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RAS PhysiologyРоссийский физиологический журнал им. И.М. Сеченова Russian Journal of Physiology

  • ISSN (Print) 0869-8139
  • ISSN (Online) 2658-655X

Immunological Effect of Moderately Hypoxic Mesenchymal Stromal Cell Culture Conditions on Uterine Healing in Rats

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PII
S2658655X25070061-1
DOI
10.7868/S2658655X25070061
Publication type
Article
Status
Published
Authors
N.B. Tikhonova
  • Affiliation: Petrovsky National Research Center of Surgery
A.A. Temnov
  • Affiliation: Institute of Cell Biophysics of the Russian Academy of Sciences
V.V. Aleksankina
  • Affiliation: Petrovsky National Research Center of Surgery
A.P. Aleksankin
  • Affiliation: Petrovsky National Research Center of Surgery
T.V. Fokina
  • Affiliation: Petrovsky National Research Center of Surgery
A.N. Sklifas
  • Affiliation: Institute of Cell Biophysics of the Russian Academy of Sciences
E.V. Kuznetsova
  • Affiliation: Petrovsky National Research Center of Surgery
A.P. Milovanov
  • Affiliation: Petrovsky National Research Center of Surgery
L.M. Mikhaleva
  • Affiliation: Petrovsky National Research Center of Surgery
Volume/ Edition
Volume 111 / Issue number 7
Pages
1101-1116
Abstract
The aim is to determine the influence of conditioned medium of autologous bone marrow stromal cells (CMSC) cultured at 10% O, on the healing of the rat uterus after a thorough surgical incision. Methods: In the treated group of animals ( = 14), the edges of the uterine wound were processed with a conditioned medium prior to suturing, in the control group of animals ( = 14), the incision was not processed. Results: On the 5th and 15th days after the operation, morphological studies of the healing zone were carried out. The number of macrophages CD68, FABP4 cells and the level of mRNA expression of inflammatory cytokine IL-1b, IL-6 and anti-inflammatory IL-4, IL-10 were assessed. The healing area in the treated group was lower than the reference area in all monitoring periods ( < 0.05). From the 5th to the 15th day, the expression of IL-1b, IL-4, IL-6 and IL-10 in the control group decreased ( < 0.05), in the processed group no valid differences were found ( < 0.05). On the 5th day in the treatment group, the expression of IL-4 and IL-10 was lower than in the control, and on the 15th day the expression of IL-1b was lower in the control group. The number of macrophages of CD68 decreased by 15th day in the treated group compared to 5th day and was lower than in the control group. The FABP4 cell clusters in the area of damaged myometrium at 15 days in both groups were almost eliminated except for 2 animals in the control group. In the area of damaged perimetrium, FABP4 clusters increased in the control group by 15th day, and in the treated group decreased and was reliably lower than in the control group. Thus, the application of CMSC has resulted in a reduction of the damage area, reduced inflammatory response and accelerated recovery of the uterine wall.
Keywords
матка крысы заживление раны кондиционированная среда макрофаги адипоциты интерлейкины
Date of publication
21.12.2025
Year of publication
2025
Number of purchasers
0
Views
20

