Implications of Cellular Senescence in Tissue Damage Response, Tumor Suppression, and Stem Cell Biology

Abstract

Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.

Telomerase enzymatic component hTERT shortens long telomeres in human cells

“…[42][43][44] Critically short telomeres trigger cellular growth arrest that drives progressive atrophy and functional decline in highturnover tissues. 45,46 Thus, progressive telomere loss was proposed to be the basis of cellular senescence and aging. 47 On the other hand, telomere-associated replicative senescence is regarded as an important tumor-suppressive mechanism.…”

Cellular senescence impact on immune cell fate and function

“…NK cells, macrophages, and cytotoxic CD8 + T cells are chemo‐attracted by the inflamed tissues to promote cell death, thus facilitating senescent cell replacement and a return to tissue homeostasis (Hoenicke & Zender, 2012; Davies et al ., 2013). NK cells are especially important in the immunosurveillance of senescent cells during tissue repair (Krizhanovsky et al ., 2008a,b). They are attracted to senescent cells through a p53‐dependent secretion of CCL2 [chemokine (C‐C) ligand 2] (Iannello et al ., 2013).…”

“…NK cells then recognize these senescent cells through CD58‐ICAM1 binding (Chien et al ., 2011; Sagiv & Krizhanovsky, 2013). Furthermore, senescent cells express, in an ATM/ATR (ataxia telangiectasia mutated/Rad3‐related kinases)‐dependent manner, ligands for two NK cell activating receptors NKG2D and DNAM1 and secrete IL‐15, a cytokine that promotes NKG2D and DNAM1 expression in NK cells (Krizhanovsky et al ., 2008a; Soriani et al ., 2009). Following receptor activation, NK cells can then specifically induce the death of senescent cells through perforin release by exocytosis (Sedelies et al ., 2008; Sagiv et al ., 2013).…”

Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss

“…Further shortened telomere loose their capping function at the end of the chromosomes which results in nonreciprocal translocations, (damaged chromosome captures a telomere from another chromosome) thus resulting in chromosomal instability or rearrangements [7] deletions, aneuploidy & DNA damage [8].…”