Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

Yu, Qinghao; Walters, Hannah; Pasquini, Giovanni; Singh, Sumeet Pal; Perinan, Daniel Leon; Petzold, A.; Kesavan, Preethi; Subiran, Cristina; Suner, Ines Garteizgogeascoa; Knapp, Dunja; Wagner, Anne; Bernardos, Andrea; Alfonso, María; Nadar, Gayathri; Dahl, Andreas; Busskamp, Volker; Manaez, Ramon; Yun, Maximina H.

doi:10.1101/2022.09.01.506196

Cited by 5 publications

(5 citation statements)

References 72 publications

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“…While we have not observed sustained, pro-proliferative effects specific to the muscle progenitors in the blastema (Figure 1h), it remains conceivable that senescent cells promote proliferation of additional blastema populations, which may explain the notable acceleration of blastema development observed upon senescent cell implantation (Figure 1b-d). This is in agreement with further data from our group (Yu et al, 2022), which reports that senescent cells facilitate progenitor cell expansion in the axolotl. Additionally, senescent cell clearance in salamanders is achieved by macrophages (Yun et al, 2015), raising the possibility that senescent cells may have indirect functions via recruitment or regulation of immune cell activity, important in other regenerative contexts (Ratnayake et al, 2021).…”

Section: Discussionsupporting

confidence: 94%

“…Notophthalmus viridescens limb‐derived A1 cells (Ferretti & Brockes, 1988 ) and A1n gfp cells (Yun et al, 2015 ) were cultured as previously described (Yu et al, 2022 ; Oliveira et al, 2022 ); in brief, cells were grown on gelatin‐coated flasks in MEM (Gibco) supplemented with 2 nM L‐glutamine (Gibco), 10 μg/mL insulin (Sigma), 100 U/mL penicillin/streptomycin (Gibco), 10% heat‐inactivated FCS (Gibco) and 25% v/v dH 2 O. Cells were passaged 1:2 when approaching 70–80% confluence and maintained at 25°C and 2% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…In vitro senescence induction was performed according to Yu et al (2023), using UV-irradiation (3 J/m 2 , UV Stratalinker) or 24-h exposure to 20 μM etoposide, both followed by treatment with 1 μM Nutlin-3a. Senescence induction following 12 days' treatment was confirmed by positive SAβ-gal staining, a significant reduction in EdU incorporation, expansion of mitochondrial and lysosomal networks and persistent DNA damage foci (Yu et al, 2022). Control proliferating cells were seeded in parallel, treated only with identical volumes of DMSO and passaged during the 12day senescence induction to avoid confluence.…”

Section: Senescence Induction and Conditioned Media Generationmentioning

confidence: 99%

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Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

et al. 2023

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Salamanders are able to regenerate their entire limbs throughout lifespan, through a process that involves significant modulation of cellular plasticity. Limb regeneration is accompanied by the endogenous induction of cellular senescence, a state of irreversible cell cycle arrest associated with profound non‐cell‐autonomous consequences. While traditionally associated with detrimental physiological effects, here, we show that senescent cells can enhance newt limb regeneration. Through a lineage tracing approach, we demonstrate that exogenously derived senescent cells promote dedifferentiation of mature muscle tissue to generate regenerative progenitors. In a paradigm of newt myotube dedifferentiation, we uncover that senescent cells promote myotube cell cycle re‐entry and reversal of muscle identity via secreted factors. Transcriptomic profiling and loss of function approaches identify the FGF‐ERK signalling axis as a critical mediator of senescence‐induced muscle dedifferentiation. While chronic senescence constrains muscle regeneration in physiological mammalian contexts, we thus highlight a beneficial role for cellular senescence as an important modulator of dedifferentiation, a key mechanism for regeneration of complex structures.

