009 Jul;15(7):1751-61.
    pmc: PMC2792097pubmed: 19196139doi: 10.1089/ten.tea.2008.0254google scholar: lookup
  15. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells.. Circulation 2004 Mar 16;109(10):1292-8.
  16. Wagner J, Kean T, Young R, Dennis JE, Caplan AI. Optimizing mesenchymal stem cell-based therapeutics.. Curr Opin Biotechnol 2009 Oct;20(5):531-6.
    pubmed: 19783424doi: 10.1016/j.copbio.2009.08.009google scholar: lookup
  17. Mambelli LI, Santos EJ, Frazão PJ, Chaparro MB, Kerkis A, Zoppa AL, Kerkis I. Characterization of equine adipose tissue-derived progenitor cells before and after cryopreservation.. Tissue Eng Part C Methods 2009 Mar;15(1):87-94.
    pubmed: 19196122doi: 10.1089/ten.tec.2008.0186google scholar: lookup
  18. Kenney RM, Doig PA. Equine endometrial biopsy. Current Therapy in Theriogenology 723–729.
  19. Mambelli LI, Winter GH, Kerkis A, Malschitzky E, Mattos RC, Kerkis I. A novel strategy of mesenchymal stem cells delivery in the uterus of mares with endometrosis.. Theriogenology 2013 Mar 15;79(5):744-50.
  20. Schoon HA, Schoon D, Klug E. Die Endometriumbiopsie bei der Stute im klinisch-gynakologischen Kontext. Pferdeheilkunde 13: 453–464.
  21. Schoon HA, Wiegandt I, Schoon D, Aupperle H, Bartmann CP. Functional disturbances in the endometrium of barren mares: a histological and immunohistological study.. J Reprod Fertil Suppl 2000;(56):381-91.
    pubmed: 20681150
  22. Kozubenko N, Turnovcova K, Kapcalova M, Butenko O, Anderova M, Rusnakova V, Kubista M, Hampl A, Jendelova P, Sykova E. Analysis of in vitro and in vivo characteristics of human embryonic stem cell-derived neural precursors.. Cell Transplant 2010;19(4):471-86.
    pubmed: 20021734doi: 10.3727/096368909x484707google scholar: lookup
  23. Sémont A, Mouiseddine M, François A, Demarquay C, Mathieu N, Chapel A, Saché A, Thierry D, Laloi P, Gourmelon P. Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis.. Cell Death Differ 2010 Jun;17(6):952-61.
    pubmed: 20019749doi: 10.1038/cdd.2009.187google scholar: lookup
  24. Franke WW, Appelhans B, Schmid E, Freudenstein C, Osborn M, Weber K. The organization of cytokeratin filaments in the intestinal epithelium.. Eur J Cell Biol 1979 Aug;19(3):255-68.
    pubmed: 385321
  25. Aupperle H, Schoon D, Schoon HA. Physiological and pathological expression of intermediate filaments in the equine endometrium.. Res Vet Sci 2004 Jun;76(3):249-55.
    pubmed: 15046960doi: 10.1016/j.rvsc.2003.11.003google scholar: lookup
  26. Bader H, Kremer H, Vogt C, Schoon HA. Investigations on the protein patterns of the equine uterine secretions as functional parameter of the endometrium. Pferdeheilkunde 5: 544.
  27. Norwitz ER, Fernandez-Shaw S, Barlow DH, Starkey PM. Expression of intermediate filament in endometrial glands changes with the onset of pregnancy and in endometriosis.. Hum Reprod 1991 Nov;6(10):1470-3.
