A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians

Wurtzel, Omri; Cote, Lauren E.; Poirier, Amber; Satija, Rahul; Regev, Aviv; Reddien, Peter W.

doi:10.1016/j.devcel.2015.11.004

Cited by 198 publications

(403 citation statements)

References 57 publications

(107 reference statements)

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“…Congruent with our previous results, single-cell RNA sequencing (scRNAseq) [13,27] of stem and differentiated tissues demonstrated that yki was not enriched in any of the stem cell sub-classes (γ, z or σ), and instead, was primarily expressed in differentiated tissues, such as the epidermis, muscle, and gut (S1D Fig) [22]. Interestingly, these same differentiated tissues have recently been shown to be enriched for the expression of wound-induced genes, collectively known as the "transcriptional injury response" [13].…”

Section: Yorkie Restricts Stem Cell Proliferation During Regenerationmentioning

confidence: 99%

“…https://doi.org/10.1371/journal.pgen.1006874.g001 two waves of transcription: an immediate "early wave" that peaks in expression by~6 hpa, and; a subsequent "late wave" that lasts in expression until~24 hpa [12,13]. In yki(RNA), the early-wave marker fos-1, was precociously expressed at 0.5 hpa and was prolonged until 12 hpa (Fig 2A).…”

Section: Yorkie Restricts Stem Cell Proliferation During Regenerationmentioning

confidence: 99%

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Yorkie is required to restrict the injury responses in planarians

Lin

Pearson

2016

Preprint

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Regeneration requires the precise integration of cues that initiate proliferation, direct differentiation, and ultimately re-pattern tissues to the proper size and scale. Yet how these processes are integrated with wounding responses remains relatively unknown. The freshwater planarian, Schmidtea mediterranea, is an ideal model to study the stereotyped proliferative and transcriptional responses to injury due to its high capacity for regeneration. Here, we characterize the effector of the Hippo signalling cascade, yorkie, during planarian regeneration and its role in restricting early injury responses. In yki(RNAi) regenerating animals, wound responses are hyper-activated such that both stem cell proliferation and the transcriptional wound response program are heighted and prolonged. Using this observation, we also uncovered novel woundinduced genes by RNAseq that were de-repressed in yki(RNAi) animals compared with controls. Additionally, we show that yki(RNAi) animals have expanded epidermal and muscle cell populations, which we hypothesize are the increased sources of wound-induced genes. Finally, we show that in yki(RNAi) animals, the sensing of the size of an injury by eyes or the pharynx is not appropriate, and the brain, gut, and midline cannot remodel or scale correctly to the size of the regenerating fragment. Taken together, our results suggest that yki functions as a key molecule that can integrate multiple aspects of the injury response including proliferation, apoptosis, injury-induced transcription, and patterning. Author summaryThe planarian displays a remarkable ability to regenerate any tissue from mere fragments of its original size. This high capacity to regenerate is attributed to the abundant population of pluripotent adult stem cells. In response to an injury, such as an amputation, stem cells proliferate and replace the lost tissues de novo (epimorphosis), whereas existing tissue must rescale to the correct proportions in relation to the new fragment size (morphallaxis). Currently, the molecules that control either the responses to injury or the ones that mediate size and scaling are not well understood. For instance, how are the injury responses precisely activated and shut down to ensure regenerating tissues are not underor overgrown? Here, we find that Yki, the effector of the Hippo signalling cascade, is a critical molecule that influences several injury processes during regeneration. Loss of Yki function in regenerating animals resulted in increased and temporally dysregulated expression of wound-induced genes, proliferation, and apoptosis. Genes that are injury induced were mis-expressed in yki(RNAi) animals, which also showed increases in the epidermal and muscle cell populations. Taken together, our findings suggest that the injury responses must be restricted to ensure proper regenerative outcomes of correct scale, and that Yki is a key regulator in these processes.

