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Cell and Tissue Biology

, Volume 13, Issue 4, pp 292–304 | Cite as

The Effect of Basic Fibroblast Growth Factor on Signaling Pathways in Adult Human Retinal Pigment Epithelial Cells

  • A. V. KuznetsovaEmail author
  • L. A. Rzhanova
  • A. M. Kurinov
  • M. A. Aleksandrova
Article
  • 18 Downloads

Abstract

Retinal pigment epithelium (RPE) plays a key role in the development of many eye diseases characterized by visual impairment and even blindness. The use of cell cultures to model changes in RPE makes it possible to study stimulating factors and signaling pathways that coordinate the cellular and molecular mechanisms of intercellular interactions under pathological conditions. In addition, it is possible to identify targets and develop a specific therapy to eliminate pathological changes in the retina. Based on the results of previously obtained experimental data on decreased differentiation of RPE cells in the direction of the neuroepithelium after a single exposure to basic fibroblast growth factor (bFGF), research in this area was continued and changes in Wnt-, BMP-, and Notch-signaling pathways were examined. It is necessary for a deeper understanding of the mechanisms that decrease the level of differentiation of RPE cells. It was found that the addition of bFGF to culture decreased immunocytochemical staining for β-catenin; increased staining for Wnt7a, BMP2, and BMP7; and altered localization of stained BMP4. In addition, quantitative real-time PCR of RPE cells treated with bFGF revealed enhanced expression of mRNA of BMP2, a decreased expression of mRNA genes, such as CTNNB1, BMP4, and BMPR2, as well as mRNA of Notch-signaling genes, such as JAG1, NOTCH1, HES1, and HEY1. Analysis of the data indicates inactivation of the Wnt/β-catenin and Notch-signaling pathways, activation of the noncanonical Wnt/PCP signaling pathway, and modulating of BMP-signaling with a decrease in the level of differentiation of adult RPE cells after their a single (short-term) exposure to bFGF. Thus, the results obtained clarify the mechanisms of dedifferentiation of RPE cells under the influence of bFGF.

Keywords:

adult human retinal pigment epithelial cells basic fibroblast growth factor Wnt ВМР Notch 

Notes

ACKNOWLEDGMENTS

This work was performed using the equipment of the Center for Collective Use of the Institute of Developmental Biology, Russian Academy of Sciences.

FUNDING

This work was performed as part of a state order of the Institute of Developmental Biology, Russian Academy of Sciences, no. 0108-2019-0004.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interests. The authors declare that they have no conflict of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.