  28. Tabibzadeh S. Human endometrium: an active site of cytokine production and action.. Endocr Rev 1991 Aug;12(3):272-90.
    pubmed: 1935822doi: 10.1210/edrv-12-3-272google scholar: lookup
  29. Nisolle M, Casanas-Roux F, Donnez J. Coexpression of cytokeratin and vimentin in eutopic endometrium and endometriosis throughout the menstrual cycle: evaluation by a computerized method.. Fertil Steril 1995 Jul;64(1):69-75.
    pubmed: 7540565
  30. McNutt MA, Bolen JW, Gown AM, Hammar SP, Vogel AM. Coexpression of intermediate filaments in human epithelial neoplasms.. Ultrastruct Pathol 1985;9(1-2):31-43.
    pubmed: 2418559doi: 10.3109/01913128509055483google scholar: lookup
  31. Dabbs DJ, Geisinger KR, Norris HT. Intermediate filaments in endometrial and endocervical carcinomas. The diagnostic utility of vimentin patterns.. Am J Surg Pathol 1986 Aug;10(8):568-76.
  32. Schmitt-Gräff A, Desmoulière A, Gabbiani G. Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity.. Virchows Arch 1994;425(1):3-24.
    pubmed: 7921410doi: 10.1007/bf00193944google scholar: lookup
  33. Czernobilsky B, Remadi S, Gabbiani G. Alpha-smooth muscle actin and other stromal markers in endometrial mucosa.. Virchows Arch A Pathol Anat Histopathol 1993;422(4):313-7.
    pubmed: 8506625doi: 10.1007/bf01608341google scholar: lookup
  34. Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM, Martin GR. Laminin--a glycoprotein from basement membranes.. J Biol Chem 1979 Oct 10;254(19):9933-7.
    pubmed: 114518

Citations

This article has been cited 18 times.
  1. Bhaskar V, Saini S, Ansari S, Ghai S, Thakur A, Chopra S, Verma V, Malakar D. Allogenic adipose derived mesenchymal stem cells are effective than antibiotics in treating endometritis.. Sci Rep 2023 Jul 12;13(1):11280.
    doi: 10.1038/s41598-023-36820-ypubmed: 37438398google scholar: lookup
  2. Jasiński T, Zdrojkowski Ł, Ferreira-Dias G, Kautz E, Juszczuk-Kubiak E, Domino M. Molecular Mechanism of Equine Endometrosis: The NF-κB-Dependent Pathway Underlies the Ovarian Steroid Receptors' Dysfunction.. Int J Mol Sci 2022 Jul 1;23(13).
    doi: 10.3390/ijms23137360pubmed: 35806363google scholar: lookup
  3. Westendorf J, Wobeser B, Epp T. IIB or not IIB, part 2: assessing inter-rater and intra-rater repeatability of the Kenney-Doig scale in equine endometrial biopsy evaluation.. J Vet Diagn Invest 2022 Mar;34(2):215-225.
    doi: 10.1177/10406387211062866pubmed: 34965793google scholar: lookup
  4. Chen JM, Huang QY, Zhao YX, Chen WH, Lin S, Shi QY. The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous.. Front Immunol 2021;12:785717.
    doi: 10.3389/fimmu.2021.785717pubmed: 34868069google scholar: lookup
  5. Cequier A, Sanz C, Rodellar C, Barrachina L. The Usefulness of Mesenchymal Stem Cells beyond the Musculoskeletal System in Horses.. Animals (Basel) 2021 Mar 25;11(4).
    doi: 10.3390/ani11040931pubmed: 33805967google scholar: lookup
  6. Amaral A, Fernandes C, Morazzo S, Rebordão MR, Szóstek-Mioduchowska A, Lukasik K, Gawronska-Kozak B, Telo da Gama L, Skarzynski DJ, Ferreira-Dias G. The Inhibition of Cathepsin G on Endometrial Explants With Endometrosis in the Mare.. Front Vet Sci 2020;7:582211.
    doi: 10.3389/fvets.2020.582211pubmed: 33195599google scholar: lookup
  7. Bukowska J, Szóstek-Mioduchowska AZ, Kopcewicz M, Walendzik K, Machcińska S, Gawrońska-Kozak B. Adipose-Derived Stromal/Stem Cells from Large Animal Models: from Basic to Applied Science.. Stem Cell Rev Rep 2021 Jun;17(3):719-738.
