Senotherapeutics: Targeting senescence in idiopathic pulmonary fibrosis

Merkt, Wolfgang; Bueno, Marta; Mora, Ana L.; Lagares, David

doi:10.1016/j.semcdb.2019.12.008

Cited by 80 publications

(56 citation statements)

References 101 publications

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“…Inhibition of myofibroblast contraction, perception of extracellular stress, and/or ECM mechanics have all been proposed as therapeutic approaches to improve wound healing and reduce fibrosis. 122,[229][230][231] It will exceed the scope of this review to elaborate on the details of these strategies and we will here restrict ourselves to provide an overview on the concepts. To change ECM mechanical properties, attractive targets are crosslinking and remodelling enzymes, such as lysyl oxidases, LOX-like enzymes, tissue transglutaminases, lysyl hydroxylases, and MMPs.…”

Section: Concepts To Target Ecm and Fibroblast Mechanics For Therapeutic Approachesmentioning

confidence: 99%

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Sawant

Hinz

Schönborn

et al. 2021

Wound Repair Regeneration

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Our skin is continuously exposed to mechanical challenge, including shear, stretch, and compression. The extracellular matrix of the dermis is perfectly suited to resist these challenges and maintain integrity of normal skin even upon large strains. Fibroblasts are the key cells that interpret mechanical and chemical cues in their environment to turnover matrix and maintain homeostasis in the skin of healthy adults. Upon tissue injury, fibroblasts and an exclusive selection of other cells become activated into myofibroblasts with the task to restore skin integrity by forming structurally imperfect but mechanically stable scar tissue. Failure of myofibroblasts to terminate their actions after successful repair or upon chronic inflammation results in dysregulated myofibroblast activities which can lead to hypertrophic scarring and/or skin fibrosis. After providing an overview on the major fibrillar matrix components in normal skin, we will interrogate the various origins of fibroblasts and myofibroblasts in the skin. We then examine the role of the matrix as signaling hub and how fibroblasts respond to mechanical matrix cues to restore order in the confusing environment of a healing wound.

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Section: Concepts To Target Ecm and Fibroblast Mechanics For Therapeutic Approachesmentioning

confidence: 99%

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Sawant

Hinz

Schönborn

et al. 2021

Wound Repair Regeneration

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“…In addition, one should investigate the interaction with other cell types of the lung such as myofibroblasts and immune cells to distinguish cell-autonomous vs. non-autonomous effects. Moreover, the senescent program of aberrant basaloid cells in IPF might be specifically targeted by anti-senescent therapies such as senotherapeutics (45). Among these are senolytic compounds that aim to overcome apoptosis-resistance in senescent cells (46).…”

Section: Discussionmentioning

confidence: 99%

Senescent Cells in IPF: Locked in Repair?

Meiners

Lehmann

2020

Front. Med.

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“…Myofibroblast senescence has been traditionally associated with the resolution of the normal tissue repair programme and that elimination of senescent myofibroblasts prevents the development of fibrosis. 52,57 However, a growing body of evidence suggests that impaired clearance of senescent myofibroblasts shifts their pro-repair activities to pro-fibrotic via persistent secretion of pro-inflammatory and profibrotic mediators 50,[136][137][138][139][140][141] . In this regard, the SASP of pro-fibrotic senescent myofibroblast has been shown to contain pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and IL-8), pro-fibrotic cytokines (TGF-β, PDGF) and ECM proteins (fibronectin, collagens).…”

Section: Cellular Senescencementioning

confidence: 99%

Myofibroblast fate plasticity in tissue repair and fibrosis: Deactivation, apoptosis, senescence and reprogramming

Merkt

Zhou

Han

et al. 2021

Wound Repair Regeneration

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In response to tissue injury, fibroblasts differentiate into professional repair cells called myofibroblasts, which orchestrate many aspects of the normal tissue repair programme including synthesis, deposition and contraction of extracellular matrix proteins, leading to wound closure. Successful tissue repair responses involve termination of myofibroblast activities in order to prevent pathologic fibrotic scarring. Here, we discuss the cellular and molecular mechanisms limiting myofibroblast activities during physiological tissue repair, including myofibroblast deactivation, apoptosis, reprogramming and immune clearance of senescent myofibroblasts. In addition, we summarize pathological mechanisms leading to myofibroblast persistence and survival, a hallmark of fibrotic diseases. Finally, we discuss emerging anti-fibrotic therapies aimed at targeting myofibroblast fate such as senolytics, gene therapy, cellular immunotherapy and CAR-T cells.

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Senotherapeutics: Targeting senescence in idiopathic pulmonary fibrosis

Cited by 80 publications

References 101 publications

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

Senescent Cells in IPF: Locked in Repair?

Myofibroblast fate plasticity in tissue repair and fibrosis: Deactivation, apoptosis, senescence and reprogramming

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