REFERENCES

  1. 1.
    Al-Hussaini, H., Kam, J.H., Vugler, A., Semo, M., and Jeffery, G., Mature retinal pigment epithelium cells are retained in the cell cycle and proliferate in vivo, Mol. Vis., 2008, vol. 14, pp. 1784–1791.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Baldwin, A.K., Cain, S.A., Lennon, R., Godwin, A., Merry, C, .L.R., and Kielty, C.M., Epithelial-mesenchymal status influences how cells deposit fibrillin microfibrils, J. Cell Sci., 2014, vol. 127, pp. 158–171.  https://doi.org/10.1242/jcs.134270 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bikkavilli, R.K., Avasarala, S., Van, Scoyk, M., Arcaroli, J., Brzezinski, C., Zhang, W., Edwards, M.G., Rathinam, M.K.K., Zhou, T., Tauler, J., Borowicz, S., Lussier, Y.A., Parr, B.A., Cool, C.D., and Winn, R.A., Wnt7a is a novel inducer of B-catenin-independent tumor-suppressive cellular senescence in lung cancer, Oncogene, 2015, vol. 34, pp. 5317–5328.  https://doi.org/10.1038/onc.2015.2 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Blauwkamp, T.A., Nigam, S., Ardehali, R., Weissman, I.L., and Nusse, R., Endogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors, Nat. Commun., 2012, vol. 3, p. 1070.  https://doi.org/10.1038/ncomms2064 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cao, W., Wen, R., Li, F., Lavail, M.M., and Steinberg, R.H., Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina, Exp. Eye Res., 1997, vol. 65, pp. 241–248.  https://doi.org/10.1006/exer.1997.0328 CrossRefPubMedGoogle Scholar
  6. 6.
    Chen, X., Xiao, W., Wang, W., Luo, L., Ye, S., and Liu, Y., The complex interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch signaling pathways in the regulation of epithelial–mesenchymal transition in retinal pigment epithelium cells, PLoS One, 2014, vol. 9, no. 5. e96365.  https://doi.org/10.1371/journal.pone.0096365 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chiba, C., Hoshino, A., Nakamura, K., Susaki, K., Yamano, Y., Kaneko, Y., Kuwata, O., Maruo, F., and Saito, T., Visual cycle protein RPE65 persists in new retinal cells during retinal regeneration of adult newt, J. Comp. Neurol., 2006, vol. 495, pp. 391–407.  https://doi.org/10.1002/cne.20880 CrossRefPubMedGoogle Scholar
  8. 8.
    Cho, I.H., Park, S.J., Lee, S.H., Nah, S.K., Park, H.Y., Yang, J.Y., Madrakhimov, S.B., Lyu, J., and Park, T.K., The role of Wnt/β-catenin signaling in the restoration of induced pluripotent stem cell-derived retinal pigment epithelium after laser photocoagulation, Lasers Med Sci., 2018.  https://doi.org/10.1007/s10103-018-2631-5
  9. 9.
    Clevers, H., Wnt/beta-catenin signaling in development and disease, Cell, 2006, vol. 127, pp. 469–480.  https://doi.org/10.1016/j.cell.2006.10.018 CrossRefPubMedGoogle Scholar
  10. 10.
    Ding, V.M.Y., Ling, L., Natarajan, S., Yap, M.G.S., Cool, S.M., and Choo, A.B.H., FGF-2 modulates Wnt signaling in undifferentiated hESC and iPS cells through activated PI3-K/GSK3β signaling, J. Cell. Physiol., 2010, vol. 225, pp. 417–428.  https://doi.org/10.1002/jcp.22214 CrossRefPubMedGoogle Scholar
  11. 11.
    Espinosa, L., Inglés-Esteve, J., Aguilera, C., and Bigas, A., Phosphorylation by glycogen synthase kinase-3β down-regulates Notch activity, a link for Notch and Wnt pathways, J. Biol. Chem., 2003, vol. 278, pp. 32227–32235.  https://doi.org/10.1074/jbc.M304001200 CrossRefPubMedGoogle Scholar
  12. 12.
    Frank, R.N., Amin, R.H., Eliott, D., Puklin, J.E., and Abrams, G.W., Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes, Am. J. Ophthalmol., 1996, vol. 122, pp. 393–403.CrossRefPubMedGoogle Scholar
  13. 13.
    Fujimura, N., Taketo, M.M., Mori, M., Korinek, V., and Kozmik, Z., Spatial and temporal regulation of Wnt/beta-catenin signaling is essential for development of the retinal pigment epithelium, Dev. Biol., 2009, vol. 334, pp. 31–45.  https://doi.org/10.1016/j.ydbio.2009.07.002 CrossRefPubMedGoogle Scholar
  14. 14.
    Galy, A., Néron, B., Planque, N., Saule, S., and Eychène, A., Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina, Dev. Biol., 2002, vol. 248, pp. 251–264.CrossRefPubMedGoogle Scholar
  15. 15.