References

  1. 1. Kosaric N, Kiwanuka H, Gurtner GC (2019) Stem cell therapies for wound healing. Expert Opin Biol Ther 19(6): 575-585. https://doi.org/10.1080/14712598.2019.1596257
  2. 2. Raghuram AC, Yu RP, Lo AI, Sung CJ, Bircan M, Thompson HJ, Wong AK (2020) Role of stem cell therapies in treating chronic wounds: A systematic review. World J Stem Cells 12(7): 659-675. https://doi.org/10.4252/wjsc.v12.i7.659
  3. 3. Abdel-Gawad DRI, Moselhy WA, Ahmed RR, Al-Muzafar HM, Amin KA, Amin MM, El-Nahass ES, Abdou KAH (2021) Therapeutic effect of mesenchymal stem cells on histopathological, immunohistochemical, and molecular analysis in second-grade burn model. Stem Cell Res Ther 12(1): 308. https://doi.org/10.1186/s13287-021-02365-y
  4. 4. Zhou J, Shi Y (2023) Mesenchymal stem/stromal cells (MSCs): origin, immune regulation, and clinical applications. Cell Mol Immunol 20(6): 555-557. https://doi.org/10.1038/s41423-023-01034-9
  5. 5. Egger D, Tripisciano C, Weber V, Dominici M, Kasper C (2018) Dynamic Cultivation of Mesenchymal Stem Cell Aggregates. Bioengineering (Basel) 5(2): 48. https://doi.org/10.3390/bioengineering5020048
  6. 6. Mazes G, Sipos F (2022) Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases. Cells 11(15): 2300. https://doi.org/10.3390/cells11152300
  7. 7. Giovannelli L, Bari E, Jommi C, Tartara F, Armocida D, Garbossa D, Cofano F, Torre ML, Segale L (2023) Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access. Bioact Mater 29: 16-35. https://doi.org/10.1016/j.bioactmat.2023.06.013
  8. 8. Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Goncalves RM (2018) Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Preconditioning. Front Immunol 9: 2837. https://doi.org/10.3389/fimmu.2018.02837
  9. 9. Volkova MV, Shen N, Polyanskaya A, Qi X, Boyarintsev VY, Kovaleva EV, Troftmenko AV, Filkov GI, Mezentsev AV, Rybdikin SP, Durymanov MO (2023) Tissue-Oxygen-Adaptation of Bone Marrow-Derived Mesenchymal Stromal Cells Enhances Their Immunomodulatory and Pro-Angiogenic Capacity, Resulting in Accelerated Healing of Chemical Burns. Int J Mol Sci 24(4): 4102. https://doi.org/10.3390/ijms24044102
  10. 10. Pezzi A, Amorin B, Laureano A, Valim V, Dahmer A, Zambonato B, Sehn F, Wilke I, Bruschi L, Silva MALD, Filippi-Chiela E, Silla L (2017) Effects of Hypoxia in Long-Term In Vitro Expansion of Human Bone Marrow Derived Mesenchymal Stem Cells. J Cell Biochem 118(10): 3072-3079. https://doi.org/10.1002/jcb.25953
  11. 11. Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobryshev YV (2017) CD68/macrosialin: not just a histochemical marker. Lab Invest 97(1): 4-13. https://doi.org/10.1038/labinvest.2016.116
  12. 12. Lopez-Castejon G, Brough D (2011) Understanding the mechanism of IL-1β secretion. Cytokine Growth Factor Rev 22(4): 189-195. https://doi.org/10.1016/j.cytogfr.2011.10.001
  13. 13. Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10): a016295 https://doi.org/10.1101/cshperspect.a016295
  14. 14. Chatterjee P, Chiasson YL, Bounds KR, Mitchell BM (2014) Regulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy. Front Immunol 5: 253. https://doi.org/10.3389/fimmu.2014.00253
  15. 15. Park DW, Yang KM (2011) Hormonal regulation of uterine chemokines and immune cells. Clin Exp Reprod Med38(4): 179-185. https://doi.org/10.5653/cerm.2011.38.4.179
  16. 16. Engeland CG, Sabzehei B, Marucha PT (2009) Sex hormones and mucosal wound healing. Brain Behav Immun 23(5): 629-635. https://doi.org/10.1016/j.bbi.2008.12.001
  17. 17. Hubscher CH, Brooks DL, Johnson JR (2005) A quantitative method for assessing stages of the rat estrous cycle. Biotech Histochem 80(2): 79-87. https://doi.org/10.1080/10520290500138422
  18. 18. Tikhonova NB, Milovanov AP, Aleksankina VV, Fokina TV, Boltovskaya MN, Aleksankin AP, Artem'eva KA (2021) Analysis of Healing of Rat Uterine Wall After Full-Thickness Surgical Incision. Bull Exp Biol Med 172(1): 100-104. https://doi.org/10.1007/s10517-021-05340-y
  19. 19. Tikhonova NB, Milovanov AP, Aleksankina VV, Fokina TV, Boltovskaya MN, Aleksankin AP (2021) The role of adipose tissue in the healing of rat uterine wall after a full-thickness surgical incision. Clin Exp Morphol 10: 72-80. https://doi.org/10.31088/CEM2021.10.4.72-80
  20. 20. Temnov AA, Rogov KA, Skifas AN, Klychnikova EV, Hartl M, Djinovic-Carugo K, Charnagalov A (2019) Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure. Mol Biol Rep 46(3): 3101-3112. https://doi.org/10.1007/s11033-019-04765-z
  21. 21. Bustin SA, Benes Y, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Yandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4): 611-622. https://doi.org/10.1373/clinchem.2008.112797
