Senescence promotes in vivo reprogramming through p16INK4a and IL‐6

Senescence promotes in vivo reprogramming through p16INK4a and IL‐6 Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin‐6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c‐Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf‐null tissues cannot undergo senescence, fail to produce IL6, and cannot reprogram efficiently; whereas p53‐null tissues undergo extensive damage and senescence, produce high levels of IL6, and reprogram efficiently. Here, we have further explored the genetic determinants of in vivo reprogramming. We report that Ink4a, but not Arf, is necessary for OSKM‐induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53‐independent manner, and we show that p21‐null tissues present increased levels of senescence, IL6, and reprogramming. We also report that Il6‐mutant tissues are impaired in undergoing reprogramming, thus reinforcing the critical role of IL6 in reprogramming. Finally, young female mice present lower efficiency of in vivo reprogramming compared to male mice, and this gender difference disappears with aging, both observations being consistent with the known anti‐inflammatory effect of estrogens. The current findings regarding the interplay between senescence and reprogramming may conceivably apply to other contexts of tissue damage. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aging Cell Wiley

Senescence promotes in vivo reprogramming through p16INK4a and IL‐6

11 pages
Read Article

Loading next page...
 
/lp/wiley/senescence-promotes-in-vivo-reprogramming-through-p16ink4a-and-il-6-D4MtRHacuP
Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
Copyright © 2018 The Anatomical Society and John Wiley & Sons Ltd.
ISSN
1474-9718
eISSN
1474-9726
D.O.I.
10.1111/acel.12711
Publisher site
See Article on Publisher Site

Abstract

Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin‐6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c‐Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf‐null tissues cannot undergo senescence, fail to produce IL6, and cannot reprogram efficiently; whereas p53‐null tissues undergo extensive damage and senescence, produce high levels of IL6, and reprogram efficiently. Here, we have further explored the genetic determinants of in vivo reprogramming. We report that Ink4a, but not Arf, is necessary for OSKM‐induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53‐independent manner, and we show that p21‐null tissues present increased levels of senescence, IL6, and reprogramming. We also report that Il6‐mutant tissues are impaired in undergoing reprogramming, thus reinforcing the critical role of IL6 in reprogramming. Finally, young female mice present lower efficiency of in vivo reprogramming compared to male mice, and this gender difference disappears with aging, both observations being consistent with the known anti‐inflammatory effect of estrogens. The current findings regarding the interplay between senescence and reprogramming may conceivably apply to other contexts of tissue damage.

Journal

Aging Cell – Wiley

Published: Jan 1, 2018

Keywords: ; ; ; ; ; ;

