Цитология, 2023, T. 65, № 6, стр. 509-521

Частичное репрограммирование клеток как способ ревитализации живых систем

М. А. Шорохова *

Институт цитологии РАН
194064 Санкт-Петербург, Россия

* E-mail: shili-mariya@yandex.ru

Поступила в редакцию 01.07.2023
После доработки 06.08.2023
Принята к публикации 01.09.2023

Аннотация

Старение и ассоциированные с ними заболевания – острая проблема современной биологии и медицины. Хотя старение в настоящее время невозможно предотвратить, его влияние на продолжительность жизни и здоровье пожилых людей потенциально может быть сведено к минимуму с помощью вмешательств, направленных на возвращение клеток к нормальному функционированию. Постоянный поиск путей омоложения и улучшения регенеративной способности клеток привел к открытию в 2016 г. метода частичного репрограммирования, основанного на краткосрочной экспрессии факторов репрограммирования (Oct4, Sox2, Klf4 и c-Myc). В результате происходит восстановление молодой эпигенетической сигнатуры стареющих клеток. Эффективность метода показана как в системе in vitro, так и в системе in vivo. В представленном обзоре обсуждаются основные успехи частичного репрограммирования, а также проблемы и нерешенные вопросы, с которыми столкнулись исследователи. Отдельно обсуждаются данные о молекулярных изменениях в процессе частичного репрограммирования. Метод частичного репрограммирования дает широкий спектр возможностей для фундаментальных исследований старения и омоложения. А дальнейшие работы в этом направлении могут привести к разработке терапевтических стратегий с целью облегчения возрастных заболеваний и, таким образом, к улучшению здоровья и долголетию.

Ключевые слова: частичное репрограммирование, клеточная идентичность, плюрипотентность, омоложение, соматические клетки

Список литературы

  1. Abad M., Mosteiro L., Pantoja C., Cañamero M., Rayon T., Ors I., Graña O., Megías D., Domínguez O., Martínez D., Manzanares M., Ortega S., Serrano M. 2013. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature. V. 502. P. 340. https://doi.org/10.1038/nature12586

  2. Alle Q., Le Borgne E., Bensadoun P., Lemey C., Béchir N., Gabanou M., Estermann F., Bertrand-Gaday C., Pessemesse L., Toupet K., Vialaret J., Hirtz C., Noël D., Jorgensen C., Casas F., Milhavet O., Lemaitre J.-M. 2021. A single short reprogramming early in life improves fitness and increases lifespan in old age. BioRxiv. V. 21. P. e13714. https://doi.org/10.1111/acel.13714

  3. Bell C.G., Lowe R., Adams P.D., Baccarelli A.A., Beck S., Bell J.T., Christensen B.C., Gladyshev V.N., Heijmans B.T., Horvath S., Ideker T., Issa J.P.J., Kelsey K.T., Marioni R.E., Reik W. et al. 2019. DNA methylation aging clocks: challenóges and recommendations. Genome Biol. V. 20. P. 249. https://doi.org/10.1186/s13059-019-1824-y

  4. Blagosklonny M.V. 2013. TOR-centric view on insulin resistance and diabetic complications: Perspective for endocrinologists and gerontologists. Cell Death Disease. V. 4: e964. https://doi.org/10.1038/cddis.2013.506

  5. Bocklandt S., Lin W., Sehl M.E., Sánchez F.J., Sinsheimer J.S., Horvath S., Vilain E. 2011. Epigenetic predictor of age. PLoS One V. 6: e14821. https://doi.org/10.1371/journal.pone.0014821

  6. Brandhorst S., Choi I.Y., Wei M., Cheng C.W., Sedrakyan S., Navarrete G., Dubeau L., Yap L.P., Park R., Vinciguerra M., Di Biase S., Mirzaei H., Mirisola M.G., Childress P., Ji L., Groshen S. et al. 2015. A Periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. V. 22. P. 86.

  7. Brett J.O., Rando T.A. 2014. Alive and well? Exploring disease by studying lifespan. Curr. Opin. Genet. Dev. V. 26. P. 33.

  8. Chen Y., Lüttmann F.F., Schoger E., Schöler H.R., Zelarayán L.C., Kim K.P., Haigh J.J., Kim J., Braun T. 2021. Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice. Science. V. 373. P. 80.

