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Programmed Cell Senescence during Mammalian Embryonic Development
Open accessAbstract
Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.
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“recent reports showed a beneficial role for the SASP during embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013) and a role in limiting fibrosis after tissue injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Muñoz-Espín et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“it was reported that senescence occurs in a programmed manner and contributes to mammalian embryonic development and tissue patterning, although mainly via induction of p21, p15 and mediators of the SASP rather than through overt DDR signalling131,132.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A distinct form of cellular senescence occurs in the mammalian developing embryo and in the placenta to control growth and patterning131,132,142,143.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Among these cell types, NK cells, T cells and macrophages can physically interact with senescent cells in pathological and physiological conditions131,132,145,150,153–156.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16 Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [9]
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In the citing paper
“Furthermore, recent studies showing that senescent cells have beneficial effects in injury repair and tissue remodelling 6 - 10 have called into question the simplistic view of senescence as only a driver of age-dependent pathologies, raising the specter that senescent cell clearance might remove useful cells in addition to detrimental ones.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“SASP factors mediate developmental senescence (Mun ˜ oz-Espı ´n et al., 2013; Storer et al., 2013), wound healing (Demaria et al., 2014), and tissue plasticity (Mosteiro et al., 2016) and also contribute to persistent chronic inflammation (known as inflammaging) (Franceschi and Campisi, 2014).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Munoz-Espin et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Senescent cells play crucial roles in development, tumor suppression, and tissue repair (Demaria et al, 2014; Muñoz-Espín et al, 2013; Serrano et al, 1997).”
From Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues (2025) · cites this paper as Muñoz-Espín et al, 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition to tissue repair, SASP factors are involved in embryonic development of the apical ectodermal ridge and neural roof plate.40, 41”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [41]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Immune-mediated clearance of senescent cells suppresses tumor initiation (Kang et al. 2011), contributes to tumor regression (Xue et al. 2007), and is essential during development (Muñoz-Espín et al. 2013; Storer et al. 2013).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Muñoz-Espín et al. 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“By contrast, senescent cells have shown beneficial effects as tumour suppressors, during embryo development, and in liver and skin repair18–21 or reprogramming22–24.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“defective senescence programmes or removal of senescent cells during various developmental stages results in patterning abnormalities 1 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [1]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Of possible relevance to this puzzle, senescent cells were recently detected during embryogenesis, where they appear to play a nonessential role in optimizing the development of certain embryonic structures (Muñoz-Espín et al., 2013; Storer et al., 2013).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Muñoz-Espín et al., 2013
The cited source says what the claim attributes to it.
In the citing paper
“Senescence, much like apoptosis, contributes to embryonic patterning (Muñoz-Espín et al. 2013; Storer et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Muñoz-Espín et al. 2013
The cited source says what the claim attributes to it.
In the citing paper
“In addition, two recent studies have identified “programmed” cellular senescence, which contributes to tissue remodeling during mammalian embryonic development at multiple regions (Muñoz-Espín et al. 2013; Storer et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Muñoz-Espín et al. 2013
In the citing paper
“Senescence plays key physiological roles in normal development (Muñoz-Espín et al., 2013; Storer et al., 2013), maintaining tissue homeostasis, tissue remodeling and repair (Yun et al., 2015), wound healing (Ramakrishna et al., 2012; Demaria et al., 2014), secretion of insulin by pancreatic beta cells (Helman et al., 2016), and limits tumor progression by ensuring that potentially dysfunctional,”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“Upregulation of p21WAF1/CIP1 plays a key role in developmental senescence as mice lacking it show defects in embryonic senescence, apical ectodermal ridge maintenance and patterning as well as other developmental defects.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“Developmental senescence is a transient programmed cellular senescence that occurs during mammalian embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“However, despite this, DDR markers have a limited potential for identifying senescent cells in vivo since DDR independent mechanisms are also capable of inducing senescence via p53/p21WAF1/CIP1 pathway (Alimonti et al., 2010; Freund et al., 2011; Muñoz-Espín et al., 2013; Storer et al., 2013; Salama et al., 2014).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“developmentally programmed and transiently-regulated senescence is established to be vital in promoting tissue remodeling, embryogenesis and patterning”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [91]
In the citing paper
“This pathway can positively contribute to normal development and wound healing (15, 17, 61, 62).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [61]
In the citing paper