    Grigoryan, E.N., Markitantova, Y.V., Avdonin, P.P., and Radugina, E.A., Study of regeneration in amphibians in age of molecular-genetic approaches and methods, Russ. J. Genet., 2013, vol. 49, no. 1, pp. 46–62.  https://doi.org/10.1134/S1022795413010043 CrossRefGoogle Scholar
  16. 16.
    Guha, S., Cullen, J.P., Morrow, D., Colombo, A., Lally, C., Walls, D., Redmond, E.M., and Cahill, P.A., Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival, Basic Res. Cardiol., 2011, vol. 106, pp. 773–785.  https://doi.org/10.1007/s00395-011-0189-5 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hogan, B.L., Bone morphogenetic proteins in development, Curr. Opin. Genet. Dev., 1996, vol. 6, pp. 432–438.CrossRefPubMedGoogle Scholar
  18. 18.
    Isaeva, A.V., Zima, A.P., Shabalova, I.P., Ryazan-tseva, N.V., Vasil’eva, O.A., Kasoayn, K.T., Saprina, T.V., Latypova, V.N. Berezkina, I.S., and Novitskii, VV., β-Catenin: structure, function and role in malignant transformation of epithelial cells, Vestn. Ross. Akad. Med. Nauk, 2015, vol. 70, no. 4, pp. 475–483.  https://doi.org/10.15690/vramn.v70.i4.1415 CrossRefGoogle Scholar
  19. 19.
    Jensen, E.C., Quantitative analysis of histological staining and fluorescence using ImageJ, Anat. Rec., 2013, vol. 296, pp. 378–381.  https://doi.org/10.1002/ar.22641 CrossRefGoogle Scholar
  20. 20.
    Katoh, M. and Katoh, M., Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate Beta-catenin and SNAIL signaling cascades, Cancer Biol. Ther., 2006, vol. 5, pp. 1059–1064.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim, T.-H., Moon, J.-Y., Kim, S.-H., Paik, S.S., Yoon, H.J., Shin, D.H., Park, S.S., and Sohn, J.W., Clinical significance of aberrant Wnt7a promoter methylation in human non-small cell lung cancer in Koreans, J. Korean Med. Sci., 2015, vol. 30, pp. 155–161.  https://doi.org/10.3346/jkms.2015.30.2.155 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kulikova, K.V., Kibardin, A.V., Gnuchev, N.V., Georgiev, G.P., and Larin, S.S., Wnt signaling pathway and its significance for melanoma development, Sovr. Tekhnol. Med., 2012, vol. 3, pp. 107–112.Google Scholar
  23. 23.
    Kuznetsova, A.V., Grigoryan, E.N., and Aleksandrova, M.A., Human adult retinal pigment epithelial cells as potential cell source for retina recovery, Cell Tissue Biol., 2011, vol. 5, no. 5, pp. 495–502.CrossRefGoogle Scholar
  24. 24.
    Kuznetsova, A.V., Kurinov, A.M., and Aleksandrova, M.A., Cell models to study regulation of cell transformation in pathologies of retinal pigment epithelium, J. Ophthalmol., 2014, vol. 2014, pp. 1–18.  https://doi.org/10.1155/2014/801787 CrossRefGoogle Scholar
  25. 25.
    Kuznetsova, A.V., Kurinov, A.M., Chentsova, E V., Makarov, P.V., and Aleksandrova, M.A., Effect of hrWnt7a on human retinal pigment epithelial cells in vitro, Bull. Exp. Biol. Med., 2015, vol. 159, no. 4, pp. 534–540.CrossRefPubMedGoogle Scholar
  26. 26.
    Kuznetsova, A.V., Aleksandrova, M.A., Kurinov, A.M., Chentsova, E.V., and Makarov, P.V., Plasticity of adult human retinal pigment epithelial cells, Int. J. Clin. Exp. Med., 2016, vol. 9, pp. 20892–20906.Google Scholar
  27. 27.
    Kuznetsova, A.V., Kurinov, A.M., Rzhanova, L.A. and Aleksandrova, M.A., Mechanisms of dedifferentiation of the adult human retinal pigment epithelial cells in vitro: morphological and molecular-genetic analysis, Cell Tissue Biol., 2019, vol. 13 (in press).Google Scholar
  28. 28.
    Lee, H.C., Lim, S., and Han, J.Y., Wnt/β-catenin signaling pathway activation is required for proliferation of chicken primordial germ cells in vitro, Sci. Rep., 2016, vol. 6, p. 34510.  https://doi.org/10.1038/srep34510 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Li, B., Qu, C., Chen, C., Liu, Y., Akiyama, K., Yang, R., Chen, F., Zhao, Y., and Shi, S., Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling, Oral Dis., 2015, vol. 18, pp. 285–292.  https://doi.org/10.1111/j.1601-0825.2011.01878.x CrossRefGoogle Scholar
  30. 30.
