scholarly journals Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish

2012 ◽  
Vol 199 (2) ◽  
pp. 225-234 ◽  
Author(s):  
Sa Kan Yoo ◽  
Christina M. Freisinger ◽  
Danny C. LeBert ◽  
Anna Huttenlocher
Keyword(s):  
Calcium Signaling ◽  
Tissue Regeneration ◽  
Tissue Injury ◽  
Src Family Kinase ◽  
Fin Regeneration ◽  
Epimorphic Regeneration ◽  
Zebrafish Larvae ◽  
Redox Sensor ◽  
Wound Responses ◽  
Early Wound

Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H2O2 at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H2O2. A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate “wound signals” that integrate early wound responses and late epimorphic regeneration.

scholarly journals Citrullination regulates wound responses and tissue regeneration in zebrafish

2019 ◽  
Author(s):  
Netta Golenberg ◽  
Jayne M. Squirrell ◽  
David A. Bennin ◽  
Julie Rindy ◽  
Paige E. Pistono ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Tissue Regeneration ◽  
Protein Function ◽  
Tissue Injury ◽  
Post Translational Modification ◽  
Early Step ◽  
Calcium Dependent ◽  
Efficient Regeneration ◽  
Wound Responses ◽  
Histone Citrullination

AbstractCalcium signaling is an important early step in wound healing, yet how these early signals promote regeneration remains unclear. Peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes, catalyze citrullination, a post-translational modification that alters protein function and has been implicated in autoimmune diseases. We generated a mutation in the single zebrafish ancestral pad gene, padi2, resulting in a loss of detectable calcium-dependent citrullination. The padi2 mutants exhibit impaired resolution of inflammation and regeneration after caudal fin transection. Further, we identified a new subpopulation of cells displaying citrullinated histones within the notochord bead following tissue injury. Citrullination of histones in this region was absent and wound-induced proliferation was perturbed in Padi2-deficient larvae. Taken together, our results show that Padi2 is required for the citrullination of histones within a group of cells in the notochord bead, and for promoting wound-induced proliferation required for efficient regeneration. These findings identify Padi2 as a potential intermediary between early calcium signaling and subsequent tissue regeneration.SummaryGolenberg et al. developed a citrullination-deficient zebrafish and demonstrated a role for Padi2 in fin wound responses and regeneration. This work identified a distinct population of cells within the regenerative notochord bead that exhibited wound-induced histone citrullination.

Early redox, Src family kinase, and calcium signaling integrates wound responses and tissue regeneration in zebrafish

2012 ◽  
Vol 140 (5) ◽  
pp. i7-i7
Author(s):  
Sa Kan Yoo ◽  
Christina M. Freisinger ◽  
Danny C. LeBert ◽  
Anna Huttenlocher
Keyword(s):  
Calcium Signaling ◽  
Tissue Regeneration ◽  
Src Family Kinase ◽  
Wound Responses

scholarly journals Citrullination regulates wound responses and tissue regeneration in zebrafish

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Netta Golenberg ◽  
Jayne M. Squirrell ◽  
David A. Bennin ◽  
Julie Rindy ◽  
Paige E. Pistono ◽  
...  
Keyword(s):  
Wound Healing ◽  
Calcium Signaling ◽  
Tissue Regeneration ◽  
Protein Function ◽  
Tissue Injury ◽  
Post Translational Modification ◽  
Calcium Dependent ◽  
Early Signal ◽  
Efficient Regeneration ◽  
Wound Responses

Calcium is an important early signal in wound healing, yet how these early signals promote regeneration remains unclear. Peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes, catalyze citrullination, a post-translational modification that alters protein function and has been implicated in autoimmune diseases. We generated a mutation in the single zebrafish ancestral pad gene, padi2, that results in a loss of detectable calcium-dependent citrullination. The mutants exhibit impaired resolution of inflammation and regeneration after caudal fin transection. We identified a new subpopulation of cells displaying citrullinated histones within the notochord bead following tissue injury. Citrullination of histones in this region was absent, and wound-induced proliferation was perturbed in Padi2-deficient larvae. Taken together, our results show that Padi2 is required for the citrullination of histones within a group of cells in the notochord bead and for promoting wound-induced proliferation required for efficient regeneration. These findings identify Padi2 as a potential intermediary between early calcium signaling and subsequent tissue regeneration.