  9. Childs B.G., Durik M., Baker D.J., Van Deursen J.M. 2015. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature Medicine. V. 21. P. 1424.

  10. Chondronasiou D., Gill D., Mosteiro L., Urdinguio R.G., Berenguer-Llergo A., Aguilera M., Durand S., Aprahamian F., Nirmalathasan N., Abad M., Martin-Herranz D.E., Stephan-Otto Attolini C., Prats N. et al. 2022. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming. Aging Cell V. 21: e13578. https://doi.org/10.1111/acel.13578

  11. Conboy I.M., Conboy M.J., Wagers A.J., Girma E.R., Weismann I.L., Rando T.A. 2005. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature V. 433. P. 760.

  12. Cuervo A.M., Bergamini E., Brunk U.T., Dröge W., Ffrench M., Terman A. 2005. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy. V. 1. P. 131. https://doi.org/10.4161/auto.1.3.2017

  13. Dungan C.M., Figueiredo V.C., Wen Y., VonLehmden G.L., Zdunek C.J., Thomas N.T., Mobley C.B., Murach K.A., Brightwell C.R., Long D.E., Fry C.S., Kern P.A., McCarthy J.J., Peterson C.A. 2022. Senolytic treatment rescues blunted muscle hypertrophy in old mice. GeroScience V. 44. P. 1925. https://doi.org/10.1007/s11357-022-00542-2

  14. Galkin F., Mamoshina P., Aliper A., de Magalhães J.P., Gladyshev V.N., Zhavoronkov A. 2020. Biohorology and biomarkers of aging: current state-of-the-art, challenges and opportunities. ARR. V. 60: e 60:101050. https://doi.org/10.1016/j.arr.2020.101050

  15. Gems D., Partridge L. 2013. Genetics of longevity in model organisms: debates and paradigm shifts. Annu. Rev. Physiol. V. 75. P. 621.

  16. Gill D., Parry A., Santos F., Okkenhaug H., Todd C.D., Hernando-Herraez I., Stubbs T.M., Milagre I., Reik W. 2022. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. Elife V. 11: e71624. https://doi.org/10.7554/eLife.71624

  17. Gladyshev V.N., Kritchevsky S.B., Clarke S.G., Cuervo A.M., Fiehn O., de Magalhães J.P., Mau T., Maes M., Moritz R.L., Niedernhofer L.J., Van Schaftingen E., Tranah G.J., Walsh K., Yura Y., Zhang B., Cummings S.R. 2021. Molecular damage in aging. Nature Aging. V.1: 1096. https://doi.org/10.1038/s43587-021-00150-3

  18. Guan J., Wang G., Wang J., Zhang Z., Fu Y., Cheng L., Meng G., Lyu Y., Zhu J., Li Y., Wang Y., Liuyang S., Liu B., Yang Z., He H., Zhong X., Chen Q. et al. 2022. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature. V. 605. P. 325.

  19. Guderyon M.J., Chen C., Bhattacharjee A., Ge G., Fernandez R.A., Gelfond J.A.L., Gorena K.M., Cheng C.J., Li Y., Nelson J.F., Strong R.J., Hornsby P.J., Clark R.A., Li S. 2020. Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice. Aging Cell. V. 19: e13110. https://doi.org/10.1111/acel.13110

  20. Haigis M.C., Yankner B.A. 2010. The aging stress response. Mol. Cell. V. 40. P. 333.

  21. Hishida T., Yamamoto M., Hishida-Nozaki Y., Shao C., Huang L., Wang C., Shojima K., Xue Y., Hang Y., Shokhirev M., Memczak S., Sahu S.K., Hatanaka F., Ros R.R., Maxwell M. et al. 2022. In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell Rep. V. 39: 110730. https://doi.org/10.1016/j.celrep.2022.110730

  22. Hofmann J.W., Zhao X., De Cecco M., Peterson A.L., Pagliaroli L., Manivannan J., Hubbard G.B., Ikeno Y., Zhang Y., Feng B., Li X., Serre T., Qi W., Van Remmen H., Miller R.A., Bath K.G. et al. 2015. Reduced expression of MYC increases longevity and enhances healthspan. Cell. V. 160. P. 477.

