Transient p53-Mediated Regenerative Senescence in the Injured Heart

Sarig, Rachel; Rimmer, Rachel; Bassat, Elad; Zhang, Lingling; Umansky, Kfir Baruch; Lendengolts, Daria; Perlmoter, Gal; Yaniv, Karina; Tzahor, Eldad

doi:10.1161/circulationaha.119.040125

Cited by 63 publications

(53 citation statements)

References 6 publications

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“…However, prolonged exposure to the SASP, although further increasing stem cell gene expression, subsequently activates cell-intrinsic senescence arrest and results in papilloma formation in vivo (Ritschka et al, 2017). More recently, two studies have identified how transient senescence contributes to heart regeneration, whereas elimination of senescent cells blocks proper heart regeneration (Feng et al, 2019;Sarig et al, 2019). Together, these studies suggest that a key role of the SASP is to alter the plasticity of neighboring cells (Fig.…”

Section: Plasticity and Reprogrammingmentioning

confidence: 99%

“…2). Transient exposure to the SASP increases the efficiency of reprogramming factors, and also favors plasticity and regeneration in tissues such as the skin, liver, muscle and heart (Chiche et al, 2017;Feng et al, 2019;Mosteiro et al, 2016;Ritschka et al, 2017;Sarig et al, 2019). However, if exposure to the SASP is prolonged, as shown in the context of the skin (Ritschka et al, 2017), then the resulting increased plasticity is likely sensed by target cells as abnormal or tumorigenic, and is subsequently blocked by the activation of cell-intrinsic barrier mechanisms.…”

Section: Plasticity and Reprogrammingmentioning

confidence: 99%

“…During limb development, the gradient of factors secreted from the AER (in combination with posterior signals) establishes plasticity in the limb mesenchyme (Cooper et al, 2011;Rosello-Diez et al, 2011). It appears that a similar function might be partially reactivated when senescence is induced postnatally, using oncogenes, irradiation or iPSC reprogramming (Mosteiro et al, 2016;Ritschka et al, 2017), or during heart regeneration (Feng et al, 2019;Sarig et al, 2019).…”

Section: Patterning and Plasticitymentioning

confidence: 99%

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Cellular senescence in development, regeneration and disease

2019

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Cellular senescence is a state comprising an essentially irreversible proliferative arrest combined with phenotypic changes and pronounced secretory activity. Although senescence has long been linked with aging, recent studies have uncovered functional roles for senescence in embryonic development, regeneration and reprogramming, and have helped to advance our understanding of this process as a highly coordinated and programmed cellular state. In this Primer article, we summarize some of the key findings in the field and attempt to explain them in a simple model that reconciles the normal and pathological roles for senescence. We discuss how a primary role of cellular senescence is to contribute to normal development, cell plasticity and tissue repair, as a dynamic and tightly regulated cellular program. However, when this process is perturbed, the beneficial effects turn detrimental and can contribute to disease and aging.

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Section: Plasticity and Reprogrammingmentioning

confidence: 99%

Section: Plasticity and Reprogrammingmentioning

confidence: 99%

Section: Patterning and Plasticitymentioning

confidence: 99%

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Cellular senescence in development, regeneration and disease

2019

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“…Studies in recent years changed the way we perceive cellular senescence, placing it at the center of tissue remodeling in disease settings by limiting fibrosis, namely in wound healing (Jun and Lau, 2010; Demaria et al , 2014), damaged livers (Krizhanovsky et al , 2008; Kong et al , 2012) and infarcted hearts (Meyer et al , 2016). In regenerative models, such as salamander limbs, zebrafish hearts and fins and neonatal mouse hearts, a burst of transient senescent cells (SCs) was shown to be induced after an injury (Yun, Davaapil and Brockes, 2015; Da Silva-Álvarez et al , 2019; Sarig et al , 2019). These cells were shown to be efficiently cleared from the tissues as regeneration progressed possibly by macrophages (Yun, Davaapil and Brockes, 2015).…”

Section: Introductionmentioning

confidence: 99%

Depletion of senescent cells improves functional recovery after spinal cord injury

Paramos-de-Carvalho

Martins

Cristóvão

et al. 2020

Preprint

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Persistent senescent cells (SCs) are known to underlie ageing-related chronic disorders, but it is now recognized that SCs may be at the center of tissue remodeling events, namely during development or organ repair. Here we show that two distinct senescence profiles are induced in the context of a spinal cord injury between the regenerating zebrafish and the non-regenerating mouse. While induced-SCs in the zebrafish are progressively cleared out, they accumulate over time in mice. Depletion of SCs in spinal cord injured mice, with different senolytic drugs, improved locomotor, sensory and bladder functions. This functional recovery is associated with improved myelin sparing, reduced fibrotic scar, attenuated inflammation and increased axonal growth. Targeting SCs is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.

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“…We propose that Agrin exerts a pleiotropic therapeutic response, comprised of intrinsic (CMspecific) and extrinsic (immune cells, endothelial cells, fibroblasts (47)) arms that contribute to repair processes of injured animals. In line with this, it is becoming more evident that cardiac regeneration and repair strategies should focus on augmenting several cellular events (i.e.…”

Section: Discussionmentioning

confidence: 99%

Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs

Baehr

Umansky

Bassat

et al. 2019

Preprint

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Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We have recently reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days (d) reperfusion period. We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner.Single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiment along with complementary murine MI studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin's mechanisms of action. We conclude that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving cardiac function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.

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Transient p53-Mediated Regenerative Senescence in the Injured Heart

Cited by 63 publications

References 6 publications

Cellular senescence in development, regeneration and disease

Cellular senescence in development, regeneration and disease

Depletion of senescent cells improves functional recovery after spinal cord injury

Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs

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