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Senescence Helps Regeneration

2014; Elsevier BV; Volume: 31; Issue: 6 Linguagem: Inglês

10.1016/j.devcel.2014.12.007

1878-1551

Manuel Serrano,

Genetics, Aging, and Longevity in Model Organisms

Cellular senescence is a response to damage that involves inflammation and extracellular matrix remodeling and that resolves with the phagocytic elimination of the senescent cells. Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar in this issue of Developmental Cell demonstrate that cellular senescence plays an active and positive role during tissue regeneration. Cellular senescence is a response to damage that involves inflammation and extracellular matrix remodeling and that resolves with the phagocytic elimination of the senescent cells. Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar in this issue of Developmental Cell demonstrate that cellular senescence plays an active and positive role during tissue regeneration. The concept of cellular senescence dates back more than 50 years, much earlier than the concept of apoptosis. Since its initial description, our understanding of cellular senescence has evolved dramatically. For many years, cellular senescence was conceptualized as a poorly defined cell-cycle arrest akin to organismal aging. Today, cellular senescence can be considered to be a variant of the apoptotic cellular suicide paradigm and, more specifically, an "assisted cellular suicide." The current script of cellular senescence (reviewed in Muñoz-Espín and Serrano, 2014Muñoz-Espín D. Serrano M. Nat. Rev. Mol. Cell Biol. 2014; 15: 482-496Crossref PubMed Scopus (1461) Google Scholar) can be summarized as follows. In response to cellular damage, stress, oncogenic signaling, or even during embryonic development, cells can stably disable their proliferation machinery through the action, in various combinations, of tumor suppressors, including p16INK4a, retinoblastoma, p53, p21CIP1, and others. Senescent cells generally present two characteristic features: an expansion of the lysosomal compartment, which results in increased lysosomal β-galactosidase activity (known as senescence-associated β-galactosidase, or SAβG), and the formation of distinctive heterochromatic structures (known as senescence-associated heterochromatin foci, or SAHFs). At a functional level, senescent cells release a complex mixture of extracellular matrix proteases, growth factors, chemokines, and cytokines (collectively known as senescence-associated secretory phenotype, or SASP), which has profound effects on the tissue microenvironment. In particular, the SASP may activate the motility and proliferation of surrounding cells and may recruit immune and phagocytic cells, including macrophages. The latter are the final "assistants" for the demise of senescent cells. Therefore, in contrast to the rather individual and silent process of apoptosis (cellular suicide), senescence (assisted cellular suicide) involves a cast of characters with complex roles. Still, the ultimate logic of senescence has remained speculative. If the purpose of senescence is the elimination of cells, then why not use the direct and fast route of apoptosis? An emerging concept, based on the aforementioned events, is that senescent cells, before dying, make a late service to their host tissue by eliciting a tissue remodeling process that includes their own elimination. A particularly striking example of the role of senescence in tissue remodeling has been the recent demonstration that senescence participates in multiple developmental processes in vertebrates (Muñoz-Espín et al., 2013Muñoz-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. Cell. 2013; 155: 1104-1118Abstract Full Text Full Text PDF PubMed Scopus (843) Google Scholar, Storer et al., 2013Storer M. Mas A. Robert-Moreno A. Pecoraro M. Ortells M.C. Di Giacomo V. Yosef R. Pilpel N. Krizhanovsky V. Sharpe J. Keyes W.M. Cell. 2013; 155: 1119-1130Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). A new paper from Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar now provides further evidence for a physiological role of senescence in tissue remodeling, and more specifically during wound healing. Genetically engineered mice with increased or decreased activity of genes critical for the induction of senescence often present abnormal responses to tissue damage. For example, mice deficient in p53 have an accelerated wound healing (Nakade et al., 2004Nakade K. Zheng H. Ganguli G. Buchwalter G. Gross C. Wasylyk B. Mol. Cell. Biol. 2004; 24: 1132-1142Crossref PubMed Scopus (18) Google Scholar), while mice with excessive p53 activity have a delayed wound healing (Gannon et al., 2011Gannon H.S. Donehower L.A. Lyle S. Jones S.N. Dev. Biol. 2011; 353: 1-9Crossref PubMed Scopus (62) Google Scholar). While these observations are certainly of great interest, the experimental models used cannot distinguish the contribution of p53-dependent senescence from the many other processes regulated by p53, including proliferation, apoptosis, differentiation, immune responses, or angiogenesis. To address the physiological role of senescence, it is necessary to develop clever strategies that allow the selective elimination of senescent cells in vivo. Two groups have been able to achieve this by employing independent but similar strategies (Baker et al., 2011Baker D.J. Wijshake T. Tchkonia T. LeBrasseur N.K. Childs B.G. van de Sluis B. Kirkland J.L. van Deursen J.M. Nature. 