    doi: 10.1007/s12015-020-10049-ypubmed: 33025392google scholar: lookup
  8. Schöniger S, Schoon HA. The Healthy and Diseased Equine Endometrium: A Review of Morphological Features and Molecular Analyses.. Animals (Basel) 2020 Apr 5;10(4).
    doi: 10.3390/ani10040625pubmed: 32260515google scholar: lookup
  9. Canisso IF, Segabinazzi LGTM, Fedorka CE. Persistent Breeding-Induced Endometritis in Mares - a Multifaceted Challenge: From Clinical Aspects to Immunopathogenesis and Pathobiology.. Int J Mol Sci 2020 Feb 20;21(4).
    doi: 10.3390/ijms21041432pubmed: 32093296google scholar: lookup
  10. Zheng HX, Zhao Y, Xu Y, Zhang ZJ, Zhu JJ, Fan YF, Lin N. Long-time qingyan formula extract treatment exerts estrogenic activities on reproductive tissues without side effects in ovariectomized rats and via active ER to ERE-independent gene regulation.. Aging (Albany NY) 2019 Jun 19;11(12):4032-4049.
    doi: 10.18632/aging.102035pubmed: 31219800google scholar: lookup
  11. Sultana T, Lee S, Yoon HY, Lee JI. Current Status of Canine Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Veterinary Medicine.. Stem Cells Int 2018;2018:8329174.
    doi: 10.1155/2018/8329174pubmed: 30123294google scholar: lookup
  12. Rink BE, Beyer T, French HM, Watson E, Aurich C, Donadeu FX. The Fate of Autologous Endometrial Mesenchymal Stromal Cells After Application in the Healthy Equine Uterus.. Stem Cells Dev 2018 Aug 1;27(15):1046-1052.
    doi: 10.1089/scd.2018.0056pubmed: 29790424google scholar: lookup
  13. Tibary A. Grand Challenge Animal Reproduction-Theriogenology: From the Bench to Application to Animal Production and Reproductive Medicine.. Front Vet Sci 2017;4:114.
    doi: 10.3389/fvets.2017.00114pubmed: 28770218google scholar: lookup
  14. Liang RN, Li PS, Zou Y, Liu YL, Jiang Z, Liu Z, Fan P, Xu L, Peng JH, Sun XY. Ping-Chong-Jiang-Ni Formula Induces Apoptosis and Inhibits Proliferation of Human Ectopic Endometrial Stromal Cells in Endometriosis via the Activation of JNK Signaling Pathway.. Evid Based Complement Alternat Med 2017;2017:6489427.
    doi: 10.1155/2017/6489427pubmed: 28656053google scholar: lookup
  15. Wang Y, Xu S, Wu Y, Zhang J. Cucurbitacin E inhibits osteosarcoma cells proliferation and invasion through attenuation of PI3K/AKT/mTOR signalling pathway.. Biosci Rep 2016 Dec;36(6).
    doi: 10.1042/BSR20160165pubmed: 27653525google scholar: lookup
  16. Kim HR, Lee J, Byeon JS, Gu NY, Lee J, Cho IS, Cha SH. Extensive characterization of feline intra-abdominal adipose-derived mesenchymal stem cells.. J Vet Sci 2017 Sep 30;18(3):299-306.
    doi: 10.4142/jvs.2017.18.3.299pubmed: 27456770google scholar: lookup
  17. Xu Y, Ma XP, An JN, Zhang ZJ, Ding J, Qu YK, Liu ZL, Lin N. Short-time QiBaoMeiRan Formula Treatment Exerts Estrogenic Activities without Side Effects on Reproductive Tissues in Immature Mice.. Sci Rep 2015 Dec 8;5:17436.
    doi: 10.1038/srep17436pubmed: 26644197google scholar: lookup
  18. Łupicka M, Socha B, Szczepańska A, Korzekwa A. Expression of pluripotency markers in the bovine uterus with adenomyosis.. Reprod Biol Endocrinol 2015 Sep 29;13:110.
    doi: 10.1186/s12958-015-0106-0pubmed: 26416515google scholar: lookup