Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence
Open accessAbstract
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A. We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16 INK4a, p21 CIP1, and p15 INK4b, preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.
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The mechanistic target of rapamycin (mTOR) complex can either counteract or facilitate reprogramming by cell-intrinsic and cell-extrinsic mechanisms, respectively.
“In this sense, a crucial role for the mechanistic target of rapamycin (mTOR) complex has recently been unveiled, whereby it can either counteract or facilitate reprogramming by cell-intrinsic and cell-extrinsic mechanisms, respectively.69”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [69]
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Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Viable offspring derived from fetal and adult mammalian cells
Wilmut, I., Schnieke, A., McWhir, J., Kind, A., & Campbell, K. (1997) · Nature · doi:10.1038/385810a0 · Cited by 4,976 · see citing works
Full-length RNA-seq from single cells using Smart-seq2
Picelli, S., Faridani, O. R., Björklund, Å. K., Winberg, G., Sagasser, S., & Sandberg, R. (2014) · Nature Protocols · doi:10.1038/nprot.2014.006 · Cited by 4,137 · see citing works
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,891 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Senescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Dixit, A., Parnas, O., Li, B., Chen, J., Fulco, C. P., Jerby-Arnon, L., Marjanovic, N. D., Dionne, D., Burks, T., Raychowdhury, R., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.038 · Cited by 1,863 · see citing works
Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · cited 2× · see citing works
“Genetic screening is a powerful tool that has been exploited with success to identify genes regulating senescence (Jacobs et al. 2000; Rowland et al. 2005; Acosta et al. 2008; Tordella et al. 2016; Wang et al. 2016) or cellular reprogramming (Qin et al. 2014; Sakurai et al. 2014; Yang et al. 2014).”
Self-citationcGAS surveillance of micronuclei links genome instability to innate immunity
Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., et al. (2017) · Nature · doi:10.1038/nature23449 · Cited by 1,752 · see citing works
Self-citationInduced pluripotent stem cell technology: a decade of progress.
Shi, Y., Inoue, H., Wu, J. C., & Yamanaka, S. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.245 · Cited by 1,525 · see citing works
Suppression of induced pluripotent stem cell generation by the p53–p21 pathway
Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., & Yamanaka, S. (2009) · Nature · doi:10.1038/nature08235 · Cited by 1,301 · see citing works
Adamson, B., Norman, T. M., Jost, M., Cho, M. Y., Nuñez, J. K., Chen, Y., Villalta, J. E., Gilbert, L. A., Horlbeck, M. A., Hein, M. Y., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.048 · Cited by 1,193 · see citing works
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · cited 1× · see citing works
“In general, the accumulation of senescent cells is detrimental (Munoz-Espin and Serrano 2014), and their elimination ameliorates many age-related pathologies (Baker et al. 2016), whereas senescence induction limits fibrosis (Krizhanovsky et al. 2008) and cancer (Collado and Serrano 2010).”
Linking the p53 tumour suppressor pathway to somatic cell reprogramming
Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Belmonte, J. C. I. (2009) · Nature · doi:10.1038/nature08311 · Cited by 1,115 · see citing works
A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
Marión, R. M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., & Blasco, M. A. (2009) · Nature · doi:10.1038/nature08287 · Cited by 1,028 · cited 2× · see citing works
“Key tumor suppressors such as p53, p16 INK4a , or p21 CIP1 control the senescence response to OSKM, and their inhibition increases reprogramming (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marion et al. 2009; Utikal et al. 2009).”
The Ink4/Arf locus is a barrier for iPS cell reprogramming
Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Cañamero, M., Blasco, M. A., & Serrano, M. (2009) · Nature · doi:10.1038/nature08290 · Cited by 968 · see citing works
Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.