2011; 479: 232-236Crossref PubMed Scopus (2178) Google Scholar, Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar). The groups of Jan van Deursen and Judith Campisi have generated transgenic mice in which the promoter of p16INK4a directs the expression of pro-apoptotic proteins that can be turned on with a chemical switch. Because senescent cells are known to express high levels of p16INK4a, it is reasonable to assume that the targeted cells are senescent. Therefore, in vivo administration of the chemical switch converts senescence into apoptosis. The group of van Deursen has previously used their "inducible senescence-to-apoptosis" system in a progeric mouse model (bearing homozygous hypomorphic alleles of the BubR1 gene). These progeric mice suffer widespread and continuous cellular damage that rapidly builds up to produce accelerated aging and the accumulation of senescent cells. By inducing the senescence-to-apoptosis switch, the overload of senescent cells was decreased, and, remarkably, some advanced progeric pathologies, such as cataracts or muscle atrophy, were partially reverted (Baker et al., 2011Baker D.J. Wijshake T. Tchkonia T. LeBrasseur N.K. Childs B.G. van de Sluis B. Kirkland J.L. van Deursen J.M. Nature. 2011; 479: 232-236Crossref PubMed Scopus (2178) Google Scholar). From this and other studies, it can be concluded that in aged organisms (or in organisms undergoing severe levels of damage), senescent cells are not properly cleared by phagocytic cells, accumulate and eventually aggravate tissue dysfunction. Conceivably, aged or chronically damaged tissues are not amenable to senescence-induced tissue remodeling, probably reflecting a combination of factors, such as a more static extracellular matrix, inefficient recruitment of phagocytic cells, impaired clearance of senescenct cells, or defective regenerative capacity of neighbor progenitor cells. In the current issue of Developmental Cell, the Campisi group uses their "inducible senescence-to-apoptosis" mice to study the role of senescence during skin wound healing (Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar). It is important to emphasize that, aside from harboring the senescence-to-apoptosis transgene, the mice employed are young and healthy, with no additional genetic defects that may introduce confounding effects. The investigators observed that during wound healing there is a transient burst of senescent cells that vanishes with wound closure. Importantly, conversion of senescence into apoptosis blunted the peak of senescence and this translated into a significantly delayed wound healing. These observations constitute the first direct demonstration, in a truly normal in vivo context, that cellular senescence contributes to tissue remodeling. Like the phoenix of ancient Greek mythology, it can then be said that skin wounds regenerate from the ashes of senescence. When the healing process was carefully examined histologically, the investigators found that, in the absence of senescence, wounds accumulated excessive fibrotic tissue (which macroscopically translates to a more pronounced scar) (Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar). This is in line with previous studies, which also concluded that cellular senescence is important for limiting fibrosis during tissue repair, as it has been shown in skin (Jun and Lau, 2010Jun J.I. Lau L.F. Nat. Cell Biol. 2010; 12: 676-685Crossref PubMed Scopus (619) Google Scholar), liver (Krizhanovsky et al., 2008Krizhanovsky V. Yon M. Dickins R.A. Hearn S. Simon J. Miething C. Yee H. Zender L. Lowe S.W. Cell. 2008; 134: 657-667Abstract Full Text Full Text PDF PubMed Scopus (1314) Google Scholar), and several other fibrotic pathologies (Muñoz-Espín and Serrano, 2014Muñoz-Espín D. Serrano M. Nat. Rev. Mol. Cell Biol. 2014; 15: 482-496Crossref PubMed Scopus (1461) Google Scholar). A very useful feature of the mice developed by Campisi and coworkers is that the p16INK4a-regulated transgene also directs the expression of a fluorescent protein (Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar). Using this tool, the investigators were able to isolate and characterize the cells that undergo senescence during skin wound healing. Two important findings emerged from these analyses: first, the cells that undergo senescence are fibroblasts and endothelial cells, but not keratinocytes; and, second, the growth factor PDGF-A is characteristically expressed in senescent fibroblasts and endothelial cells during wound healing. The latter finding is of relevance because the related PDGF-B factor is clinically approved for the treatment of skin ulcers (Jeffcoate and Game, 2014Jeffcoate W.J. Game F.L. BioDrugs. 2014; 28: 1-6Crossref PubMed Scopus (5) Google Scholar). In line with this, the abnormal wound healing observed in the absence of senescence was fully rescued by topical administration of recombinant PDGF-A to the wounds (Demaria et al., 2014Demaria M. Ohtani N. Youssef S.A. Rodier F. Toussaint W. Mitchell J.R. Laberge R. Vijg J. Van Steeg H. Dollé M.E.T. et al.Dev. Cell. 2014; 31 (this issue): 722-733Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar). Studies like this are changing our understanding of cellular senescence, placing this response at the center of tissue regeneration. The full benefits of senescence are achieved when the process includes the clearance of the senescent cells, thereby restoring the pre-damage status of the tissue. However, in chronic pathological situations, including aging, senescent cells are not efficiently cleared and continuous damage eventually results in the accumulation of senescent cells, which can further aggravate tissue dysfunction. This double-edged sword of senescence is reminiscent of inflammation, which is beneficial when it is transient and efficiently resolved but pathological when chronic and unresolved. These nuances and complexities of senescence demand further investigations into the therapeutic potential of enhancing or blocking senescence, depending on the context. The current report is inspiration for such investigation, as it integrates the role of senescence in regeneration together with the therapeutic benefits of PDGF in wound healing. An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AADemaria et al.Developmental CellDecember 11, 2014In BriefUsing a mouse model in which senescent cells can be visualized and eliminated, Demaria et al. show that senescent cells appear in response to skin injury and that these cells promote healing by secreting PDGF-AA, which promotes optimal wound closure. In mice lacking senescent cells, wound closure is slower. 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