  23. Horvath S. 2013. DNA methylation age of human tissues and cell types. Genome Biol. V. 14. P. R115.

  24. Hou P., Li Y., Zhang X., Liu C., Guan J., Li H., Zhao T., Ye J., Yang W., Liu K., Ge J., Xu J., Zhang Q., Zhao Y., Deng H. 2013. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. V. 341. P. 651.

  25. Hu K. 2014. All roads lead to induced pluripotent stem cells: the technologies of iPSC generation. Stem Cells Dev. V. 23. P. 1285.

  26. Kim Y., Jeong J., Choi D. 2020. Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Exp. Mol. Med. V. 52. P. 213.

  27. Klawitter S., Fuchs N.V., Upton K.R., Muñoz-Lopez M., Shukla R., Wang J., Garcia-Cañadas M., Lopez-Ruiz C., Gerhardt D.J., Sebe A., Grabundzija I., Merkert S., Gerdes P., Pulgarin J.A., Bock A., et al. 2016. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nat. Commun. V. 7: 10286. https://doi.org/10.1038/ncomms10286

  28. Koch C.M., Reck K., Shao K., Lin Q., Joussen S., Ziegler P., Walenda G., Drescher W., Opalka B., May T., Brummendorf T., Zenke M., Saric T., Wagner W. 2013. Pluripotent stem cells escape from senescenceassociated DNA methylation changes. Genome Res. V. 23. P. 248.

  29. Koch C.M., Wagner W. 2011. Epigenetic-aging-signature to determine age in different tissues. Aging (Albany. NY). V. 3. P. 1018.

  30. Lapasset L., Milhavet O., Prieur A., Besnard E., Babled A., Ät-Hamou N., Leschik J., Pellestor F., Ramirez J.M., De Vos J., Lehmann S., Lemaitre J.M. 2011. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. V. 25. P. 2248. https://doi.org/10.1101/gad.173922.111

  31. Lee C., Raffaghello L., Brandhorst S., Safdie F.M., Bianchi G., Martin-Montalvo A., Pistoia V., Wei M., Hwang S., Merlino A., Emionite L., De Cabo R., Longo V.D. 2012. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. V. 4: 124ra27. https://doi.org/10.1126/scitranslmed.3003293

  32. Lee C., Safdie F.M., Raffaghello L., Wei M., Madia F., Parrella E., Hwang D., Cohen P., Bianchi G., Longo V.D. 2010. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. V. 70. P. 1564.

  33. Lewis-McDougall F.C., Ruchaya P.J., Domenjo-Vila E., Shin Teoh T., Prata L., Cottle B.J., Clark J.E., Punjabi P.P., Awad W., Torella D., Tchkonia T., Kirkland J.L., Ellison-Hughes G.M. 2019. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. V. 18: e12931. https://doi.org/10.1111/acel.12931

  34. Lin Q., Weidner C.I., Costa I.G., Marioni R.E., Ferreira M.R.P., Deary I.J., Wagner W. 2016. DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy. Aging (Albany. NY). V. 8. P. 394.

  35. Liu X., Ouyang J.F., Rossello F.J., Tan J.P., Davidson K.C., Valdes D.S., Schröder J., Sun Y.B.Y., Chen J., Knaupp A.S., Sun G., Chy H.S., Huang Z., Pflueger J., Firas J. et al. 2020. Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature. V. 586. P. 101.

  36. Longo V.D., Finch C.E. 2003. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science. V. 299. P. 1342.

  37. López-Otín C., Blasco M.A., Partridge L., Serrano M., Kroemer G. 2013. The hallmarks of aging. Cell. V. 153. P. 1194.

  38. Lu A.T., Quach A., Wilson J.G., Reiner A.P., Aviv A., Raj K., Hou L., Baccarelli A.A., Li Y., Stewart J.D., Whitsel E.A., Assimes T.L., Ferrucci L., Horvath S. 2019. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany. NY). V. 11. P. 303.