Reynisdóttir, I., Polyak, K., Iavarone, A., & Massagué, J. (1995) · Genes & Development · doi:10.1101/gad.9.15.1831 · Cited by 962 · see citing works
Chang, H. Y., Sneddon, J. B., Alizadeh, A. A., Sood, R., West, R. B., Montgomery, K. D., Chi, J., van de Rijn, M., Botstein, D., & Brown, P. O. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020007 · Cited by 952 · see citing works
Immortalization eliminates a roadblock during cellular reprogramming into iPS cells
Utikal, J., Polo, J., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R. M., Khalil, A., Rheinwald, J., & Hochedlinger, K. (2009) · Nature · doi:10.1038/nature08285 · Cited by 896 · see citing works
Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells
Tada, M., Takahama, Y., Abe, K., Nakatsuji, N., & Tada, T. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00459-6 · Cited by 891 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
Scaling single-cell genomics from phenomenology to mechanism
Tanay, A., & Regev, A. (2017) · Nature · doi:10.1038/nature21350 · Cited by 792 · see citing works
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3225 · Cited by 788 · see citing works
Self-citationDissecting Immune Circuits by Linking CRISPR-Pooled Screens with Single-Cell RNA-Seq
Jaitin, D. A., Weiner, A., Yofe, I., Lara-Astiaso, D., Keren-Shaul, H., David, E., Salame, T. M., Tanay, A., van Oudenaarden, A., & Amit, I. (2016) · Cell · doi:10.1016/j.cell.2016.11.039 · Cited by 777 · see citing works
Tzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O. M., Mupo, A., Grinkevich, V., Li, M., Mazan, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.079 · Cited by 761 · see citing works
An Optimized microRNA Backbone for Effective Single-Copy RNAi
Fellmann, C., Hoffmann, T., Sridhar, V., Hopfgartner, B., Muhar, M., Roth, M., Lai, D. Y., Barbosa, I. A. M., Kwon, J. S., Guan, Y., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.11.020 · Cited by 705 · see citing works
Self-citationSenescence impairs successful reprogramming to pluripotent stem cells
Banito, A., Rashid, S. T., Acosta, J. C., Li, S., Pereira, C. F., Geti, I., Pinho, S., Silva, J. C., Azuara, V., Walsh, M., et al. (2009) · Genes & Development · doi:10.1101/gad.1811609 · Cited by 642 · see citing works
Self-citationTissue damage and senescence provide critical signals for cellular reprogramming in vivo
Mosteiro, L., Pantoja, C., Alcazar, N., Marión, R. M., Chondronasiou, D., Rovira, M., Fernandez-Marcos, P. J., Muñoz-Martin, M., Blanco-Aparicio, C., Pastor, J., et al. (2016) · Science · doi:10.1126/science.aaf4445 · Cited by 589 · see citing works
Rowland, B. D., Bernards, R., & Peeper, D. S. (2005) · Nature Cell Biology · doi:10.1038/ncb1314 · Cited by 583 · see citing works
Probing tumor phenotypes using stable and regulated synthetic microRNA precursors
Dickins, R., Hemann, M., Zilfou, J. T., Simpson, D. R., Ibarra, I., Hannon, G., & Lowe, S. (2005) · Nature Genetics · doi:10.1038/ng1651 · Cited by 561 · see citing works
Adult frogs derived from the nuclei of single somatic cells
Gurdon, J. B. (1962) · Developmental Biology · doi:10.1016/0012-1606(62)90043-x · Cited by 462 · see citing works
Jacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., et al. (2000) · Nature Genetics · doi:10.1038/81583 · Cited by 368 · see citing works
The promises and perils of p53
Krizhanovsky, V., & Lowe, S. W. (2009) · Nature · doi:10.1038/4601085a · Cited by 274 · see citing works
The histone chaperone CAF-1 safeguards somatic cell identity
Cheloufi, S., Elling, U., Hopfgartner, B., Jung, Y. L., Murn, J., Ninova, M., Hubmann, M., Badeaux, A. I., Ang, C. E., Tenen, D. E., et al. (2015) · Nature · doi:10.1038/nature15749 · Cited by 274 · see citing works