scholarly journals The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Robert G Hesse ◽  
Gayle K Kouklis ◽  
Nadav Ahituv ◽  
Jason H Pomerantz
Keyword(s):  
Tumor Suppressor ◽  
Tissue Regeneration ◽  
Tumor Suppressor Genes ◽  
Growth And Development ◽  
Human Tumor ◽  
Zebrafish Genome ◽  
Regenerative Capacity ◽  
Fin Regeneration ◽  
Epimorphic Regeneration ◽  
Proliferation And Differentiation

The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species’ regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF –p53 axis activation.

scholarly journals Redox and Src family kinase signaling control leukocyte wound attraction and neutrophil reverse migration

2014 ◽  
Vol 207 (5) ◽  
pp. 589-598 ◽  
Author(s):  
Sebastien Tauzin ◽  
Taylor W. Starnes ◽  
Francisco Barros Becker ◽  
Pui-ying Lam ◽  
Anna Huttenlocher
Keyword(s):  
Tissue Regeneration ◽  
Tissue Damage ◽  
Redox Signaling ◽  
Kinase Signaling ◽  
Src Family Kinase ◽  
Reverse Migration ◽  
Early Recruitment

Tissue damage induces early recruitment of neutrophils through redox-regulated Src family kinase (SFK) signaling in neutrophils. Redox-SFK signaling in epithelium is also necessary for wound resolution and tissue regeneration. How neutrophil-mediated inflammation resolves remains unclear. In this paper, we studied the interactions between macrophages and neutrophils in response to tissue damage in zebrafish and found that macrophages contact neutrophils and induce resolution via neutrophil reverse migration. We found that redox-SFK signaling through p22phox and Yes-related kinase is necessary for macrophage wound attraction and the subsequent reverse migration of neutrophils. Importantly, macrophage-specific reconstitution of p22phox revealed that macrophage redox signaling is necessary for neutrophil reverse migration. Thus, redox-SFK signaling in adjacent tissues is essential for coordinated leukocyte wound attraction and repulsion through pathways that involve contact-mediated guidance.

scholarly journals Two Different Transgenes to Study Gene Silencing and Re-Expression During Zebrafish Caudal Fin and Retinal Regeneration

2006 ◽  
Vol 6 ◽  
pp. 65-81 ◽  
Author(s):  
Ryan Thummel ◽  
Christopher T. Burket ◽  
David R. Hyde
Keyword(s):  
Tissue Regeneration ◽  
Transgene Expression ◽  
Egfp Expression ◽  
Transgenic Zebrafish ◽  
Retinal Regeneration ◽  
Caudal Fin ◽  
Fin Regeneration ◽  
Differentiated Cells ◽  
Neuronal Progenitors ◽  
Wound Epithelium

We used the 500-bpXenopusef1-α promoter and the 2-kb zebrafish histone2A.F/Zpromoter to generate several independent transgenic zebrafish lines expressing EGFP. While both promoters drive ubiquitous EGFP expression in early zebrafish development, they are systematically silenced in several adult tissues, including the retina and caudal fin. However, EGFP expression is temporarily renewed in the adult during either caudal fin or retinal regeneration. In the Tg(H2A.F/Z:EGFP)ntline, EGFP is moderately expressed in both the wound epithelium and blastema of the regenerating caudal fin. In the Tg(ef1-α:EGFP)ntline, EGFP expression is reinitiated and restricted to the blastema of the regenerating caudal fin and colabels with BrdU, PCNA, andmsxc-positive cells. Thus, these two ubiquitous promoters drive EGFP transgene expression in different cell populations during caudal fin regeneration. We further analyzed the ability of theef1-α:EGFPtransgene to label nonterminally differentiated cells during adult tissue regeneration. First, we demonstrated that the transgene is highly methylated in adult zebrafish caudal fin tissue, but not during fin regeneration, implicating methylation as a potential means of transgene silencing in this line. Next, we determined that theef1-α:EGFPtransgene is also re-expressed during adult retinal regeneration. Specifically, theef1-α:EGFPtransgene colabels with PCNA in the Müglia, a specialized cell that is the source of neuronal progenitors during zebrafish retinal regeneration. Thus, we concluded that Tg(ef1-α:EGFP)nt line visually marks nonterminally differentiated cells in multiple adult regeneration environments and may prove to be a useful marker in tissue regeneration studies in zebrafish.