    Li, Q., Rycaj, K., Chen, X., and Tang, D.G., Cancer stem cells and cell size: a causal link?, Semin. Cancer Biol., 2015, vol. 35, pp. 191–199.  https://doi.org/10.1016/j.semcancer.2015.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu, W., Jin, G., Long, C., Zhou, X., Tang, Y., Huang, S., Kuang, X., Wu, L., Zhang, Q., and Shen, H., Blockage of Notch signaling inhibits the migration and proliferation of retinal pigment epithelial cells, Sci. World J., 2013, vol. 2013, p. 178708.  https://doi.org/10.1155/2013/178708 CrossRefGoogle Scholar
  32. 32.
    Lotz, S., Goderie, S., Tokas, N., Hirsch, S.E., Ahmad, F., Corneo, B., Le, S., Banerjee, A., Kane, R.S., Stern, J.H., Temple, S., and Fasano, C.A., Sustained levels of FGF2 maintain undifferentiated stem cell cultures with biweekly feeding, PLoS One, 2013, vol. 8. e56289.  https://doi.org/10.1371/journal.pone.0056289 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ludwig, T.E., Levenstein, M.E., Jones, J.M., Berggren, W.T., Mitchen, E.R., Frane, J.L., Crandall, L.J., Daigh, C.A., Conard, K.R., Piekarczyk, M.S., Llanas, R.A., and Thomson, J.A., Derivation of human embryonic stem cells in defined conditions, Nat. Biotechnol., 2006, vol. 24, pp. 185–187.  https://doi.org/10.1038/nbt1177 CrossRefPubMedGoogle Scholar
  34. 34.
    Luz-Madrigal, A., Grajales-Esquivel, E., McCorkle, A., DiLorenzo, A.M., Barbosa-Sabanero, K., Tsonis, P.A., and Del, Rio-Tsonis, K., Reprogramming of the chick retinal pigmented epithelium after retinal injury, BMC Biol., 2014, vol. 12, p. 28.  https://doi.org/10.1186/1741-7007-12-28 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mathura, J.R., Jafari, N., Chang, J.T., Hackett, S.F., Wahlin, K.J., Della, N.G., Okamoto, N., Zack, D.J., and Campochiaro, P.A., Bone morphogenetic proteins-2 and -4: negative growth regulators in adult retinal pigmented epithelium, Invest. Ophthalmol. Vis. Sci., 2000, vol. 41, pp. 592–600.PubMedGoogle Scholar
  36. 36.
    Medina, M. and Wandosell, F., Deconstructing GSK-3: the fine regulation of its activity, Int. J. Alzheimers. Dis., 2011, vol. 2011, p. 479249.  https://doi.org/10.4061/2011/479249 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Milyushina, L.A., Kuznetsova, A.V., Grigoryan, E.N., and Aleksandrova, M.A., Phenotypic plasticity of retinal pigment epithelial cells from adult human eye in vitro, Bull. Exp. Biol. Med., 2011, vol. 151, no. 4, pp. 506–511.CrossRefPubMedGoogle Scholar
  38. 38.
    Nowwarote, N., Sawangmake, C., Pavasant, P., and Osathanon, T., Review of the role of basic fibroblast growth factor in dental tissue-derived mesenchymal stem cells, Asian Biomed., 2015, vol. 9, pp. 271–283.  https://doi.org/10.5372/1905-7415.0903.395 CrossRefGoogle Scholar
  39. 39.
    Ohira, T., Gemmill, R.M., Ferguson, K., Kusy, S., Roche, J., Brambilla, E., Zeng, C., Baron, A., Bemis, L., Erickson, P., Wilder, E., Rustgi, A., Kitajewski, J., Gabrielson, E., Bremnes, R., Franklin, W., and Drabkin, H.A., WNT7a induces E-cadherin in lung cancer cells, Proc. Natl. Acad. Sci. U. S. A., 2003, vol. 100, pp. 10429–1034.  https://doi.org/10.1073/pnas.1734137100 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Qi, X., Li, T.-G., Hao, J., Hu, J., Wang, J., Simmons, H., Miura, S., Mishina, Y., and Zhao, G.-Q., BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways, Proc. Natl. Acad. Sci. U. S. A., 2004, vol. 101, pp. 6027–6032.  https://doi.org/10.1073/pnas.0401367101 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Reya, T., Duncan, A.W., Ailles, L., Domen, J., Scherer, D.C., Willert, K., Hintz, L., Nusse, R., and Weissman, I.L., A role for Wnt signalling in self-renewal of haematopoietic stem cells, Nature, 2003, vol. 423, pp. 409–414.  https://doi.org/10.1038/nature01593 CrossRefPubMedGoogle Scholar
  42. 42.
    Rocher, C., Singla, R., Singal, P.K., Parthasarathy, S., and Singla, D.K., Bone morphogenetic protein 7 polarizes THP-1 cells into M2 macrophages, Can. J. Physiol. Pharmacol., 2012, vol. 90, pp. 947–951.  https://doi.org/10.1139/y2012-102 CrossRefPubMedGoogle Scholar
  43. 43.
    Shtein, G.I. and Kudryavtsev, B.N., Use of confocal microscopy for microfluorimetric research in cell biology, Cell Tissue Biol., 2019, vol. 13 (in press).Google Scholar
  44. 44.
    Shtein, G.I., Panteleyev, V.G., and Kudryavtsev, B.N., Methodological problems of digital cytophotometry, Tsitologiia, 2016, vol. 58, no. 3, pp. 234–242.Google Scholar