Self-citationWang, S., Xia, P., Ye, B., Huang, G., Liu, J., & Fan, Z. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.10.005 · Cited by 209 · see citing works
Chen, T., Shen, L., Yu, J., Wan, H., Guo, A., Chen, J., Long, Y., Zhao, J., & Pei, G. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00722.x · Cited by 204 · see citing works
Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
Deschênes-Simard, X., Gaumont-Leclerc, M.-F., Bourdeau, V., Lessard, F., Moiseeva, O., Forest, V., Igelmann, S., Mallette, F. A., Saba-El-Leil, M. K., Meloche, S., et al. (2013) · Genes & Development · doi:10.1101/gad.203984.112 · Cited by 194 · see citing works
High-resolution analysis with novel cell-surface markers identifies routes to iPS cells
O’Malley, A. J., Skylaki, S., Iwabuchi, K. A., Chantzoura, E., Ruetz, T. J., Johnsson, A., Tomlinson, S. R., Linnarsson, S., & Kaji, K. (2013) · Nature · doi:10.1038/nature12243 · Cited by 150 · see citing works
Self-citationNuber, U. A., Schwarz, S. E., Kaiser, P., Schneider, R., & Scheffner, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.5.2795 · Cited by 150 · see citing works
Induced pluripotent stem cells and senescence: learning the biology to improve the technology
Banito, A., & Gil, J. (2010) · EMBO Reports · doi:10.1038/embor.2010.47 · Cited by 117 · see citing works
Self-citationThe Palladin/Myotilin/Myopalladin Family of Actin‐Associated Scaffolds
Otey, C. A., Rachlin, A., Moza, M., Arneman, D., & Carpén, O. (2005) · International review of cytology · doi:10.1016/s0074-7696(05)46002-7 · Cited by 114 · see citing works
Brady Jennifer, J., Li, M., Suthram, S., Jiang, H., Wong, W. H., & Blau, H. M. (2013) · Nature Cell Biology · doi:10.1038/ncb2835 · Cited by 101 · see citing works
Systematic Identification of Barriers to Human iPSC Generation
Qin, H., Diaz, A. A., Blouin, L., Lebbink, R. J., Patena, W., Tanbun, P., LeProust, E. M., McManus, M. T., Song, J. S., & Ramalho‐Santos, M. (2014) · Cell · doi:10.1016/j.cell.2014.05.040 · Cited by 95 · see citing works
Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming
Wu, Y., Li, Y., Zhang, H., Huang, Y., Zhao, P., Tang, Y., Qiu, X., Yue, Y., Li, W., Ni, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3172 · Cited by 85 · see citing works
Sakurai, K., Talukdar, I., Patil, V. S., Dang, J. W., Li, Z., Chang, K., Lu, C., Delorme, V., DerMardirossian, C. M., Anderson, K., et al. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.03.001 · Cited by 67 · see citing works
Yang, C., Chang, K., & Rana, T. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.002 · Cited by 63 · see citing works
SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancerPreprint
Tordella, L., Khan, S. S., Hohmeyer, A., Banito, A., Klotz, S., Raguz, S., Martin, N., Dhamarlingam, G., Carroll, T. D., González-Meljem, J. M., et al. (2016) · Genes & Development · doi:10.1101/gad.286112.116 · Cited by 59 · see citing works
Self-citationVijayachandra, K., Higgins, W., Lee, J., & Glick, A. B. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20472 · Cited by 57 · see citing works
THE RESEMBLANCE BETWEEN TWINS, A STATISTICAL EXAMINATION OF LAUTERBACH'S MEASUREMENTS
Fisher, R. A. (1925) · Genetics · doi:10.1093/genetics/10.6.569 · Cited by 43 · see citing works
Reprogramming Roadblocks Are System Dependent
Chantzoura, E., Skylaki, S., Ménendez, S., Kim, S., Johnsson, A., Linnarsson, S., Woltjen, K., Chambers, I., & Kaji, K. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.07.007 · Cited by 33 · see citing works
Self-citationWang, Y., Xu, Q., Sack, L. M., Kang, C., & Elledge, S. J. (2016) · Genes & Development · doi:10.1101/gad.271445.115 · Cited by 24 · see citing works
Flagged first, then by citations
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Sorted by citations
MULTI-seq: sample multiplexing for single-cell RNA sequencing using lipid-tagged indices
