Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

Yu, Qinghao; Walters, Hannah E.; Pasquini, Giovanni; Pal Singh, Sumeet; Lachnit, Martina; Oliveira, Catarina R.; León-Periñán, Daniel; Petzold, Andreas; Kesavan, Preethi; Subiran Adrados, Cristina; Garteizgogeascoa, Ines; Knapp, Dunja; Wagner, Anne; Bernardos, Andrea; Alfonso, María; Nadar, Gayathri; Graf, Alwin M.; Troyanovskiy, Konstantin E.; Dahl, Andreas; Busskamp, Volker; Martínez-Máñez, Ramón; Yun, Maximina H.

doi:10.1016/j.devcel.2023.09.009

Cited by 15 publications

(3 citation statements)

References 58 publications

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“…The iris epithelium and stroma consist of a heterogeneous cell population (iPECs, keratinocytes, melanocytes, muscle, blood, and infiltrating immune cells, such as macrophages). In axolotls and zebrafish, not only immune cells, but also other cell types, such as blastema progenitors, senescent cells and fin epithelial cells (in limb and fin, respectively) can produce cytokines that modulate the inflammatory response and influence the outcome of regeneration [ 93 , 150 , 151 ]. Future studies utilizing technologies with the ability to resolve cell types, such as cell sorting, single-cell RNA sequencing, and/or spatial transcriptomics will shed light on how each cell population contributes differently during lens regeneration.…”

Section: Discussionmentioning

confidence: 99%

Macrophages modulate fibrosis during newt lens regeneration

Tsissios,

Sallese,

Perez-Estrada

et al. 2024

Stem Cell Res Ther

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Background Previous studies have suggested that macrophages are present during lens regeneration in newts, but their role in the process is yet to be elucidated. Methods Here we generated a transgenic reporter line using the newt, Pleurodeles waltl, that traces macrophages during lens regeneration. Furthermore, we assessed early changes in gene expression during lens regeneration using two newt species, Notophthalmus viridescens and Pleurodeles waltl. Finally, we used clodronate liposomes to deplete macrophages during lens regeneration in both species and tested the effect of a subsequent secondary injury after macrophage recovery. Results Macrophage depletion abrogated lens regeneration, induced the formation of scar-like tissue, led to inflammation, decreased iris pigment epithelial cell (iPEC) proliferation, and increased rates of apoptosis in the eye. Some of these phenotypes persisted throughout the last observation period of 100 days and could be attenuated by exogenous FGF2 administration. A distinct transcript profile encoding acute inflammatory effectors was established for the dorsal iris. Reinjury of the newt eye alleviated the effects of macrophage depletion, including the resolution of scar-like tissue, and re-initiated the regeneration process. Conclusions Together, our findings highlight the importance of macrophages for facilitating a pro-regenerative environment in the newt eye by regulating fibrotic responses, modulating the overall inflammatory landscape, and maintaining the proper balance of early proliferation and late apoptosis of the iPECs.

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Section: Discussionmentioning

confidence: 99%

Macrophages modulate fibrosis during newt lens regeneration

Tsissios,

Sallese,

Perez-Estrada

et al. 2024

Stem Cell Res Ther

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“…In salamanders, limb regeneration can proceed despite the accumulation of senescent cells, since these can be efficiently cleared by macrophages 42 . In fact, regeneration-induced transient accumulation of senescent cells has been found to be required for regeneration, likely since senescent cells secrete pro-regenerative factors 43,44 . Of note, our data indicate that zebrafish CMs that experience replication stress do not become senescent.…”

Section: Discussionmentioning

confidence: 99%

BMP signaling promotes heart regeneration via alleviation of replication stress

Vasudevarao,

Pena,

Ihle

et al. 2024

Preprint

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One hallmark of aging is a decline in tissue regeneration, which can be caused by DNA replication stress. Whether highly regenerative species like zebrafish are immune from such hindrances to replication is unknown. In contrast to most mammals, adult zebrafish achieve complete heart regeneration via cell cycle entry and proliferation of mature cardiomyocytes. We found that cycling cardiomyocytes experience replication stress, which is induced by the demands of regeneration, but does not occur during physiological heart growth. Since zebrafish cardiomyocyte regeneration is remarkably efficient, heart regeneration appears to depend on elevated capabilities to overcome replication stress. Indeed, pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for heart regeneration. Using inducible overexpression of ligands and inhibitors of the Bone Morphogenetic Protein (BMP)-Smad pathway, combined with analysis of genetic mutants, we found that BMP signaling alleviates cardiomyocyte replication stress. In the absence of BMP signaling, cardiomyocytes become arrested in the S-phase of the cell cycle, which prevents progression to mitosis and results in heart regeneration failure. Interestingly, BMP signaling can also rescue neonatal mouse cardiomyocytes and human fibroblasts from hydroxyurea-induced replication stress. DNA fiber spreading assays in human cancer cells and human hematopoietic stem and progenitor cells (HSPCs) indicate that BMP signaling acts directly on replication dynamics by accelerating DNA replication fork progression and by facilitating their re-start after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated heart regeneration capacity in zebrafish. Notably, the conserved capability of BMP signaling to promote stress-free DNA replication might unlock new avenues towards anti-aging and pro-regenerative applications in humans.

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“…In non-mammalian animals, even more complex structures can be regenerated in adult animals through senescent cells and the SASP. Salamanders regenerate whole limbs, and senescent cells were reported to create a proregenerative environment promoting limb regeneration via the SASP and the WNT pathway ( Yun et al, 2015 ; Yu et al, 2023 ). Fin amputation in zebrafish leads to the accumulation of senescent cells that contribute to fin regeneration ( Da Silva-Álvarez et al, 2020 ).…”

Section: Discovery Of the Sasp And Evolution Of A Paradigm: From An E...mentioning

confidence: 99%

Regulation of cell function and identity by cellular senescence

Huna,

Massemin,

Makulyte

et al. 2024

Journal of Cell Biology

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During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.

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Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

Cited by 15 publications

References 58 publications

Macrophages modulate fibrosis during newt lens regeneration

Macrophages modulate fibrosis during newt lens regeneration

BMP signaling promotes heart regeneration via alleviation of replication stress

Regulation of cell function and identity by cellular senescence

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