Breathe it in – Spotlight on senescence and regeneration in the lung

Highlights

• Senescence is a heterogenous cellular state with beneficial and detrimental roles.

• Extent of senescence-associated stress determines its program and function in vivo.

• Transient senescence aids regeneration to preserve functional integrity of a tissue.

• Chronic senescence is a driver of aging-related decline in organ function.

Abstract

Cellular senescence, a highly coordinated and programmed cellular state, has a functional role in both lung physiology and pathology. While the contribution of senescent cells is recognized in the context of ageing and age-related pulmonary diseases, relatively less is known how cellular senescence of functionally distinct cell types leads to the progression of these pathologies. Recent advances in tools to track and isolate senescent cells from tissues, shed a light on the identity, behavior and function of senescent cells in vivo. The transient presence of senescent cells has an indispensable role in limiting lung damage and contributes to organ regenerative capacity upon acute stress insults. In contrast, persistent accumulation of senescent cells is a driver of age-related decline in organ function. Here, we discuss lung physiology and pathology as an example of seemingly contradictory role of senescence in structural and functional integrity of the tissue upon damage, and in age-related pulmonary diseases.

Introduction

Cellular senescence is a state of prolonged and essentially irreversible cell-cycle withdrawal. It is an alarm response to numerous triggers, including DNA replication stress, telomere dysfunction, oncogene activation, oxidative stress, DNA damage, genomic instability and cell-cell fusion (Gorgoulis et al., 2019). The stress signal and its duration, identity of cell undergoing senescence, microenvironment and time after senescence induction, can influence the senescence program and biological function of senescent cells (Hernandez-Segura et al., 2017). Senescent cells are heterogeneous and exhibit a complex phenotype. Thus, they are identified by a number of molecular markers representing different characteristics of senescent cells. These molecular markers include: senescence-associated β-galactosidase (SA-β-gal), based on increased lysosomal β-galactosidase activity (Lee et al., 2006; Dimri et al., 1995; Biran et al., 2017), markers of cell cycle arrest machinery (e.g. p16, p53, p21), apoptosis resistance markers (e.g. DCR2, Bcl-xL), secretory factors (e.g. IL-6, IL-8), markers of activation of DNA damage response (DDR) (e.g. p53BP1, γH2AX) and upregulation of immune surveillance genes (Gorgoulis et al., 2019; Burton and Krizhanovsky, 2014; Sagiv et al., 2016). Since there is no single biomarker exclusive to senescent cells, combination of senescence-related markers is used for their identification. Still, however, it is challenging to reliably detect and tract senescent cells in vivo, what is indispensable to fully understand their role at the organismal level.

High heterogeneity of senescent cells is reflected by their engagement in a number of physiological processes and pathological conditions, with beneficial and detrimental effect respectively (Gorgoulis et al., 2019; Burton and Krizhanovsky, 2014; Childs et al., 2017; Munoz-Espin and Serrano, 2014). On one hand, senescence response limits propagation of damaged cells and thus tumorigenesis, but it also plays indispensable role upon tissue injury. In the lung, cellular senescence prevents massive cell death by induction of an anti-apoptotic mechanisms and helps in restoration of lung structure following lung damage (Blazquez-Prieto et al., 2021; Kobayashi et al., 2020; Strunz et al., 2020; Reyes de Mochel et al., 2020). Conversely, long-term presence of senescent cells in the lungs limits the potential for tissue renewal and promotes lung ageing and age-related diseases (Childs et al., 2017; Munoz-Espin and Serrano, 2014; Kobayashi et al., 2020; Di Micco et al., 2021; Ovadya and Krizhanovsky, 2014; Camell et al., 2021). To assist these tasks, senescent cells regulate their own immunosurveillance by expression of immune ligands (Sagiv et al., 2016; Sagiv and Krizhanovsky, 2013). However, with ageing immune system deteriorates, what might impede the removal of senescent cells and consequently promote paracrine senescence via their secretory milieu (van Deursen, 2014). The senescence secretome includes pro-inflammatory cytokines, chemokines, growth factors, matrix remodeling enzymes and angiogenic factors collectively known as Senescent Associated Secretory Phenotype (SASP) (Acosta et al., 2013; Coppe et al., 2010; Kuilman and Peeper, 2009). SASP is a hallmark of senescent cells and mediates their pathological and physiological effects. SASP can reinforce cell growth arrest of neighboring cells, modulate microenvironment, promote local inflammation, facilitate immunosurveillance of senescent cell, but it can also contribute to tissue remodeling and regeneration (Acosta et al., 2013; Coppe et al., 2010; Kuilman and Peeper, 2009; Demaria et al., 2014; Krizhanovsky et al., 2008a; Mosteiro et al., 2016; Gal et al., 2021). Therefore, the functional role of senescence in the lung might depend on the temporary presence of senescent cells or their accumulation over time.

Cellular senescence contributes to wide spectrum of age-related lung diseases, including inflammatory diseases, tissue fibrosis, degeneration and cancer. Recently, it became appreciated that senescent cells are highly heterogeneous with complex cellular phenotype and can play functional role in both, lung physiology and pathology. Here, we will discuss how senescence of lung specific cell populations drive chronic tissue damage and the mechanisms that regulate this process. We will also discuss recent advances in understanding the role of senescence in limiting lung damage in acute lung injury and its emerging role in lung regeneration.