Mathematical modeling of Erk activity waves in regenerating zebrafish scales

Hayden, Luke; Poss, Kenneth D.; Simone, Alessandro De; Talia, Stefano Di

doi:10.1016/j.bpj.2021.05.004

Cited by 10 publications

(15 citation statements)

References 48 publications

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“…Both phosphokinases subsequently display fast decay towards basal levels. Interestingly, whereas phospho-AKT levels remain at basal levels at 24 h following stimulation with CCN2, phospho-ERK1/2 levels display secondary peak activities around 24 h, indicative of oscillatory-like activity according to previous reports ( 31 , 32 ). In other cell types, delayed or sustained stimulation of phospho-ERK levels have also been reported ( 33 ).…”

Section: Resultssupporting

confidence: 81%

The carboxyl-terminal TSP1-homology domain is the biologically active effector peptide of matricellular protein CCN5 that counteracts profibrotic CCN2

Zolfaghari

Kaasbøll²,

Monsen³

et al. 2023

Journal of Biological Chemistry

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Section: Resultssupporting

confidence: 81%

The carboxyl-terminal TSP1-homology domain is the biologically active effector peptide of matricellular protein CCN5 that counteracts profibrotic CCN2

Zolfaghari

Kaasbøll²,

Monsen³

et al. 2023

Journal of Biological Chemistry

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Section: Biological Examplesmentioning

confidence: 93%

“…This three-variable excitable system, including positive and negative feedback via ERK, was formalized as a mathematical model in a reaction-diffusion scheme. The simulation results thoroughly explained the ERK activity waves observed during the regeneration of zebrafish scale bone [96,97]. Chemical diffusion-based wave propagation is considered to exist in various other systems, such as skeletal and nervous tissues, and would be a common framework for the transmission of biological information [98,99].…”

Section: Scale Bone Regeneration -Erk Propagation Via Ligand Diffusionmentioning

confidence: 99%

“…Chemical diffusion-based wave propagation is considered to exist in various other systems, such as skeletal and nervous tissues, and would be a common framework for the transmission of biological information [ 98 , 99 ]. Indeed, it enables the achievement of long-range transmission of signals even at the millimeter scale without the loss of signal amplitude [ 96 , 97 ]. However, to enable robust spatial information transfer, it is essential to ensure that the microenvironments of extracellular spaces be stably maintained to avoid disturbances during ligand diffusion, as these transmissions are susceptible to extracellular environments.…”

Section: Biological Examplesmentioning

confidence: 99%

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Live imaging approach of dynamic multicellular responses in ERK signaling during vertebrate tissue development

Hirashima

2022

Biochemical Journal

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The chemical and mechanical responses of cells via the exchange of information during growth and development result in the formation of biological tissues. Information processing within the cells through the signaling pathways and networks inherent to the constituent cells has been well-studied. However, the cell signaling mechanisms responsible for generating dynamic multicellular responses in developing tissues remain unclear. Here, I review the dynamic multicellular response systems during the development and growth of vertebrate tissues based on the extracellular signal-regulated kinase (ERK) pathway. First, an overview of the function of the ERK signaling network in cells is provided, followed by descriptions of biosensors essential for live imaging of the quantification of ERK activity in tissues. Then adducing four examples, I highlight the contribution of live imaging techniques for studying the involvement of spatio-temporal patterns of ERK activity change in tissue development and growth. In addition, theoretical implications of ERK signaling are also discussed from the viewpoint of dynamic systems. This review might help in understanding ERK-mediated dynamic multicellular responses and tissue morphogenesis.

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“…This is an understudied model system compared to other tissue regeneration in zebrafish. However, it offers great opportunities to perform live imaging, genetic manipulations and mathematical modeling (Hayden et al, 2021).…”

Section: Adult Zebrafish Scale Regenerationmentioning

confidence: 99%

Interleukin-11 signaling is a global molecular switch between regeneration and scarring in zebrafish