McGinnis, C. S., Patterson, D. M., Winkler, J., Conrad, D. N., Hein, M. Y., Srivastava, V., Hu, J. L., Murrow, L. M., Weissman, J. S., Werb, Z., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0433-8 · Cited by 643 · see citing works
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
Shifrut, E., Carnevale, J., Tobin, V., Roth, T. L., Woo, J. M., Bui, C. T., Li, P. J., Diolaiti, M. E., Ashworth, A., & Marson, A. (2018) · Cell · doi:10.1016/j.cell.2018.10.024 · Cited by 573 · see citing works
Georgilis, A., Klotz, S., Hanley, C. J., Herranz, N., Weirich, B., Morancho, B., Leote, A. C., D'Artista, L., Gallage, S., Seehawer, M., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.06.007 · Cited by 237 · see citing works
Self-citationSingle-cell analyses of aging, inflammation and senescence
Uyar, B., Palmer, D. H., Kowald, A., Escobar, H. M., Barrantes, I., Möller, S., Akalin, A., & Fuellen, G. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101156 · Cited by 202 · see citing works
Paracrine roles of cellular senescence in promoting tumourigenesis
Gonzalez-Meljem, J. M., Apps, J. R., Fraser, H. C., & Martinez-Barbera, J. P. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0066-1 · Cited by 183 · see citing works
Galactose‐modified duocarmycin prodrugs as senolytics
Guerrero, A., Guiho, R., Herranz, N., Uren, A., Withers, D. J., Martínez‐Barbera, J. P., Tietze, L. F., & Gil, J. (2020) · Aging Cell · doi:10.1111/acel.13133 · Cited by 172 · see citing works
Self-citationRegulation of senescence traits by MAPKs
Anerillas, C., Abdelmohsen, K., & Gorospe, M. (2020) · GeroScience · doi:10.1007/s11357-020-00183-3 · Cited by 166 · see citing works
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147 · see citing works
Power in Numbers: Single-Cell RNA-Seq Strategies to Dissect Complex Tissues
Birnbaum, K. D. (2018) · Annual Review of Genetics · doi:10.1146/annurev-genet-120417-031247 · Cited by 113 · see citing works
Tolios, A., Rivas, J. D. L., Hovig, E. J., Trouillas, P., Scorilas, A., & Mohr, T. T. (2019) · Drug Resistance Updates · doi:10.1016/j.drup.2019.100662 · Cited by 63 · see citing works
Rapamycin, proliferation and geroconversion to senescence
Blagosklonny, M. V. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1554781 · Cited by 61 · see citing works
Translational Control during Cellular Senescence
Payea, M. J., Anerillas, C., Tharakan, R., & Gorospe, M. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00512-20 · Cited by 54 · see citing works
Hedblom, A., Hejazi, S. M., Canesin, G., Choudhury, R., Hanafy, K. A., Csizmadia, E., Persson, J. L., & Wegiel, B. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1342-6 · Cited by 46 · see citing works
Integrated multi-omics approach revealed cellular senescence landscape
Song, Q., Hou, Y., Zhang, Y., Liu, J., Wang, Y., Fu, J., Zhang, C., Cao, M., Cui, Y., Zhang, X., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac885 · Cited by 42 · see citing works
Sample-multiplexing approaches for single-cell sequencing
Zhang, Y., Xu, S., Wen, Z., Gao, J., Li, S., Weissman, S. M., & Pan, X. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04482-0 · Cited by 40 · see citing works
Functional annotation of lncRNA in high-throughput screening
Yip, C. W., Sivaraman, D. M., Prabhu, A. V., & Shin, J. W. (2021) · Essays in Biochemistry · doi:10.1042/ebc20200061 · Cited by 38 · see citing works
Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome
(2024) · doi:10.1038/s43587-024-00695-z · Cited by 31 · see citing works
Self-citationRibosomal S6 kinase 1 regulates ‘inflammaging’ via the senescence secretome
Gallage, S., Irvine, E. E., Pedroni, S. M. A., Barragan Avila, J. E., Khadayate, S., Pombo, J., Brookes, S., Heide, D., Dharmalingham, G., Choudhury, A. I., et al. (2023) · doi:10.1101/2023.10.17.562098 · Cited by 31 · see citing works