  45. 45.
    Staal, F.J.T., Wnt signalling meets epigenetics, Stem Cell Investig., 2016, vol. 3, p. 38.  https://doi.org/10.21037/sci.2016.08.01 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Steindl-Kuscher, K., Krugluger, W., Boulton, M.E., Haas, P., Schrattbauer, K., Feichtinger, H., Adlassnig, W., and Binder, S., Activation of the B-catenin signaling pathway and its impact on RPE cell cycle, Investig. Opthalmol. Vis. Sci., 2009, vol. 50, pp. 4471–4476.  https://doi.org/10.1167/iovs.08-3139 CrossRefGoogle Scholar
  47. 47.
    Takeuchi, A., Fukazawa, S., Chida, K., Taguchi, M., Shirataka, M., and Ikeda, N., Semi-automatic counting of connexin 32s immunolocalized in cultured fetal rat hepatocytes using image processing, Acta Histochem., 2012, vol. 114, pp. 318–326.  https://doi.org/10.1016/j.acthis.2011.06.008 CrossRefPubMedGoogle Scholar
  48. 48.
    Teryukova, N.P., Sakhenberg, E.I., Ivanov, V.A., and Snopov, S.A., Establishment and characterization of clonal lines with cancer stem-and progenitor-cell properties from monolayer zajdela hepatoma, Cell Tissue Biol., 2016, vol. 11, no. 2, pp. 161–171.CrossRefGoogle Scholar
  49. 49.
    Tian, J., Ishibashi, K., Honda, S., Boylan, S.A., Hjelmeland, L.M., and Handa, J.T., The expression of native and cultured human retinal pigment epithelial cells grown in different culture conditions, Br. J. Ophthalmol., 2005, vol. 89, pp. 1510–1517.  https://doi.org/10.1136/bjo.2005.072108 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Urbán, N. and Guillemot, F., Neurogenesis in the embryonic and adult brain: same regulators, different roles, Front. Cell. Neurosci., 2014, vol. 8, p. 396.  https://doi.org/10.3389/fncel.2014.00396 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wen, R., Song, Y., Cheng, T., Matthes, M.T., Yasumura, D., LaVail, M.M., and Steinberg, R.H., Injury-induced upregulation of bFGF and CNTF MRNAS in the rat retina, J. Neurosci., 1995, vol. 15, no. 11, pp. 7377–7385.CrossRefPubMedGoogle Scholar
  52. 52.
    Wordinger, R.J. and Clark, A.F., Bone morphogenetic proteins and their receptors in the eye, Exp. Biol. Med. (Maywood)., 2007, vol. 232, pp. 979–992.  https://doi.org/10.3181/0510-MR-345 CrossRefGoogle Scholar
  53. 53.
    Xiao, W., Chen, X., Liu, X., Luo, L., Ye, S., and Liu, Y., Trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial–mesenchymal transition in retinal pigment epithelium cells, J. Cell. Mol. Med., 2014, vol. 18, pp. 646–655.  https://doi.org/10.1111/jcmm.12212 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Yang, S., Li, H., Li, M., and Wang, F., Mechanisms of epithelial–mesenchymal transition in proliferative vitreoretinopathy, Discov. Med., 2015, vol. 20, pp. 207–217.PubMedGoogle Scholar
  55. 55.
    Zeisberg, M., Hanai, J., Sugimoto, H., Mammoto, T., Charytan, D., Strutz, F., and Kalluri, R., BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury, Nat. Med., 2003, vol. 9, pp. 964–968.  https://doi.org/10.1038/nm888 CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang, C., Su, L., Huang, L., and Song, Z.-Y., GSK3β inhibits epithelial-mesenchymal transition via the Wnt/β-catenin and PI3K/Akt pathways, Int. J. Ophthalmol., 2018, vol. 11, pp. 1120–1128.  https://doi.org/10.18240/ijo.2018.07.08 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zheng, L. and Conner, S.D., Glycogen synthase kinase 3β inhibition enhances Notch1 recycling, Mol. Biol. Cell., 2018, vol. 29, pp. 389–395.  https://doi.org/10.1091/mbc.E17-07-0474 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zhu, J., Luz-Madrigal, A., Haynes, T., Zavada, J., Burke, A.K., and Del Rio-Tsonis, K., β -Catenin inactivation is a pre-requisite for chick retina regeneration, PLoS One, 2014, vol. 9, no. 7. e101748.  https://doi.org/10.1371/journal.pone.0101748 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • A. V. Kuznetsova
    • 1
    Email author
  • L. A. Rzhanova
    • 1
  • A. M. Kurinov
    • 1
  • M. A. Aleksandrova
    • 1
  1. 1.Koltzov Institute of Developmental Biology, Russian Academy of SciencesMoscowRussia

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