  39. Lu Y., Brommer B., Tian X., Krishnan A., Meer M., Wang C., Vera D.L., Zeng Q., Yu D., Bonkowski M.S., Yang J.H., Zhou S., Hoffmann E.M., Karg M.M., Schultz M.B., Kane A.E., Davidsohn N. et al. 2020. Reprogramming to recover youthful epigenetic information and restore vision. Nature. V. 588. P. 124.

  40. Ludwig F.C., Elashoff R.M. 1972. Mortality in syngeneic rat parabionts of different chronological age. Trans. N.Y. Acad. Sci. V. 34. P. 582.

  41. Madeo F., Tavernarakis N., Kroemer G. 2010. Can autophagy promote longevity? Nat. Cell Biol. V. 12. P. 842.

  42. Mair W., Dillin A. 2008. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. V. 77. P. 727.

  43. Manukyan M., Singh P.B. 2014. Epigenome rejuvenation: HP1β mobility as a measure of pluripotent and senescent chromatin ground states. Sci. Rep. V. 4. P. 4789.

  44. Marioni R.E., Shah S., McRae A.F., Chen B.H., Colicino E., Harris S.E., Gibson J., Henders A.K., Redmond P., Cox S.R., Pattie A., Corley J., Murphy L., Martin N.G., Montgomery G.W. et al. 2015. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. V. 16. P. 25.

  45. Mertens J., Paquola A.C.M., Ku M., Hatch E., Böhnke L., Ladjevardi S., McGrath S., Campbell B., Lee H., Herdy J.R., Gonçalves J.T., Toda T., Kim Y., Winkler J., Yao J. et al. 2015. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell. V. 17. P. 705.

  46. Miller J.D., Ganat Y.M., Kishinevsky S., Bowman R.L., Liu B., Tu E.Y., Mandal P.K., Vera E., Shim J.W., Kriks S., Taldone T., Fusaki N., Tomishima M.J., Krainc D., Milner T.A. et al. 2013. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell V. 13. P. 691.

  47. Narasimhan S.D., Yen K., Tissenbaum H.A. 2009. Converging pathways in lifespan regulation. Curr. Biol. V. 19: R657. https://doi.org/10.1016/j.cub.2009.06.013

  48. Nishimura T., Kaneko S., Kawana-Tachikawa A., Tajima Y., Goto H., Zhu D., Nakayama-Hosoya K., Iriguchi S., Uemura Y., Shimizu T., Takayama N., Yamada D., Nishimura K., Ohtaka M. et al. 2013. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell. V. 12. P. 114.

  49. Ocampo A., Reddy P., Martinez-Redondo P., Platero-Luengo A., Hatanaka F., Hishida T., Li M., Lam D., Kurita M., Beyret E., Araoka T., Vazquez-Ferrer E., Donoso D., Roman J. L. et al. C. 2016. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. V. 167. P. 1719.

  50. Ohnishi K., Semi K., Yamamoto T., Shimizu M., Tanaka A., Mitsunaga K., Okita K., Osafune K., Arioka Y., Maeda T., Soejima H., Moriwaki H., Yamanaka S., Woltjen K., Yamada Y. 2014. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. V. 156. P.663.

  51. Ohnuki M., Tanabe K., Sutou K., Teramoto I., Sawamura Y., Narita M., Nakamura M., Tokunaga Y., Nakamura M., Watanabe A., Yamanaka S., Takahashi K. 2014. Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential. Proc. Natl. Acad. Sci. USA. V. 111. P. 12426.

  52. Olova N., Simpson D.J., Marioni R.E., Chandra T. 2019. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell. V. 18: e12877. https://doi.org/10.1111/acel.12877

  53. Raffaghello L., Lee C., Safdie F.M., Wei M., Madia F., Bianchi G., Longo V.D. 2008. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. USA. V. 105. P. 8215.

  54. Rodríguez-Matellán A., Alcazar N., Hernández F., Serrano M., Ávila J. 2020. In vivo reprogramming ameliorates aging features in dentate gyrus cells and improves memory in mice. Stem Cell Reports V. 15. P. 1056.

  55. Roux A.E., Zhang C., Paw J., Zavala-Solorio J., Malahias E., Vijay T., Kolumam G., Kenyon C., Kimmel J.C. 2022. Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity. Cell Syst. V. 13. P. 574.

