Регуляция клеточной пластичности — историческое развитие научных представлений

В современной клеточной биологии с  понятием пластичности связано значительное количество работ, включающих исследования плюрипотентного статуса, механизмов регенерации и  онкогенеза, биотехнологических приложений, математических моделей клеточной дифференцировки, биоинформатического анализа траекторий развития и дифференцировки и многое другое. По каждой из этих областей можно найти обширную литературу, в том числе обзоры. Полное рассмотрение всех деталей и аспектов развития теории клеточной пластичности может быть предметом отдельного обширного исследования. Цель данного обзора — кратко обозначить главные вехи эволюции концепций клеточной пластичности от классической детерминистской парадигмы до современных воззрений в  русле динамических систем, эпигенетических ландшафтов и аттракторов. Рассматриваются ключевые открытия и их значение для развития представлений о клеточной пластичности.

1. Kloc M, Zagrodzinska B. Chromatin elimination — an oddity or a common mechanism in differentiation and development? Differentiation. 2001;68(2–3):84–91. DOI: 10.1046/j.1432-0436.2001.680202.x

2. Virchow R. Abstract of an address on metaplasia. The British medical journal. 1884;August 30:408.

3. Хрущов НГ. Вопросы дедифференцировки тканей и метаплазии в свете современных данных экспериментальной гистологии. В кн.: Материалы Второй гистологической конференции «Пластические и восстановительные процессы». М.; 1959.

4. Spemann H, Mangold H. Induction of embryonic primordia by implantation of organizers from a different species. Roux’s Arch. Entw. Mech. 1924;100:599–638.

5. Gehring W. Clonal analysis of determination dynamics in cultures of imaginal disks in Drosophila melanogaster. Dev. Biol. 1967;16:438–456.

6. Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryol. Exp. Morphol. 1975;34:125–154.

7. Beetschen JC, Fischer JL. Yves Delage (1854–1920) as a forerunner of modern nuclear transfer experiments. Int J Dev Biol. 2004;48(7):607–612. DOI: 10.1387/ijdb.041827jb

8. Briggs R, King TJ. Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. Proc. Natl. Acad. Sci. U.S.A. 1952;38(5):455–463. DOI: 10.1073/pnas.38.5.455

9. Fischberg M, Gurdon J, Elsdale T. Nuclear Transplantation in Xenopus laevis. Nature. 1958;181:424. DOI: 10.1038/181424a0

10. Gurdon J, Uehlinger V. “Fertile” Intestine Nuclei. Nature. 1966;210:1240–1241. DOI: 10.1038/2101240a0

11. Строева ОГ, Никитина АА. Пересадка ядер у амфибий и ее значение для исследования проблемы дифференцировки. Журн. общ. биол. 1960;21:336–346.

12. Blau HM, Chiu CP, Webster C. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell. 1983;32(4):1171–1180.

13. Kraft A, Rubin BP. Changing cells: An analysis of the concept of plasticity in the context of cellular differentiation. BioSocieties. 2016;11:497–525. DOI: 10.1057/s41292-016-0027-y

14. Blau HM, Pavlath GK, Hardeman EC, Chiu CP, Silberstein L, Webster SG, et al. Plasticity of the differentiated state. Science. 1985;230(4727):758–766. DOI: 10.1126/science.2414846

15. Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51:987–1000.

16. Schneuwly S, Klemenz R, Gehring WJ. Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature. 1987;325:816–818.

17. Gehring WJ. The master control gene for morphogenesis and evolution of the eye. Genes Cells. 1996;1:11–15.

18. Зеленин АВ, Кущ АА, Прудовский ИА. Реконструированная клетка. М.: Наука; 1983. 207 с.

19. Прудовский ИА, Зеленин АВ. Зачем лишать клетку ядра? Природа. 1983;7:15–24.

20. Harris H. The reactivation of the red cell nucleus. J. Cell Sci. 1967;2:23–32.

21. Неверова МЕ, Полуновский ВА, Хрущов НГ. Морфологическое и радиоавтографическое исследование реактивации ядер клеток перитонеального экссудата в гетерокарионах. Онтогенез. 1976;7(5):475–483.

22. Kushch AA, Prudovskii IA, Zelenin AV. Chromatin activation in peritoneal exudate leukocytes after fusion with L cell cytoplasts. Cytobiologie. 1978;18:59–66.

