Initiating a regenerative response; cellular and molecular features of wound healing in the cnidarian Nematostella vectensis

Abstract

BackgroundWound healing is the first stage of a series of cellular events that are necessary to initiate a regenerative response. Defective wound healing can block regeneration even in animals with a high regenerative capacity. Understanding how signals generated during wound healing promote regeneration of lost structures is highly important, considering that virtually all animals have the ability to heal but many lack the ability to regenerate missing structures. Cnidarians are the phylogenetic sister taxa to bilaterians and are highly regenerative animals. To gain a greater understanding of how early animals generate a regenerative response, we examined the cellular and molecular components involved during wound healing in the anthozoan cnidarian Nematostella vectensis.ResultsPharmacological inhibition of extracellular signal-regulated kinases (ERK) signaling blocks regeneration and wound healing in Nematostella. We characterized early and late wound healing events through genome-wide microarray analysis, quantitative PCR, and in situ hybridization to identify potential wound healing targets. We identified a number of genes directly related to the wound healing response in other animals (metalloproteinases, growth factors, transcription factors) and suggest that glycoproteins (mucins and uromodulin) play a key role in early wound healing events. This study also identified a novel cnidarian-specific gene, for a thiamine biosynthesis enzyme (vitamin B synthesis), that may have been incorporated into the genome by lateral gene transfer from bacteria and now functions during wound healing. Lastly, we suggest that ERK signaling is a shared element of the early wound response for animals with a high regenerative capacity.ConclusionsThis research describes the temporal events involved during Nematostella wound healing, and provides a foundation for comparative analysis with other regenerative and non-regenerative species. We have shown that the same genes that heal puncture wounds are also activated after oral-aboral bisection, indicating a clear link with the initiation of regenerative healing. This study demonstrates the strength of using a forward approach (microarray) to characterize a developmental phenomenon (wound healing) at a phylogenetically important crossroad of animal evolution (cnidarian-bilaterian ancestor). Accumulation of data on the early wound healing events across numerous systems may provide clues as to why some animals have limited regenerative abilities.

Reconsidering regeneration in metazoans: an evo-devo approach

“…Such responses are tightly bound to some sort of "immune response, " i.e., the infiltration in the wound area of immune cells. This varies between organisms, and ranges from the transient intervention of amoeboid cells in cnidarians to the complex adaptive immune response of vertebrates (Kawakami and Nakanishi, 2001;Eming et al, 2009;Nakanishi et al, 2011;Palmer et al, 2011;Gold and Jacobs, 2013;Dubuc et al, 2014;Wenger et al, 2014). The relationship between wound healing, particularly the immune response phase, and the regenerative event is not clear, and is probably not a conserved feature (see next section).…”

Regulation of AP-1 by MAPK Signaling in Metal-Stressed Sea Anemone

“…In Cnidaria, AP-1 was suggested to mediate stress responses such as upon elevation in seawater temperature and injury as well as exposure to heavy metals, which we previously showed to affect fos transcript [25, 26, 28, 54]. Here, we show the involvement of MAPKs in the regulation of AP-1 transcripts fos1 and jun1 in the presence of Hg.…”

“…Anemones were exposed to HgCl 2 at a concentration of 200 µg/L (0.74 µM) in 10 ml medium for 1, 6 and 24 h and compared to control untreated anemones. The kinase inhibitors were reported to display high sequence specificity and are widely used in different organisms including, to some extent, in Nematostella [26, 30-33]; however, their specificity in Nematostella has not yet been established. Kinase inhibitors dissolved in DMSO or only DMSO (control) were added two hours before the introduction of Hg.…”

“…Among our findings, we have identified rapid activation of several immediate-early response genes such as the transcription factors early growth response1 ( egr1 ) and fos . Furthermore, fos transcript was shown to be up-regulated by injury in Nematostella [26], during head regeneration in Hydra and during metamorphosis of coral larvae [27-29]. …”

Integrin suppresses neurogenesis and regulates brain tissue assembly in planarian regeneration

“…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.…”