Characterizing the lens regeneration process in Pleurodeles waltl

Tsissios, Georgios; Theodoroudis-Rapp, Gabriella; Chen, Wei-Hao; Sallese, Anthony; Smucker, Byran J.; Ernst, Lake; Chen, Junfan; Xu, Yiqi; Ratvasky, Sophia; Wang, Hui; Rio‐Tsonis, Katia Del

doi:10.1016/j.diff.2023.02.003

Cited by 5 publications

(10 citation statements)

References 60 publications

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“…2 A, where animals were 3 years old). This observation is consistent with our previous study showing that lens regeneration is delayed in older P. waltl [ 44 ]. Our data support that, while macrophage depletion does not cause an apoptotic response during the early timepoints evaluated in this study, macrophages do play a role in the induction of cell cycle re-entry of iPECs.…”

Section: Resultssupporting

confidence: 94%

“…The non-invasive nature of SD-OCT allowed us to monitor the lens regeneration process from the same newt in real time [ 78 ]. Using SD-OCT, we recently demonstrated that ECM remodeling is dynamic and highly orchestrated during lens regeneration [ 44 ]. At 4 dpl, a cloudy opacity was observed in the anterior eye chamber between the dorsal and ventral iris of both PBS- and clodronate-treated eyes, indicating an accumulation of ECM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3 B, C . To confirm our interpretation of the SD-OCT findings, we used histology and picrosirius red staining to detect collagen fibers, a major component of the ECM [ 44 ]. Collagen accumulation appeared to be larger and denser in the anterior chamber of clodronate-treated eyes compared to control eyes at 4 dpl (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of newt lens regeneration, we observed changes in the rate of cell cycle re-entry and proliferation of iPECs, but we did not find evidence of apoptosis in dorsal iPECs at the early stages of regeneration. We used non-invasive SD-OCT to monitor the lens regeneration process from the same newts in real-time [ 44 , 78 ], and recorded the dynamic formation of scar tissue following macrophage depletion. We describe here a clodronate-induced accumulation of both collagen and myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that the lens growth rates and speed of regeneration can vary between different newt species and between different ages of the same species [ 35 , 44 , 45 ]. For this reason, we refer to lens regeneration stages (as defined in [ 44 ]), in addition to days post- lentectomy, throughout the manuscript.…”

Section: Methodsmentioning

confidence: 99%

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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: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Macrophages modulate fibrosis during newt lens regeneration

Tsissios,

Sallese,

Perez-Estrada

et al. 2024

Stem Cell Res Ther

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Macrophages modulate fibrosis during newt lens regeneration

Tsissios

Sallese

Pérez-Estrada

et al. 2023

Preprint

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Previous studies indicated that macrophages play a role during lens regeneration in newts, but their function has not been tested experimentally. Here we generated a transgenic newt reporter line in which macrophages can be visualized in vivo. Using this new tool, we analyzed the location of macrophages during lens regeneration. We uncovered early gene expression changes using bulk RNAseq in two newt species, Notophthalmus viridescens and Pleurodeles waltl. Next, we used clodronate liposomes to deplete macrophages, which inhibited lens regeneration in both newt species. Macrophage depletion induced the formation of scar-like tissue, an increased and sustained inflammatory response, an early decrease in iris pigment epithelial cell (iPEC) proliferation and a late increase in apoptosis. Some of these phenotypes persisted for at least 100 days and could be rescued by exogenous FGF2. Re-injury alleviated the effects of macrophage depletion and re-started the regeneration process. Together, our findings highlight the importance of macrophages in facilitating a pro-regenerative environment in the newt eye, helping to resolve fibrosis, modulating the overall inflammatory landscape and maintaining the proper balance of early proliferation and late apoptosis.

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Loss of the ability to regenerate body appendages in vertebrates: from side effects of evolutionary innovations to gene loss

Zaraisky,

Araslanova,

Shitikov

et al. 2024

Biological Reviews

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The ability to regenerate large body appendages is an ancestral trait of vertebrates, which varies across different animal groups. While anamniotes (fish and amphibians) commonly possess this ability, it is notably restricted in amniotes (reptiles, birds, and mammals). In this review, we explore the factors contributing to the loss of regenerative capabilities in amniotes. First, we analyse the potential negative impacts on appendage regeneration caused by four evolutionary innovations: advanced immunity, skin keratinization, whole‐body endothermy, and increased body size. These innovations emerged as amniotes transitioned to terrestrial habitats and were correlated with a decline in regeneration capability. Second, we examine the role played by the loss of regeneration‐related enhancers and genes initiated by these innovations in the fixation of an inability to regenerate body appendages at the genomic level. We propose that following the cessation of regenerative capacity, the loss of highly specific regeneration enhancers could represent an evolutionarily neutral event. Consequently, the loss of such enhancers might promptly follow the suppression of regeneration as a side effect of evolutionary innovations. By contrast, the loss of regeneration‐related genes, due to their pleiotropic functions, would only take place if such loss was accompanied by additional evolutionary innovations that compensated for the loss of pleiotropic functions unrelated to regeneration, which would remain even after participation of these genes in regeneration was lost. Through a review of the literature, we provide evidence that, in many cases, the loss in amniotes of genes associated with body appendage regeneration in anamniotes was significantly delayed relative to the time when regenerative capability was lost. We hypothesise that this delay may be attributed to the necessity for evolutionary restructuring of developmental mechanisms to create conditions where the loss of these genes was a beneficial innovation for the organism. Experimental investigation of the downregulation of genes involved in the regeneration of body appendages in anamniotes but absent in amniotes offers a promising avenue to uncover evolutionary innovations that emerged from the loss of these genes. We propose that the vast majority of regeneration‐related genes lost in amniotes (about 150 in humans) may be involved in regulating the early stages of limb and tail regeneration in anamniotes. Disruption of this stage, rather than the late stage, may not interfere with the mechanisms of limb and tail bud development during embryogenesis, as these mechanisms share similarities with those operating in the late stage of regeneration. Consequently, the most promising approach to restoring regeneration in humans may involve creating analogs of embryonic limb buds using stem cell‐based tissue‐engineering methods, followed by their transfer to the amputation stump. Due to the loss of many genes required specifically during the early stage of regeneration, this approach may be more effective than attempting to induce both early and late stages of regeneration directly in the stump itself.

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Characterizing the lens regeneration process in Pleurodeles waltl

Cited by 5 publications

References 60 publications

Macrophages modulate fibrosis during newt lens regeneration

Macrophages modulate fibrosis during newt lens regeneration

Macrophages modulate fibrosis during newt lens regeneration

Loss of the ability to regenerate body appendages in vertebrates: from side effects of evolutionary innovations to gene loss

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