23. Lipsich LA, Lucas JJ, Kates JR. Cell cycle dependence of the reactivation of chick erythrocyte nuclei after transplantation into mouse L929 cell cytoplasts. J Cell Physiol. 1978;97(2):199– 207. DOI: 10.1002/jcp.1040970209

24. Uryvaeva IV, Faktor VM. Ustoĭchivost’ regeneriruiushcheĭ pecheni k gepatotoksinam [Resistance of regenerating liver to hepatotoxins]. Biull Eksp Biol Med. 1976;81(3):283–285.

25. Willet SG, Lewis MA, Miao ZF, Liu D, Radyk MD, Cunningham RL, et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J. 2018;37(7):e98311.

26. Miao ZF, Lewis MA, Cho CJ, Adkins-Threats M, Park D, Brown JW, et al. A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle. Dev Cell. 2020;55(2):178–194.e7. DOI: 10.1016/j.devcel.2020.07.005

27. Illmensee K, Hoppe PC. Nuclear transplantation in mus musculus: Developmental potential of nuclei from preimplantation embryos. Cell. 1981;23(1):9–18.

28. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997;385:810–813.

29. Hochedlinger K, Jaenisch R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature. 2002;415:1035–1038. DOI: 10.1038/nature718

30. Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature. 2010;465(7299):704–712. DOI: 10.1038/nature09229

31. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–156.

32. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145– 1147. DOI: 10.1126/science.282.5391.1145

33. Tada M, Tada T, Lefebvre L, Barton SC, Surani MA. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J. 1997;16:6510–6520.

34. Tada M, Takahama Y, Abe K, Nakatsuji N, Tada T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 2001;11:1553–1558.

35. Kimura H, Tada M, Nakatsuji N, Tada T. Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol. Cell. Biol. 2004;24:5710–5720.

36. Kleinman DL. Science and Technology in Society: From Biotechnology to the Internet. Oxford: Oxford University Press; 2005.

37. Waddington CH. The Epigenotype. Endeavour. 1942;1:18–20.

38. Waddington CH. The strategy of the genes: a discussion of some aspects of theoretical biology. London: George Allen & Unwin; 1957.

39. Goodwin BC. Temporal Organization of Cells: A Dynamic Theory of Cellular Control Processes. London: Academic Press; 1963.

40. Kauffman SA. Metabolic stability and epigenesis in randomly constructed genetic nets. Journal of Theoretical Biology. 1969;22(3):437–467.

41. Blau HM, Baltimore D. Differentiation requires continuous regulation. J. Cell Biol. 1991; 112:781–783.

42. Lis JT. A 50 year history of technologies that drove discovery in eukaryotic transcription regulation. Nat Struct Mol Biol. 2019;26(9):777–782. DOI: 10.1038/s41594-019-0288-9

43. Latchman DS. Transcription factors: an overview. Int J Exp Pathol. 1993;74(5):417–422.

44. Karin M. Too many transcription factors: positive and negative interactions. New Biol. 1990;2(2):126–131.

45. Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc. Natl. Acad. Sci. USA. 1989;86:5434–5438.

46. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663–676.

47. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ 2, a lipid-activated transcription factor. Cell. 1994;79:1147–1156.

48. Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipogenic transcription factors PPARy and C/EBPα. Proc. Natl. Acad. Sci. USA. 1995;92:9856–9860.

49. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676.

50. Lau E, Paik DT, Wu JC. Systems-Wide Approaches in Induced Pluripotent Stem Cell Models. Annu Rev Pathol. 2019;14:395–419. DOI: 10.1146/annurev-pathmechdis-012418-013046

51. Smith A. Propagating pluripotency — The conundrum of self-renewal. BioEssays. 2024;46:e2400108. DOI: 10.1002/bies.202400108

52. Sinenko SA, Tomilin AN. Metabolic control of induced pluripotency. Front Cell Dev Biol. 2024;11:1328522. DOI: 10.3389/fcell.2023.1328522

53. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463:1035–1041.

54. Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature. 2011;475:386–389.

55. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature. 2008;455:627–632.

56. Bonfanti P, Barrandon Y, Cossu G. ‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology. EMBO Mol Med. 2012;4(5):353–361. doi: 10.1002/emmm.201200220.

57. Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science. 1975;187(4173):226–232.

58. Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209– 213. DOI: 10.1038/321209a0

59. Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA. 1964;51(5):786–794. DOI: 10.1073/pnas.51.5.786

60. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 1997;389(6648):251–260. DOI: 10.1038/38444

61. Chiu CP, Blau HM. 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell. 1985;40:417–424.

62. Huang R, Situ Q, Lei J. Dynamics of cell-type transition mediated by epigenetic modifications. Journal of Theoretical Biology. 2024;577:111664. DOI: 10.1016/j.jtbi.2023.111664

63. Bell CC, Faulkner GJ, Gilan O. Chromatin-based memory as a self-stabilizing influence on cell identity. Genome Biol. 2024;25:320. DOI: 10.1186/s13059-024-03461-x

64. Yang J, Zhang M, Zhong Y, et al. Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions. Mol Biomed. 2026;7:60. DOI: 10.1186/s43556-026-00458-9

65. Strogatz S. Exploring complex networks. Nature. 2001;410:268–276.

66. Maslov S, Sneppen K. Specificity and stability in topology of protein networks. Science. 2002;296(5569):910–913. DOI: 10.1126/science.1065103

67. James EM, Nie X, Coca D, Andrews PW. Stem cell fate decisions: Substates and attractors. Stem Cell Reports. 2025;20(6):102532.

68. Huang S, Eichler G, Bar-Yam Y, Ingber DE. Cell fates as high-dimensional attractor states of a complex gene regulatory network. Phys Rev Lett. 2005;94(12):128701. DOI: 10.1103/PhysRevLett.94.128701

69. Casey MJ, Stumpf PS, MacArthur BD. Theory of cell fate. Wiley Interdiscip Rev Syst Biol Med. 2020;12(2):e1471. DOI: 10.1002/wsbm.1471

70. Han Y, Chen B, Zhang J, Shang X. Beyond metaphor: quantitative reconstruction of Waddington landscape and exploration of cellular behavior. Brief Bioinform. 2025;26(6): bbaf661.

71. Sáez M, Blassberg R, Camacho-Aguilar E, Siggia ED, Rand DA, Briscoe J. Statistically derived geometrical landscapes capture principles of decision-making dynamics during cell fate transitions. Cell Syst. 2022;13(1):12–28.e3. DOI: 10.1016/j.cels.2021.08.013

72. Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development. 2009;136(4):509–523. DOI: 10.1242/dev.020867

73. Wang J, Xu L, Wang E. Potential landscape and flux framework of nonequilibrium networks: robustness, dissipation, and coherence of biochemical oscillations. Proc Natl Acad Sci USA. 2008;105:12271–12276. DOI: 10.1073/pnas.0800579105

74. Wang J, Xu L, Wang E, Huang S. The potential landscape of genetic circuits imposes the arrow of time in stem cell differentiation. Biophys J. 2010;99:29–39. DOI: 10.1016/ j.bpj.2010.03.058

75. Wang J, Zhang K, Xu L, Wang E. Quantifying the Waddington landscape and biological paths for development and differentiation. Proc Natl Acad Sci USA. 2011;108:8257–8262. DOI: 10.1073/pnas.1017017108

76. Kang Z, Chen H, Li S, Wang S, Zhou SW. Evolving strategies for lineage tracing: Genetic markers, synthetic barcodes, and natural variants. Cell Stem Cell. 2026;33:1066–1083.

77. Anstine LJ, Keri R. A new view of the mammary epithelial hierarchy and its implications for breast cancer initiation and metastasis. J Cancer Metastasis Treat. 2019;5:50. DOI: 10.20517/2394-4722.2019.24

78. Jia D, Jolly MK, Kulkarni P, Levine H. Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory. Cancers (Basel). 2017;9(7):70. DOI: 10.3390/cancers9070070

79. Shen S, Clairambault J. Cell plasticity in cancer cell populations. F1000Res. 2020;9: F1000 Faculty Rev-635. DOI: 10.12688/f1000research.24803.1

80. Gorelov R, Hochedlinger K. A cellular identity crisis? Plasticity changes during aging and rejuvenation. Genes Dev. 2024;38(17–20):823–842. DOI: 10.1101/gad.351728.124

81. Viragova S, Li D, Klein OD. Activation of fetal-like molecular programs during regeneration in the intestine and beyond. Cell Stem Cell. 2024 Jul 5;31(7):949–960.

82. Kim M, Park Y, Kim YS, Ko S. Cellular Plasticity in Gut and Liver Regeneration. Gut Liver. 2024; Nov 15;18(6):949–960. DOI: 10.5009/gnl240005 83.

83. Dekoninck S, Blanpain C. Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol. 2019 Jan;21(1):18–24. DOI: 10.1038/s41556-018-0237-6