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Section: Discussionsupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Senescence Induction and Conditioned Media Generationmentioning

confidence: 99%

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Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

et al. 2023

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“…Interestingly, activation of macrophages could help in clearing the fibrosis by a facilitated infiltration within proliferating new cardiac myocytes (32). Such a proliferative process for new cardiac progenitors emerging from a blastemal 9 could also be boosted by many p21+ senescent cells that we identified in our single cell-RNA seq dataset (Fig 6 ) as found during axolotl regeneration process (33).…”

mentioning

confidence: 78%

Graft of cardiac progenitors in a pig model of right ventricular failure triggers myocardial epimorphosis, regeneration and protection of function

Lambert

Deleris

Tibourtine

et al. 2022

Preprint

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The failure of diseased adult heart to regenerate is a major burden to our societies. Besides patients with ischemia and left ventricular (LV) dysfunction, progress in pediatric surgery to repair cardiac malformations has led to a growing population of now adult congenital heart diseases (CHD) patients with right ventricular (RV) failure. In the absence of any efficient pharmacological therapy for these patients, cell therapy has turned out to be the only option to regenerate the RV myocardium. In this study, we demonstrate that the adult pig with RV failure, a model of repaired tetralogy of Fallot, has the ability of regenerative epimorphosis. Human embryonic stem cell-derived cardiac Nkx2.5+ progenitor cells were seeded in a collagen based patch to cover the whole pig failing RV. We report that these cells migrate within the myocardium while reversing the interstitial fibrosis. They then engraft and fully differentiate into fetal-like human myocytes within the myocardium. The graft triggers the reprogramming of surrounding pig myocytes into Oct4+ cells. The reprogrammed myocytes re-differentiate and proliferate around human myocytes. Altogether, our findings reveal that mammalian hearts have the ability to undergo epimorphosis, the major process of endogenous regeneration that leads to a recovery of their contractile function.

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“…These cells are then cleared by macrophages after their recruitment (H. Li et al, 2021). In addition, recent work on axolotl limb regeneration has revealed that senescent cells create a pro‐proliferative niche for progenitor cell expansion and blastema outgrowth (Yu et al, 2022). Thus, cGAS‐STING activation and cGAS suppressor downregulation during regeneration promotes cell senescence while simultaneously creating an environment primed for immune cell recruitment and tissue remodeling.…”

Section: Discussionmentioning

confidence: 99%

Suppressors of cGAS‐STING are downregulated during fin‐limb regeneration and aging in aquatic vertebrates

Mathavarajah,

Thompson,

Stoyek

et al. 2023

J Exp Zool Pt B

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During the early stages of limb and fin regeneration in aquatic vertebrates (i.e., fishes and amphibians), blastema undergo transcriptional rewiring of innate immune signaling pathways to promote immune cell recruitment. In mammals, a fundamental component of innate immune signaling is the cytosolic DNA sensing pathway, cGAS‐STING. However, to what extent the cGAS‐STING pathway influences regeneration in aquatic anamniotes is unknown. In jawed vertebrates, negative regulation of cGAS‐STING activity is accomplished by suppressors of cytosolic DNA such as Trex1, Pml, and PML‐like exon 9 (Plex9) exonucleases. Here, we examine the expression of these suppressors of cGAS‐STING, as well as inflammatory genes and cGAS activity during caudal fin and limb regeneration using the spotted gar (Lepisosteus oculatus) and axolotl (Ambystoma mexicanum) model species, and during age‐related senescence in zebrafish (Danio rerio). In the regenerative blastema of wounded gar and axolotl, we observe increased inflammatory gene expression, including interferon genes and interleukins 6 and 8. We also observed a decrease in axolotl Trex1 and gar pml expression during the early phases of wound healing which correlates with a dramatic increase in cGAS activity. In contrast, the plex9.1 gene does not change in expression during wound healing in gar. However, we observed decreased expression of plex9.1 in the senescing cardiac tissue of aged zebrafish, where 2′3′‐cGAMP levels are elevated. Finally, we demonstrate a similar pattern of Trex1, pml, and plex9.1 gene regulation across species in response to exogenous 2′3′‐cGAMP. Thus, during the early stages of limb‐fin regeneration, Pml, Trex1, and Plex9.1 exonucleases are downregulated, presumably to allow an evolutionarily ancient cGAS‐STING activity to promote inflammation and the recruitment of immune cells.

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Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

Cited by 5 publications

References 72 publications

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Graft of cardiac progenitors in a pig model of right ventricular failure triggers myocardial epimorphosis, regeneration and protection of function

Suppressors of cGAS‐STING are downregulated during fin‐limb regeneration and aging in aquatic vertebrates

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