References

  • Reprogramming in vivo produces teratomas and iPS cells with totipotency features
    Abad, M.; Mosteiro, L.; Pantoja, C.; Cañamero, M.; Rayon, T.; Ors, I.; Serrano, M.
  • Senescence impairs successful reprogramming to pluripotent stem cells
    Banito, A.; Rashid, S. T.; Acosta, J. C.; Li, S.; Pereira, C. F.; Geti, I.; Gil, J.
  • Early role for IL‐6 signalling during generation of induced pluripotent stem cells revealed by heterokaryon RNA‐Seq
    Brady, J. J.; Li, M.; Suthram, S.; Jiang, H.; Wong, W. H.; Blau, H. M.
  • Radiation‐induced cell cycle arrest compromised by p21 deficiency
    Brugarolas, J.; Chandrasekaran, C.; Gordon, J. I.; Beach, D.; Jacks, T.; Hannon, G. J.
  • Inflamm‐ageing
    Cevenini, E.; Monti, D.; Franceschi, C.
  • Injury‐induced senescence enables in vivo reprogramming in skeletal muscle
    Chiche, A.; Roux, I.; Joest, M.; Sakai, H.; Aguín, S. B.; Cazin, C.; Li, H.
  • Cell fusion induced by ERVWE1 or measles virus causes cellular senescence
    Chuprin, A.; Gal, H.; Biron‐Shental, T.; Biran, A.; Amiel, A.; Rozenblatt, S.; Krizhanovsky, V.
  • Senescence‐associated secretory phenotypes reveal cell‐nonautonomous functions of oncogenic RAS and the p53 tumor suppressor
    Coppé, J.‐P.; Patil, C. K.; Rodier, F.; Sun, Y.; Muñoz, D. P.; Goldstein, J.; Campisi, J.
  • Conserved and novel functions of programmed cellular senescence during vertebrate development
    Davaapil, H.; Brockes, J. P.; Yun, M. H.
  • An essential role for senescent cells in optimal wound healing through secretion of PDGF‐AA
    Demaria, M.; Ohtani, N.; Youssef, S. A.; Rodier, F.; Toussaint, W.; Mitchell, J. R.; Campisi, J.
  • Inflammatory cytokines promote the retrodifferentiation of tumor‐derived hepatocyte‐like cells to progenitor cells
    Dubois‐Pot‐Schneider, H.; Fekir, K.; Coulouarn, C.; Glaise, D.; Aninat, C.; Jarnouen, K.; Corlu, A.
  • Inflammatory networks during cellular senescence: Causes and consequences
    Freund, A.; Orjalo, A. V.; Desprez, P. Y.; Campisi, J.
  • Impaired cutaneous wound healing in interleukin‐6‐deficient and immunosuppressed mice
    Gallucci, R. M.; Simeonova, P. P.; Matheson, J. M.; Kommineni, C.; Guriel, J. L.; Sugawara, T.; Luster, M. I.
  • Regulation of the INK4b–ARF–INK4a tumour suppressor locus: All for one or one for all
    Gil, J.; Peters, G.
  • Direct cell reprogramming is a stochastic process amenable to acceleration
    Hanna, J.; Saha, K.; Pando, B.; Zon, J.; Lengner, C. J.; Creyghton, M. P.; Jaenisch, R.
  • 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.
  • Transcription factor cross‐talk: The estrogen receptor and NF‐κB
    Kalaitzidis, D.; Gilmore, T. D.
  • Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF
    Kamijo, T.; Zindy, F.; Roussel, M. F.; Quelle, D. E.; Downing, J. R.; Ashmun, R. A.; Sherr, C. J.
  • Linking the p53 tumour suppressor pathway to somatic cell reprogramming
    Kawamura, T.; Suzuki, J.; Wang, Y. V.; Menendez, S.; Morera, L. B.; Raya, A.; Izpisúa Belmonte, J. C.
  • Impaired immune and acute‐phase responses in interleukin‐6‐deficient mice
    Kopf, M.; Baumann, H.; Freer, G.; Freudenberg, M.; Lamers, M.; Kishimoto, T.; Köhler, G.
  • Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice
    Krimpenfort, P.; Quon, K. C.; Mooi, W. J.; Loonstra, A.; Berns, A.
  • Senescence of activated stellate cells limits liver fibrosis
    Krizhanovsky, V.; Yon, M.; Dickins, R. A.; Hearn, S.; Simon, J.; Miething, C.; Lowe, S. W.
  • Oncogene‐induced senescence relayed by an interleukin‐dependent inflammatory network
    Kuilman, T.; Michaloglou, C.; Vredeveld, L. C. W.; Douma, S.; Doorn, R.; Desmet, C. J.; Peeper, D. S.
  • The Ink4/Arf locus is a barrier for iPS cell reprogramming
    Li, H.; Collado, M.; Villasante, A.; Strati, K.; Ortega, S.; Cañamero, M.; Serrano, M.
  • Essential involvement of IL‐6 in the skin wound‐healing process as evidenced by delayed wound healing in IL‐6‐deficient mice
    Lin, Z.‐Q.; Kondo, T.; Ishida, Y.; Takayasu, T.; Mukaida, N.
  • Interleukin‐6 in aging and chronic disease: A magnificent pathway
    Maggio, M.; Guralnik, J. M.; Longo, D. L.; Ferrucci, L.
  • A p53‐mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
    Marion, R. M.; Strati, K.; Li, H.; Murga, M.; Blanco, R.; Ortega, S.; Blasco, M. A.
  • Tissue damage and senescence provide critical signals for cellular reprogramming in vivo
    Mosteiro, L.; Pantoja, C.; Alcazar, N.; Marión, R. M.; Chondronasiou, D.; Rovira, M.; Serrano, M.
  • Programmed cell senescence during mammalian embryonic development
    Muñoz‐Espín, D.; Cañamero, M.; Maraver, A.; Gómez‐López, G.; Contreras, J.; Murillo‐Cuesta, S.; Serrano, M.
  • Cellular senescence: From physiology to pathology
    Muñoz‐Espín, D.; Serrano, M.
  • Gender disparity in liver cancer due to sex differences in MyD88‐dependent IL‐6 production
    Naugler, W. E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A. M.; Karin, M.
  • Altered profiles of estradiol and progesterone associated with prolonged estrous cycles and persistent vaginal cornification in aging C57BL/6J mice
    Nelson, J. F.; Felicio, L. S.; Osterburg, H. H.; Finch, C. E.
  • Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation
    Ohnishi, K.; Semi, K.; Yamamoto, T.; Shimizu, M.; Tanaka, A.; Mitsunaga, K.; Yamada, Y.
  • The senescence‐associated secretory phenotype induces cellular plasticity and tissue regeneration
    Ritschka, B.; Storer, M.; Mas, A.; Heinzmann, F.; Ortells, M. C.; Morton, J. P.; Keyes, W. M.
  • IL‐6 pathway in the liver: From physiopathology to therapy
    Schmidt‐Arras, D.; Rose‐John, S.
  • The cyclin‐dependent kinase inhibitor p21 is regulated by RNA‐binding protein PCBP4 via mRNA stability
    Scoumanne, A.; Cho, S. J.; Zhang, J.; Chen, X.
  • Forging a signature of in vivo senescence
    Sharpless, N. E.; Sherr, C. J.
  • Senescence is a developmental mechanism that contributes to embryonic growth and patterning
    Storer, M.; Mas, A.; Robert‐Moreno, A.; Pecoraro, M.; Ortells, M. C.; Di Giacomo, V.; Keyes, W. M.
  • Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
    Takahashi, K.; Yamanaka, S.
  • Immortalization eliminates a roadblock during cellular reprogramming into iPS cells
    Utikal, J.; Polo, J. M.; Stadtfeld, M.; Maherali, N.; Kulalert, W.; Walsh, R. M.; Hochedlinger, K.
  • Restoration of p53 function leads to tumour regression in vivo
    Ventura, A.; Kirsch, D. G.; McLaughlin, M. E.; Tuveson, D. A.; Grimm, J.; Lintault, L.; Jacks, T.
  • p21WAF1 and tumourigenesis: 20 years after
    Warfel, N.; El‐Deiry, W.
  • 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.; Lowe, S. W.
  • Posttranscriptional Regulation of p53 and Its Targets by RNA‐Binding Proteins
    Zhang, J.; Chen, X.
  • Two supporting factors greatly improve the efficiency of human iPSC generation
    Zhao, Y.; Yin, X.; Qin, H.; Zhu, F.; Liu, H.; Yang, W.; Deng, H.

You’re reading a free preview. Subscribe to read the entire article.

Try 2 weeks free now

DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

or browse the journals available

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off

Sign up
for free
Start 14 day
Free Trial