Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing

Blokland, Kaj E C; Waters, Donna; Schuliga, Michael; Read, Jane; Pouwels, Simon D.; Grainge, Christopher; Jaffar, Jade; Westall, Glen P.; Mutsaers, Steven E.; Prêle, Cecilia M.; Burgess, Janette K.; Knight, Darryl A.

doi:10.3390/pharmaceutics12040389

Cited by 40 publications

(37 citation statements)

References 42 publications

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“…In addition, IPF-MSCs induce a lower proliferation of NHLFs after 72 h of co-culture. These results support the hypothesis that the senescent cells are themselves primarily characterized by an irreversible arrest of the cell cycle, but at the same time they remain metabolically active, leading to the development of a dynamic pro-inflammatory secretory profile that can affect the senescence and proliferation of neighboring cells [28][29][30]. To date, the long debate about the role of inflammation in the onset and development of IPF is still open.…”

Section: Discussionsupporting

confidence: 81%

How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

Bonifazi

Vincenzo

Caffarini

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF.

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Section: Discussionsupporting

confidence: 81%

How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

Bonifazi

Vincenzo

Caffarini

et al. 2020

IJMS

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“…The most fundamental feature of IPF is the deposition of ECM, which results from the abnormal activation of lung fibroblasts (Blokland et al, 2020). The activation of lung fibroblasts involves a series of cell behaviors changes such as proliferation, migration, and ECM production.…”

Section: Activation Abnormitymentioning

confidence: 99%

“…The senescent fibroblasts with positive α-SMA do not mean that they have fibrogenic properties or they are senescent myofibroblasts. In other words, in IPF, the senescent fibroblasts may only be activated in several limited aspects (Mellone et al, 2016;Blokland et al, 2020). The development of omics research and biological big data analysis gives us the confidence to find this answer in the future.…”

Section: Activation Abnormitymentioning

confidence: 99%

“…Elevated transcription levels of these factors can be synchronously detected in the cells (Schafer et al, 2017;Álvarez et al, 2017). SASP in IPF senescent fibroblasts includes proinflammatory cytokines (such as TNF-α, TGF-β, IL-1β, IL-6, IL-8, IL-10, IL-18), chemokines (such as CXCL1, MCP-1), growth regulators (such as FGF, CTGF, GM-CSF, M-CSF, PDGF), matrix metalloproteinases (such as MMP-2, MMP-3, MMP-9, MMP-10, MMP-12), and leukotrienes (LTs, such as LTA4, LTB4, LTC4, LTD4) (Kortlever et al, 2006;Acosta et al, 2008;Rodier et al, 2009;Kojima et al, 2012;Aoshiba et al, 2013;Demaria et al, 2014;Le et al, 2014;Hayakawa et al, 2015;Jun and Lau, 2017;Schafer et al, 2017;Álvarez et al, 2017;Wiley et al, 2019;Zhang et al, 2019;Blokland et al, 2020). Thus, SASP is essentially a concept that belongs to secretomes, which cannot be fully described by several biomarkers' up-regulation or down-regulation.…”

Section: Senescence-associated Secretory Phenotypementioning

confidence: 99%

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Fibroblast Senescence in Idiopathic Pulmonary Fibrosis

Lin

2020

Front. Cell Dev. Biol.

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Aging is an inevitable and complex natural phenomenon due to the increase in age. Cellular senescence means a non-proliferative but viable cellular physiological state. It is the basis of aging, and it exists in the body at any time point. Idiopathic pulmonary fibrosis (IPF) is an interstitial fibrous lung disease with unknown etiology, characterized by irreversible destruction of lung structure and function. Aging is one of the most critical risk factors for IPF, and extensive epidemiological data confirms IPF as an aging-related disease. Senescent fibroblasts in IPF show abnormal activation, telomere shortening, metabolic reprogramming, mitochondrial dysfunction, apoptosis resistance, autophagy deficiency, and senescence-associated secretory phenotypes (SASP). These characteristics of senescent fibroblasts establish a close link between cellular senescence and IPF. The treatment of senescence-related molecules and pathways is continually emerging, and using senolytics eliminating senescent fibroblasts is also actively tried as a new therapy for IPF. In this review, we discuss the roles of aging and cellular senescence in IPF. In particular, we summarize the signaling pathways through which senescent fibroblasts influence the occurrence and development of IPF. On this basis, we further talk about the current treatment ideas, hoping this paper can be used as a helpful reference for future researches.

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“…Of note, given that the control for establishing the expression pro ling with culture cells (Figure 4C/D) was FBS, ceAF must contain components above and beyond ordinary growth factors and/or other molecules that solely support cell growth and migration as revealed in Figure 1A/B and Figure 3B. Recently, occurrence of senescence and roles of SASP factors during embryogenesis (33) and in limiting brosis upon tissue injury (34,35) were reported. Thus, scar-less tissue repair might take place in embryos, supporting our postulation that ceAF comprises a set of evolutionarily conserved, at least among vertebrates, factors involved in wound healing.…”

Section: Further Discussion and Perspectivesmentioning

confidence: 99%

Transient Senescence Induces Wound Healing Through SASP Factors: Therapeutic Potentials of Chick Early Amniotic Fluid (ceAF)

Ahmad

Sun

Zhang

et al. 2020

Preprint

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Background Inflammatory, proliferative and remodelling phases constitute a cutaneous wound healing program. Therapeutic applications/medication are available; however, they commonly comprise fortified preservatives that might prolong the healing process. Chick early amniotic fluids (ceAF) contain native therapeutic factors with balanced chemokines, cytokines and growth-related factors; their origins in principle dictate no existence of harmful agents that would otherwise hamper embryo development. Instead, they possess a spectrum of molecules driving expeditious mitotic divisions and possibly exerting other functions. Methods Employing both in vitro and in vivo models, we examined ceAF’s therapeutic potentials in wound healing and found intriguing involvement of transient senescence, known to be intimately intermingled with Senescence Associated Secretory Phenotypes (SASP) that function in addition to or in conjunction with ceAF to facilitate wound healing. Results In our in vitro and in vivo cutaneous wound healing models, a low dose of ceAF exhibited the best efficacies; however, higher doses attenuated the wound healing, presumably by inducing p16 expression. Conclusion Our studies link an INK4/ARF locus-mediated signalling to cutaneous wound healing, implicate the therapeutic potentials of ceAF exerting functions likely by driving transient senescence and expediting cell proliferation, and conceptualize a homeostatic and/or balanced dosage strategy in medical intervention.

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Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing

Cited by 40 publications

References 42 publications

How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

Fibroblast Senescence in Idiopathic Pulmonary Fibrosis

Transient Senescence Induces Wound Healing Through SASP Factors: Therapeutic Potentials of Chick Early Amniotic Fluid (ceAF)

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