Self-citationSingle-cell and spatial detection of senescent cells using DeepScence
Qu, Y., Ji, B., Dong, R., Gu, L., Chan, C., Xie, J., Glass, C., Wang, X.-F., Nixon, A. B., & Ji, Z. (2025) · Cell Genomics · doi:10.1016/j.xgen.2025.101035 · Cited by 30 · see citing works
Rising from the ashes: cellular senescence in regeneration
Walters, H., & Yun, M. H. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.06.002 · Cited by 29 · see citing works
Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming
von Joest, M., Chen, C., Douché, T., Chantrel, J., Chiche, A., Gianetto, Q. G., Matondo, M., & Li, H. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111074 · Cited by 30 · see citing works
Wang, J., Zhou, X., Yu, P., Yao, J., Guo, P., Xu, Q., Zhao, Y., Wang, G., Li, Q., Zhu, X., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00886-2 · Cited by 28 · see citing works
SIX1 represses senescence and promotes SOX2-mediated cellular plasticity during tumorigenesis
Lope, C. D., Martín-Alonso, S., Auzmendi-Iriarte, J., Escudero‐Iriarte, C., Mulet, I., Larrasa-Alonso, J., López‐Antona, I., Matheu, A., & Palmero, I. (2019) · Scientific Reports · doi:10.1038/s41598-018-38176-0 · Cited by 26 · see citing works
Jiang, Q., Huang, X., Hu, X., Shan, Z., Wu, Y., Wu, G., & Lei, L. (2020) · Stem Cells · doi:10.1002/stem.3188 · Cited by 27 · see citing works
Transcriptome profile of bovine iPSCs derived from Sertoli Cells
Jiang, Y., An, X.-L., Yu, H., Cai, N., Zhai, Y., Li, Q., Cheng, H., Zhang, S., Tang, B., Li, Z., et al. (2019) · Theriogenology · doi:10.1016/j.theriogenology.2019.11.022 · Cited by 21 · see citing works
Cellular and molecular features of senescence in acute lung injury
Huidobro, C., Martín-Vicente, P., López‐Martínez, C., López-Alonso, I., Amado‐Rodríguez, L., Crespo, I., & Albaiceta, G. M. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111410 · Cited by 20 · see citing works
Single-Cell Toolkits Opening a New Era for Cell Engineering
Lee, S., Kim, J., & Park, J.-E. (2021) · Molecules and Cells · doi:10.14348/molcells.2021.0002 · Cited by 19 · see citing works
The crosstalk between cellular reprogramming and senescence in aging and regeneration
Chiche, A., Chen, C., & Li, H. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111005 · Cited by 21 · see citing works
Epigenetics and Pharmacoepigenetics of Age-Related Neurodegenerative Disorders
Cacabelos, R., Cacabelos, P., & Carril, J. C. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813939-4.00038-3 · Cited by 18 · see citing works
Guerrero, A., Innes, A. J., Roux, P., Buisman, S. C., Jung, J., Ortet, L., Moiseeva, V., Wagner, V., Robinson, L. J., Ausema, A., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00279-9 · Cited by 15 · see citing works
Self-citationThe application of gene silencing in proteomics: from laboratory to clinic
Brioschi, M., & Banfi, C. (2018) · Expert Review of Proteomics · doi:10.1080/14789450.2018.1521275 · Cited by 14 · see citing works
Manipulating and studying gene function in human pluripotent stem cell models
Balmas, E., Sozza, F., Bottini, S., Ratto, M. L., Savoré, G., Becca, S., Snijders, K. E., & Bertero, A. (2023) · FEBS Letters · doi:10.1002/1873-3468.14709 · Cited by 17 · see citing works
Lee, S. J., Kang, K., Kim, J.-H., Lee, B., Jung, J., Park, Y., Hong, S., & Kim, B. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0188 · Cited by 15 · see citing works
Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies
Kilmister, E. J., Hansen, L., Davis, P. F., Hall, S. R. R., & Tan, S. T. (2021) · Frontiers in Surgery · doi:10.3389/fsurg.2020.610758 · Cited by 15 · see citing works
The Potent and Paradoxical Biology of Cellular Senescence in Cancer