Troxerutin down-regulates KIM-1, modulates p38 MAPK signaling, and enhances renal regenerative capacity in a rat model of gentamycin-induced acute kidney injury

2018 ◽  
Vol 9 (12) ◽  
pp. 6632-6642 ◽  
Author(s):  
Samir A. Salama ◽  
Hany H. Arab ◽  
Ibrahim A. Maghrabi
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
P38 Mapk ◽  
Tissue Regeneration ◽  
Rat Model ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Mapk Signaling ◽  
Regenerative Capacity

Troxerutin enhances renal tissue regeneration, improves renal function, and decreases renal tissue injury in gentamycin-treated rats.

scholarly journals The CXCL12/CXCR4 signalling axis retains neutrophils at inflammatory sites in zebrafish

2019 ◽  
Author(s):  
Hannah M. Isles ◽  
Kimberly Herman ◽  
Anne L. Robertson ◽  
Catherine A. Loynes ◽  
Lynne R. Prince ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Tissue Damage ◽  
Tissue Injury ◽  
Transgenic Zebrafish ◽  
Sequencing Data ◽  
Cxcr4 Antagonist ◽  
Reverse Migration ◽  
Zebrafish Larvae ◽  
Inflammation Resolution

AbstractThe inappropriate retention of neutrophils in the lung is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signalling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridisation and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signalling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signalling axis accelerates inflammation resolution, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signalling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.

scholarly journals A Morphological and Histological Investigation of Imperfect Lungfish Fin Regeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Vivien Bothe ◽  
Igor Schneider ◽  
Nadia B. Fröbisch
Keyword(s):  
Tissue Regeneration ◽  
Molecular Mechanisms ◽  
Limb Regeneration ◽  
Body Parts ◽  
Serial Sections ◽  
Fin Regeneration ◽  
X Ray ◽  
The Past ◽  
Great Progress ◽  
Made In

Regeneration, the replacement of body parts in a living animal, has excited scientists for centuries and our knowledge of vertebrate appendage regeneration has increased significantly over the past decades. While the ability of amniotes to regenerate body parts is very limited, members of other vertebrate clades have been shown to have rather high regenerative capacities. Among tetrapods (four-limbed vertebrates), only salamanders show unparalleled capacities of epimorphic tissue regeneration including replacement of organ and body parts in an apparently perfect fashion. The closest living relatives of Tetrapoda, the lungfish, show regenerative abilities that are comparable to those of salamanders and recent studies suggest that these high regenerative capacities may indeed be ancestral for bony fish (osteichthyans) including tetrapods. While great progress has been made in recent years in understanding the cellular and molecular mechanisms deployed during appendage regeneration, comparatively few studies have investigated gross morphological and histological features of regenerated fins and limbs. Likewise, rather little is known about how fin regeneration compares morphologically to salamander limb regeneration. In this study, we investigated the morphology and histology of regenerated fins in all three modern lungfish families. Data from histological serial sections, 3D reconstructions, and x-ray microtomography scans were analyzed to assess morphological features, quality and pathologies in lungfish fin regenerates. We found several anomalies resulting from imperfect regeneration in regenerated fins in all investigated lungfish species, including fusion of skeletal elements, additional or fewer elements, and distal branching. The similarity of patterns in regeneration abnormalities compared to salamander limb regeneration lends further support to the hypothesis that high regenerative capacities are plesiomorphic for sarcopterygians.

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