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Section: Yorkie Restricts Stem Cell Proliferation During Regenerationmentioning

confidence: 99%

Section: Yorkie Restricts Stem Cell Proliferation During Regenerationmentioning

confidence: 99%

Yorkie is required to restrict the injury responses in planarians

Lin

Pearson

2016

Preprint

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“…Not all wounds initiate regeneration, and the signals that convert a generic wound response to a regenerative process are unknown (Wurtzel et al, 2015;Owlarn and Bartscherer, 2016). Kerstin Bartscherer (MPI, Muenster, Germany) showed that by blocking wound-induced ERK activity in planarians, amputated animals close their wound but do not regenerate until ERK activity is restored, thereby dissociating these two processes.…”

Section: Wound Repair and Injury-induced Signalingmentioning

confidence: 99%

Trends in tissue repair and regeneration

et al. 2017

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The 6th EMBO conference on the Molecular and Cellular Basis of Regeneration and Tissue Repair took place in Paestum (Italy) on the 17th-21st September, 2016. The 160 scientists who attended discussed the importance of cellular and tissue plasticity, biophysical aspects of regeneration, the diverse roles of injury-induced immune responses, strategies to reactivate regeneration in mammals, links between regeneration and ageing, and the impact of non-mammalian models on regenerative medicine.

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“…We could identify cells that co-expressed smedwi-1 and either β1-integrin or α-integrin-2, but the majority of FISH signal for these two genes was too disperse and punctate to assign readily to particular cells. Additionally, prior analyses found expression of these genes using RNA-seq to measure the transcriptome of FACS-sorted neoblasts as a bulk population (Labbe et al, 2012) and also in the transcriptomes of neoblasts as measured by single-cell RNA-seq, as well as expression in nonneoblast cells (Wurtzel et al, 2015) (Fig. S6F,G).…”

Section: Integrin Is Necessary For Neoblast and Neuronal Progenitor Lmentioning

confidence: 99%

“…Components or putative regulators of the ECM have been identified as expressed following injury in several regeneration models, including planarians (Wenemoser et al, 2012;Wurtzel et al, 2015), axolotl (Rao et al, 2009;Knapp et al, 2013) and sea anemone (DuBuc et al, 2014). However, the function of these in tissue assembly is unknown.…”

Section: Introductionmentioning

confidence: 99%

Integrin suppresses neurogenesis and regulates brain tissue assembly in planarian regeneration

Bonar

Petersen

2017

Development

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Animals capable of adult regeneration require specific signaling to control injury-induced cell proliferation, specification and patterning, but comparatively little is known about how the regeneration blastema assembles differentiating cells into well-structured functional tissues. Using the planarian Schmidtea mediterranea as a model, we identify β1-integrin as a crucial regulator of blastema architecture. β1-integrin(RNAi) animals formed small head blastemas with severe tissue disorganization, including ectopic neural spheroids containing differentiated neurons normally found in distinct organs. By mimicking aspects of normal brain architecture but without normal cell-type regionalization, these spheroids bore a resemblance to mammalian tissue organoids synthesized in vitro. We identified one of four planarian integrin-alpha subunits inhibition of which phenocopied these effects, suggesting that a specific receptor controls brain organization through regeneration. Neoblast stem cells and progenitor cells were mislocalized in β1-integrin(RNAi) animals without significantly altered body-wide patterning. Furthermore, tissue disorganization phenotypes were most pronounced in animals undergoing brain regeneration and not homeostatic maintenance or regeneration-induced remodeling of the brain. These results suggest that integrin signaling ensures proper progenitor recruitment after injury, enabling the generation of largescale tissue organization within the regeneration blastema.

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A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians

Cited by 198 publications

References 57 publications

Yorkie is required to restrict the injury responses in planarians

Yorkie is required to restrict the injury responses in planarians

Trends in tissue repair and regeneration

Integrin suppresses neurogenesis and regulates brain tissue assembly in planarian regeneration

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