Romesser, P. B., & Lowe, S. W. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-124434 · Cited by 14 · see citing works
Kilmister, E. J., & Tan, S. T. (2022) · Frontiers in Surgery · doi:10.3389/fsurg.2022.868187 · Cited by 13 · see citing works
Floros, K. V., Fairchild, C. K., Li, J., Zhang, K., Roberts, J. L., Kurupi, R., Paudel, D., Xing, Y., Hu, B., Kraskauskiene, V., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64665-8 · Cited by 12 · see citing works
Self-citationLi, Q. V., Rosen, B. P., & Huangfu, D. (2019) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1464 · Cited by 13 · see citing works
The occurrence and development of induced pluripotent stem cells
Chen, Y., Li, M., & Wu, Y. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1389558 · Cited by 14 · see citing works
Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence
Scanlan, R.-L., Pease, L., O’Keefe, H., Guimera, A. M., Rasmussen, L. J., Wordsworth, J., & Shanley, D. P. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1448543 · Cited by 11 · see citing works
Litjens, N. H. R., Langerak, A. W., van der List, A. C. J., Klepper, M., de Bie, M., Azmani, Z., den Dekker, A. T., Brouwer, R. W. W., Betjes, M. G. H., & van IJcken, W. F. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01999 · Cited by 6 · see citing works
Functional screening to identify senescence regulators in cancer
Lujambio, A., & Banito, A. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.02.001 · Cited by 5 · see citing works
Self-citationSingle cell transcriptional perturbome in pluripotent stem cell models
Balmas, E., Ratto, M. L., Snijders, K. E., Becca, S., Liaci, C., Ricca, I., Merlo, G. R., Calogero, R., Alessandrì, L., Mendjan, S., et al. (2025) · Molecular Systems Biology · doi:10.1038/s44320-025-00172-8 · Cited by 4 · see citing works
Molecular basis of cell fate plasticity – insights from the privileged cells
Scalf, S. M., Wu, Q., & Guo, S.-Q. (2025) · Current Opinion in Genetics and Development · doi:10.1016/j.gde.2025.102354 · Cited by 3 · see citing works
Lee, M., Guo, Q., Kim, M., Choi, J. H., Segura, A., Genceroglu, A., LeBlanc, L., Ramirez, N., Jang, Y. J., Jang, Y., et al. (2024) · Genome Research · doi:10.1101/gr.277926.123 · Cited by 3 · see citing works
Xu, Y., Sun, S., Wang, M., Shen, W., Wang, L., Ren, C., Ling, Y., Zhang, Z., & Cao, H. (2024) · Theriogenology · doi:10.1016/j.theriogenology.2024.10.025 · Cited by 3 · see citing works
The Regulatory Role of m6A Modification in the Function and Signaling Pathways of Animal Stem Cells
Yang, X. E., Xu, Y., Zhu, S., Wang, M., Cao, H., & Lu, L. (2026) · Cells · doi:10.3390/cells15020181 · Cited by 3 · see citing works
Expression of Cathepsins B, D, and G in Extracranial Arterio-Venous Malformation
Hansen, L., Brasch, H. D., Paterson, E., Patel, J., Bockett, N. A., Davis, P. F., & Tan, S. T. (2021) · Frontiers in Surgery · doi:10.3389/fsurg.2021.676871 · Cited by 3 · see citing works
Pooled Generation of Lentiviral Tetracycline-Regulated microRNA Embedded Short Hairpin RNA Libraries
Adams, F. F., Hoffmann, T., Zuber, J. A., Heckl, D., Schambach, A., & Schwarzer, A. (2018) · Human Gene Therapy Methods · doi:10.1089/hgtb.2017.182 · Cited by 3 · see citing works
Self-citationCai, W., Chong, K., Zhou, B., Zhao, Y., Lao, B., & Yin, L. (2025) · Genomics · doi:10.1016/j.ygeno.2025.111161 · Cited by 2 · see citing works
Mechanisms of cell senescence in aging
von Zglinicki, T. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00003-2 · Cited by 2 · see citing works
Amphiregulin mediates non-cell-autonomous effect of senescence on reprogrammingPreprint
von Joest, M., Chen, C., Douché, T., Chiche, A., Matondo, M., & Li, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.01.458621 · Cited by 2 · see citing works