“Waves of cellular senescence (followed by RCD) appear to contribute to developmental embryogenesis (although in a dispensable manner) [6, 946, 947] as well as to multiple pathophysiological processes in the adult, including tissue repair and regeneration, immunity, preservation of the stem cell compartment, and oncosuppression [948–957].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [946]
In the citing paper
“Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair (Krizhanovsky et al., 2008, Muñoz-Espín et al., 2013, Demaria et al., 2014, Ritschka et al., 2017).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“senescent cells detected during development, which are present transiently in tissues (Muñoz-Espín et al., 2013) are not associated with the activation of a DNA damage response”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“previous reports have shown that TGF-β regulates senescence”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“a number of studies have found that TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation, in agreement with our data (Acosta et al., 2013, Hoare et al., 2016, Muñoz-Espín et al., 2013, Storer et al., 2013).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Muñoz-Espín et al., 2013
In the citing paper
“Embryonic cell senescence is p21, but not p53, dependent, is accompanied by the SASP, and these cells are eliminated by macrophages 149,150”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [149]
In the citing paper
“Indeed, unlike chronic senescence (i.e., accumulation of deleterious senescent cells with aging), the acute induction of cellular senescence represents a transient physiological response during embryonic development [27,28] and adult tissue homeostasis (e.g., to facilitate tissue repair after liver damage, in skin fibrosis, and wound healing) [29,30,31].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“Senescence is classically viewed as a stress response but can also occur in mouse and human embryos [27,28].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“In senescent embryonic cells, p21, but not p16, enforces cell cycle arrest, together with p15 that is a p16-related CDK inhibitor.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“Other mechanisms, such as apoptosis, may partially compensate for the loss of developmental senescence in such embryos [27,28].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“Moreover, p21 is not induced by p53 or DNA damage but is regulated by the transforming growth factor (TGF)-β/SMAD and PI3K/Forkhead box O (FOXO) signaling pathways [27].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“Senescent cells can be cleared by the immune system [27,263,264] rather than directly through apoptosis.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In the citing paper
“Finally, recent work has shown that senescence contributes also to tissue remodeling during embryonic development, 21,22”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [21]
In the citing paper
“Cellular senescence plays beneficial critical roles in numerous biological processes [5], such as tumor suppression [6,7], embryonic tissue remodeling [8] and wound healing after injury [9].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [8]
In the citing paper
“For example, developmental senescent cells express p21WAF1/Cip1 but not p16INK4a9,10, while the reverse is observed in melanocytic nevi36,37.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [9]
In the citing paper
“Furthermore, the SASP is involved in valuable physiological processes such as promoting tissue repair,18–20 fine-tuning the development of embryonic structures,21–23 and stimulating immune surveillance.24,25”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [22]
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Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · cited 1×
“To further document senescence in the mesonephric tubules andendolymphatic sac,weusedmarkers of senescence-associated heterochromatin (Narita et al., 2003) and observed that epithelial cells from both structures at E14.”
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · cited 4×
“We focused on the TGF-b pathway because of its previous involvement in senescence (Acosta et al., 2013; Kuilman and Peeper, 2009) and its well-established capacity to activate the transcription of the p21 gene through SMAD complexes (Datto et al.”
InfluentialOncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
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“…induced by the infliction of DNA damage (Lafferty-Whyte et al., 2010), replicative senescence (Kim et al., 2013; Shelton et al., 1999), oncogene-induced senescence (Collado et al., 2005; Kuilman et al., 2008), or activation of tumor suppressors (Abad et al., 2007; Rovillain et al., 2011).”
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051
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Overview of molecular signatures of senescence and associated resources: pros and cons
Ntintas, O. A., Vagena, S., Pantelis, P., Theocharous, G., Petty, R., Evangelou, K., & Gorgoulis, V. G. (2026) · FEBS Open Bio · doi:10.1002/2211-5463.70134 · Cited by 6
Metadata
- Authors
- Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., & Serrano, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Universidad Complutense de Madrid (ES)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Serrano, Manuel
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 155
- Issue
- 5
- Pages
- 1104-1118
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2090067193
- Cited by
- 1,428
- References
- 64
- Citations by year
- 2026: 92 · 2025: 117 · 2024: 121 · 2023: 134 · 2022: 143 · 2021: 140 · 2020: 160 · 2019: 98 · 2018: 119 · 2017: 90 · 2016: 94 · 2015: 57 · 2014: 55 · 2013: 6
- FWCI
- 49.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Funders
- European Commission
- Ministerio de Ciencia e Innovación (SAF2011-24391)
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- embryonic development, p21, mesonephros, endolymphatic sac, TGF-β/Smad signaling, macrophage infiltration, apoptosis, human embryo
- MeSH terms
- Animals, Embryo, Mammalian, Endolymphatic Sac, Female, Humans, Kidney, Male, Mesonephros, Signal Transduction, Transforming Growth Factor beta, Cellular Senescence, Phosphatidylinositol 3-Kinases, Embryonic Development, Cyclin-Dependent Kinase Inhibitor p21, Mice, Smad Proteins
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