  56. Sarkar T.J., Quarta M., Mukherjee S., Colville A., Paine P., Doan L., Tran C.M., Chu C.R., Horvath S., Qi L.S., Bhutani N., Rando T.A., Sebastiano V. 2020. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat. Commun. V. 11. P. 1545.

  57. Schiebinger G., Shu J., Tabaka M., Cleary B., Subramanian V., Solomon A., Gould J., Liu S., Lin S., Berube P., Lee L., Chen J., Brumbaugh J., Rigollet P., Hochedlinger K. et al. 2019. Optimal-Transport analysis of single-cell gene expression identifies developmental trajectories in reprogramming. Cell. V. 176. P. 928.

  58. Schmauck-Medina T., Molière A., Lautrup S., Zhang J., Chlopicki S., Madsen H.B., Cao S., Soendenbroe C., Mansell E., Vestergaard M.B., Li Z., Shiloh Y., Opresko P.L., Egly J.M., Kirkwood T. et al. 2022. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany. NY). V. 14: 6829. https://doi.org/10.18632/aging.204248

  59. Shahini A., Rajabian N., Choudhury D., Shahini S., Vydiam K., Nguyen T., Kulczyk J., Santarelli T., Ikhapoh I., Zhang Y., Wang J., Liu S., Stablewski A., Thiyagarajan R., Seldeen K. et al. 2021. Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo. Sci. Adv. V. 7: eabe5671. https://doi.org/10.1126/sciadv.abe5671

  60. Singh P.B., Laktionov P.P., Newman A.G. 2019. Deconstructing age reprogramming. J. Biosci. V. 44. P. 106.

  61. Smith E.D., Kaeberlein T.L., Lydum B.T., Sager J., Welton K.L., Kennedy B.K., Kaeberlein M. 2008. Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans. BMC Dev. Biol. V. 8. P. 49.

  62. Stölzel F., Brosch M., Horvath S., Kramer M., Thiede C., Von Bonin M., Ammerpohl O., Middeke M., Schetelig J., Ehninger G., Hampe J., Bornhäuser M. 2017. Dynamics of epigenetic age following hematopoietic stem cell transplantation. Haematologica. V. 102: e321. https://doi.org/10.3324/haematol.2016.160481

  63. Takahashi K., Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. V. 126. P. 663.

  64. Tanabe K., Nakamura M., Narita M., Takahashi K., Yamanaka S. 2013. Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Proc. Natl. Acad. Sci. USA. V. 110. P. 12172.

  65. Verweij M., Van Ginhoven T.M., Mitchell J.R., Sluiter W., Den Engel S. Van, Roest H.P., Torabi E., Ijzermans J.N.M., Hoeijmakers J.H.J., De Bruin R.W.F. 2011. Preoperative fasting protects mice against hepatic ischemia/reperfusion injury: mechanisms and effects on liver regeneration. Liver Transplant. V. 17. P. 695.

  66. Vizioli M.G., Liu T., Miller K.N., Robertson N.A., Gilroy K., Lagnado A.B., Perez-Garcia A., Kiourtis C., Dasgupta N., Lei X., Kruger P.J., Nixon C., Clark W., Jurk D., Bird T.G. et al. 2020. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. V. 34. P. 428.

  67. Weidner C.I., Lin Q., Koch C.M., Eisele L., Beier F., Ziegler P., Bauerschlag D.O., Jöckel K.H., Erbel R., Mühleisen T.W., Zenke M., Brümmendorf T.H., Wagner W. 2014. Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol. V. 15. P. R24.

  68. Ye J., Ge J., Zhang X., Cheng L., Zhang Z., He S., Wang Y., Lin H., Yang W., Liu J., Zhao Y., Deng H. 2016. Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res. V. 26. P. 34.

  69. Yousefzadeh M.J., Flores R. R., Zhu Y., Schmiechen Z.C., Brooks R.W., Trussoni C.E., Cui Y., Angelini L., Lee K.A., McGowan S.J., Burrack A.L., Wang D., Dong Q., Lu A., Sano T., O’Kelly R.D. et al. 2021. An aged immune system drives senescence and ageing of solid organs. Nature. V. 594. P. s41586.

Дополнительные материалы отсутствуют.