Allanki¹

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The two diametrically opposing outcomes after tissue damage are regeneration and fibrotic scarring. After injury, adult mammals predominantly induce fibrotic scarring, which most often leads to patient lethality. Fibrotic scarring is the deposition of excessive extracellular matrix that matures and hinders tissue function. The scarring response is mainly orchestrated by myofibroblasts, which arise only upon tissue damage, from various cellular origins, including tissue resident fibroblasts, endothelial cells and circulating blood cells. On the contrary, species like zebrafish, possess the remarkable capacity to regenerate their damaged tissues. After injury, instead of inducing a myofibroblast-mediated fibrogenic gene program, cells in these species undergo regenerative reprogramming at the transcriptional level to activate vital cellular processes needed for regeneration, including proliferation, dedifferentiation, and migration. Several pro-regenerative mechanisms have been identified to date. Most of them, if not all, are also important for tissue homeostasis and hence, are not injury specific. Therefore, the central aim of this study is to identify injury-specific mechanisms that not only induce regeneration, but also limit fibrotic scarring. To test the notion that fibrotic scarring limits regeneration, I first compared the scarring response in the regenerative zebrafish heart after cryoinjury with what is known in the non-regenerative adult mouse heart. I found that zebrafish display ~10-fold less myofibroblast differentiation compared to adult mouse after cardiac injury. With these findings, I hypothesized that zebrafish employ mechanisms to actively suppress scarring response. Using a novel comparative transcriptomic approach coupled with genetic loss-of-function analyses, I identified that Interleukin-6 (Il-6) cytokine family-mediated Stat3 is one such pro-regenerative pathway in zebrafish. Il-6 cytokine family consists of Il-6, Interleukin-11 (Il-11), Ciliary neurotrophic factor, Leukemia inhibitory factor, Oncostatin M, and Cardiotrophin-like cytokine factor 1. Il-6 family ligands signal through their specific receptors and a common receptor subunit (Il6st or Gp130). Using gene expression analyses after adult heart and adult caudal fin injuries in zebrafish, I identified that both the Il-11 cytokine encoding paralogous genes (il11a and il11b) are the highest expressed and induced among the Il-6 family cytokines. Hence, I chose Il-11 signaling as a candidate pathway for further analysis. To investigate the role of Il-11 signaling, I generated genetic loss-of-function mutants for both the ligand (il11a and il11b) and the receptor (il11ra) encoding genes. Using various tissue regeneration models across developmental stages in these mutants, I identified that Il-11/Stat3 signaling is indispensable for global tissue regeneration in zebrafish. To investigate the cellular and molecular mechanisms by which Il-11 signaling promotes regeneration, I performed transcriptomics comparing the non-regenerative il11ra mutant hearts and fins with that of the wild types, respectively. I identified that Il-11 signaling orchestrates both global and tissue-specific aspects of regenerative reprogramming at the transcriptional level. In addition, I also found that impaired regenerative reprogramming in the il11ra mutant hearts and fins resulted in defective cardiomyocyte and osteoblast repopulation of the injured area, respectively. On the other hand, by deep phenotyping the scarring response in il11ra mutant hearts and fins, I identified that Il-11 signaling limits myofibroblast differentiation. Furthermore, I found that cardiac endothelial cells and fibroblasts are one of the major responders to injury-induced Il-11 signaling. Using lineage tracing, I found that both the endothelial and fibroblast lineages in the non-regenerative il11ra mutants commit to a myofibroblast fate, spearheading the scarring response. In addition, using cell type specific manipulations, I showed that Il-11 signaling in cardiac endothelial cells allows cardiomyocyte repopulation of the injured area. Finally, using human endothelial cells in culture, I uncovered a novel feedback mechanism by which Il-11 signaling limits fibrogenic gene expression by inhibiting its parent activator and a master regulator of tissue fibrosis, TGF-β signaling. Overall, I identified Interleukin-11/Stat3 signaling as the first global regulator of regeneration in zebrafish. Briefly, I showed that Interleukin-11 signaling promotes regeneration by regulating two crucial cellular aspects in response to injury – (1) it promotes regenerative reprogramming, thereby allowing cell repopulation of the injured area and (2) it limits mammalian-like fibrotic scarring by inhibiting myofibroblast differentiation and TGF-β signaling. Altogether, these zebrafish data, together with the contradicting mammalian data strongly indicate that the secrets of tissue regeneration lie downstream of IL-11 signaling, in the differences between regenerative and non-regenerative species. Furthermore, I establish the non-regenerative il11ra mutant as an invaluable zebrafish model to study mammalian tissue fibrosis.

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Mathematical modeling of Erk activity waves in regenerating zebrafish scales

Cited by 10 publications

References 48 publications

The carboxyl-terminal TSP1-homology domain is the biologically active effector peptide of matricellular protein CCN5 that counteracts profibrotic CCN2

The carboxyl-terminal TSP1-homology domain is the biologically active effector peptide of matricellular protein CCN5 that counteracts profibrotic CCN2

Live imaging approach of dynamic multicellular responses in ERK signaling during vertebrate tissue development

Interleukin-11 signaling is a global molecular switch between regeneration and scarring in zebrafish

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