  22. 22. De M, Wood GW (1990) Influence of oestrogen and progesterone on macrophage distribution in the mouse uterus. J Endocrinol 126(3): 417-424. https://doi.org/10.1677/joe.0.1260417
  23. 23. Huang J, Roby KF, Pace JL, Russell SW, Hunt JS (1995) Cellular localization and hormonal regulation of inducible nitric oxide synthase in cycling mouse uterus. J Leukoc Biol 57(1): 27-35. https://doi.org/10.1002/jlb.57.1.27
  24. 24. Zhang L, Long W, Xu W, Chen X, Zhao X, Wu B (2022) Digital Cell Atlas of Mouse Uterus: From Regenerative Stage to Maturational Stage. Front Genet 13: 847646. https://doi.org/10.3389/fgene.2022.847646
  25. 25. Furuhashi M, Saitoh S, Shimamoto K, Miura T (2015) Fatty Acid-Binding Protein 4 (FABP4): Pathophysiological Insights and Potent Clinical Biomarker of Metabolic and Cardiovascular Diseases. Clin Med Insights Cardiol 8(Suppl 3): 23-33. https://doi.org/10.4137/CMC.S17067
  26. 26. Shan T, Liu W, Kuang S (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27(1): 277-287. https://doi.org/10.1096/fj.12-211516
  27. 27. Elmasri H, Ghelfi E, Yu CW, Traphagen S, Cernadas M, Cao H, Shi GP, Plutzky J, Sahin M, Hotamisligil G, Cataltepe S (2012) Endothelial cell-fatty acid binding protein 4 promotes angiogenesis: role of stem cell factor/c-kit pathway. Angiogenesis 15(3): 457-468. https://doi.org/10.1007/s10456-012-9274-0
  28. 28. Steen KA, Xu H, Bernlohr DA (2017) FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2. Mol Cell Biol 37(2): e00282-16. https://doi.org/10.1128/MCB.00282-16
  29. 29. Tikhonova N, Milovanov AP, Aleksankina VV, Kulikov IA, Fokina TV, Aleksankin AP, Belousova TN, Mikhaleva LM, Niziaeva NV (2023) Adipocytes in the Uterine Wall during Experimental Healing and in Cesarean Scars during Pregnancy. Int J Mol Sci 24(20): 15255. https://doi.org/10.3390/ijms242015255
  30. 30. Hubner G, Brauchle M, Smola H, Madlener M, Fässler R, Werner S (1996) Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 8(7): 548-556. https://doi.org/10.1006/cyto.1996.0074
  31. 31. Macleod T, Berekmerl A, Bridgewood C, Stacey M, McGonagle D, Wittmann M (2021) The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier. Front Immunol 12: 808012. https://doi.org/10.3389/fimmu.2021.808012
  32. 32. Hickey DK, Fahey JV, Wira CR (2013) Mouse estrous cycle regulation of vaginal versus uterine cytokines, chemokines, α-β-defensins and TLRs. Innate Immun 19(2): 121-131. https://doi.org/10.1177/1753425912454026
  33. 33. Vicetti Miguel RD, Quispe Calla NE, Dixon D, Foster RA, Gambotto A, Pavelko SD, Hall-Stoodley L, Cherpes TL (2017) IL-4-secreting eosinophils promote endometrial stromal cell proliferation and prevent Chlamydia-induced upper genital tract damage. Proc Natl Acad Sci U S A 114(33): E6892-E6901. https://doi.org/10.1073/pnas.1621253114
  34. 34. Salmon-Elir V, Ramont L, Godeau G, Birembaut P, Guenounou M, Bernard P, Maquart FX (2000) Implication of interleukin-4 in wound healing. Lab Invest 80(8): 1337-1343. https://doi.org/10.1038/labinvest.3780141
  35. 35. Lopez MC, Stanley MA (2005) Cytokine profile of mouse vaginal and uterus lymphocytes at estrus and diestrus. Clin Dev Immunol 12(2): 159-164. https://doi.org/10.1080/17402520500141010
  36. 36. Sun Q, Tang L, Zhang D (2023) Molecular mechanisms of uterine incision healing and scar formation. Eur J Med Res 28(1): 496. https://doi.org/10.1186/s40001-023-01485-w
  37. 37. De M, Sanford TR, Wood GW (1992) Interleukin-1, interleukin-6, and tumor necrosis factor alpha are produced in the mouse uterus during the estrous cycle and are induced by estrogen and progesterone. Dev Biol 151(1): 297-305. https://doi.org/10.1016/0012-1606 (92)90234-8
  38. 38. Singampalli KL, Balaji S, Wang X, Parikh UM, Kaul A, Gilley J, Birla RK, Bollyky PL, Keswani SG (2020) The Role of an IL-10/Hyaluronan Axis in Dermal Wound Healing. Front Cell Dev Biol 8: 636. https://doi.org/10.3389/fcell.2020.00636
  39. 39. Johnson BZ, Stevenson AW, Prele CM, Fear MW, Wood FM (2020) The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing. Biomedicines 8(5): 101. https://doi.org/10.3390/biomedicines8050101. PMID: 32365896; PMCID: PMC7277690
  40. 40. Kodunov A, Tennrov A, Tereshchenko A, Trifanenkova I, Skilfas A, Shatskikh A (2022) Mechanisms of the influence of conditioned medium of cultured stem cells on the development of pathological angiogenesis in the eye cornea in experiment. Patogenez (Pathogenesis) 19(4): 41-52. https://doi.org/10.25557/2310-0435.2021.04.41-52
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