Martins-Silva, R., Kaizeler, A., & Barbosa‐Morais, N. L. (2026) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqag057 · Cited by 1 · see citing works
Altulea, A., Mackedenski, S. J., Nehme, J., & Demaria, M. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00845-6 · Cited by 1 · see citing works
Systematic transcriptomic analysis and temporal modelling of the senescent human fibroblastPreprint
Scanlan, R.-L., Pease, L., O’Keefe, H., Guimera, A. M., Shanley, D., & Wordsworth, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.16.504144 · Cited by 1 · see citing works
An Introduction to Single-Cell RNA-Seq Analysis and its Applications
Chen, W., & Tang, M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11592-2
Amphiregulin Mediates Non-Cell-Autonomous Effect of Senescence on ReprogrammingPreprint
von Joest, M., Chen, C., Douché, T., Chiche, A., Gianetto, Q. G., Matondo, M., & Li, H. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3936777
Litjens, N. H. R., Langerak, A. W., Azmani, Z., den Dekker, X., Betjes, M. G. H., Brouwer, R. W. W., & van IJcken, W. F. J. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2115-8_14
Cellular senescence during aging
von Zglinicki, T. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823761-8.00017-3
Epigenetic Iinsights into the Senescence of Porcine Fetal Fibroblasts induced by Passaging
Bi, J., Wang, D., Zhu, F., Lu, X., Xie, Y., Liu, H., Wang, M., He, X., Jiang, Y. Z., Liu, P., et al. (2023) · Cell Cycle · doi:10.1080/15384101.2023.2222521
Epigenetics and pharmacoepigenetics of age-related neurodegenerative disorders
Cacabelos, R., Martínez-Iglesias, O. A., Cacabelos, N., Cacabelos, P., & Naidoo, V. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-18722-3.00032-3
Kuklinkova, R., Benova, N., Kohli, J. S., Boyne, J. R., Roberts, W., & Anene, C. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.20.713302
Xiao, F., Wang, H., Zhao, L., Li, G., Ma, S.-Y., Yang, L.-Q., Wang, H., Zhang, Y. X., Li, J., & Kong, Q. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102767
- Authors
- Aarts, M., Georgilis, A., Beniazza, M., Beolchi, P., Banito, A., Carroll, T., Kulisic, M., Kaemena, D. F., Dharmalingam, G., Martin, N., Reik, W., Zuber, J., Kaji, K., Chandra, T., & Gil, J.
- Affiliations
- MRC London Institute of Medical Sciences (GB)
- MRC Centre for Regenerative Medicine (GB)
- Babraham Institute (GB)
- Research Institute of Molecular Pathology (AT)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-10-15
- Volume
- 31
- Issue
- 20
- Pages
- 2085-2098
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC5733499
- OpenAlex
- W2770882386
- Cited by
- 64
- References
- 53
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 8
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Genes & Development (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Medical Research Council
- Centennary Award
- Biotechnology and Biological Sciences Research Council East of Scotland BioScience Doctoral Training Partnership
- MRC-British Heart Foundation Cardiovascular Stem Cell Research Strategic Development (G0901467)
- MRC (MC_U120085810)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mTOR, induced pluripotent stem cells, OSKM, somatic cell reprogramming, senescence-associated secretory phenotype, p21, cyclin-dependent kinase inhibitors, p16INK4a, CDKN2B, fibroblasts, shRNA screen, single-cell RNA sequencing
- MeSH terms
- Kruppel-Like Factor 4, Animals, Cells, Cultured, Fibroblasts, Humans, Transcription Factors, Cellular Senescence, Sequence Analysis, RNA, Gene Expression Profiling, RNA, Small Interfering, Cyclin-Dependent Kinase Inhibitor p21, Mice, TOR Serine-Threonine Kinases, Single-Cell Analysis, Cellular Reprogramming
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