Regeneration in Invertebrates: Model Systems


The ability of animals to replace lost tissues or body parts has captured the imagination of humans for centuries. Animals with simple body parts, such as hydra and planarians, are able to re‐form complete organisms from small tissue fragments. Echinoderms such as sea urchins, starfish and sea cucumbers display a broad and diverse range of regenerative capacities that allows for the regeneration of lost organs, limbs or in some cases entire organisms. In contrast, arthropods (insects and crustaceans), which have been the most amenable invertebrates to genetic manipulation, are more limited in regenerative potential but can still faithfully regenerate complex structures of the limb. The diverse modes and capacities for regeneration in invertebrates and the advent of molecular tools to inhibit gene function and study genome‐wide changes in gene expression associated with tissue repair provide outstanding opportunities for scientists to decode the cellular and molecular underpinnings of regeneration. Here we provide an overview of prominent invertebrate organisms that are interesting models to investigate stem cell biology, cellular reprogramming and regeneration.

Key Concepts

  • Regeneration is the regrowth of lost tissues and body structures.
  • The ability to (and extent of) regeneration is diverse and distributed across many phyla and cannot necessarily be predicted by phylogenic relationships.
  • Regeneration broadly consists of four phases: wound healing, generation of proliferating cells, cell differentiation and tissue remodelling.
  • The two dominant modes of regeneration are epimorphosis, where proliferation occurs prior to differentiation, and morphallaxis, where existing tissue is re‐proportioned via transformation to restore lost body parts. Importantly, these processes are not exclusive and may occur concurrently.
  • Wound healing consists of muscle contractions and epidermal cell spreading that work together to limit further damage. In contrast to non‐regenerative organisms, this process does not involve the creation of scar tissue.
  • Crucial to epimorphic regeneration is the formation of a blastema. A blastema is a growing mass of undifferentiated cells that will eventually re‐form lost tissues.
  • Blastemal cells rely on positional cues to differentiate into proper tissues with the appropriate higher order organisation. These cues are often similar to those guiding embryonic development and consist largely of chemical morphological gradients and cell–cell signalling factors.
  • New techniques to manipulate gene expression including RNAi‐mediated gene knockdowns, targeted transgenesis using CRIPSR/Cas nucleases and transcriptomic profiling (even at single‐cell resolution) are helping to provide insights into the molecular mechanisms underlying regeneration.

Keywords: regeneration; epimorphosis; stem cells; blastema; morphogen; patterning

Figure 1. (a) A simplified illustration of a phylogenetic tree denoting diverse animal phyla in which regeneration has been observed (blue boxes). For additional information see: Dunn CW et al. (2014) Annu ev Ecol Syst 45: 371–395 and Sánchez Alvarado A and Tsonis PA. (2006) Nat Rev Genet 7: 873–884. (b) Examples of current invertebrate models of regeneration from pre‐bilaterians (Cnidaria: the colonial hydroid Hydractinia echinata), deuterostomes (Echinodermata: the sea cucumber Holothuria glaberrima), and protostomes (Platyhelminthes: the freshwater planarian Schmidtea mediterranea; Arthropoda: the crustacean Parhyale hawaiensis). Photos credits: H. echinata, Uri Frank; H. glaberrima, Vladimir Mashanov and José García‐Arrarás; P. hawaiensis, Alvina Lai.
Figure 2. Steps in regeneration and blastema formation in animals. Wounding or tissue loss triggers a wound healing response regardless of an animal's regenerative capacity. Following wound healing, signals from the wound site and pre‐existing tissues trigger a regenerative response that involves remodelling of tissues and a proliferative and migratory response of resident stem cells (top). Another mechanism involves proliferation of stem cells and the dedifferentiation or transdifferentiation of cells adjacent to the wound (bottom). In either scenario, proliferating cells ultimately generate the missing tissues that are integrated with pre‐existing tissues and then remodelled to achieve the appropriate pattern or scale. Adapted from: Sanchez Alvarado A and Tsonis PA. (2006). © US National Library of Medicine National Institutes of Health.
Figure 3. Illustration of a freshwater planarian cut at different body levels (grey dashed lines) to depict the role of canonical Wnt signalling in anterior to posterior body patterning during regeneration. Genes that express inhibitors of Wnt signalling (e.g. notum and sFRP‐2) are expressed in discrete cells located in the anterior pole or in a decreasing gradient along the A–P axis. Certain Wnt genes are expressed in the posterior pole of the animal (e.g. wnt1 and wnt11‐2). These patterns of expression are quickly re‐established in regenerating animals. Remarkably, decreasing Wnt signalling activity using RNAi leads to incorrect A–P patterning (e.g. the formation of ectopic heads or tails). Adapted from: Adell T, Cebria F and Salo E. (2010) © US National Library of Medicine National Institutes of Health.
Figure 4. Intercalation of positional values by growth in the regenerating cockroach leg. Left panels: a distally amputated tibia (positional value 5) grafted to a proximally amputated host (positional value 1) induces, regardless of the proximodistal orientation of the graft, the intercalation of the positional values 2–4. A normal tibia is regenerated. Right panels: a proximally amputated tibia (positional value 1) grafted to a distally amputated host (positional value 4) regenerates a longer than normal tibia with reversed polarity as judged by the orientation of surface bristles. The reversed orientation of regeneration is due to the reversal in positional value gradient. The proposed gradient in positional value is shown after each figure. Reproduced with permission from Wolpert and Tickle (2010) © Oxford University Press.


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Further Reading

Adell T, Cebrià F and Saló E (2010) Gradients in planarian regeneration and homeostasis. Cold Spring Harbor Perspectives in Biology 2: a000505.

Dunn CW, Giribet G, Edgecombe GD, et al. (2014) Animal phylogeny and its evolutionary implications. Annual Review of Ecology, Evolution, and Systematics 45: 371–395.

Elliott SA and Sánchez Alvarado A (2013) The history and enduring contributions of planarians to the study of animal regeneration. Wiley Interdisciplinary Reviews: Developmental Biology 2: 301–326.

Ferretti P and Géraudie J (1998) Cellular and Molecular Basis of Regeneration: From Invertebrates to Humans. Chichester, England: John Wiley & Sons.

Gilbert SF (2013) Postembryonic development: metamorphosis, regeneration, and aging. Developmental Biology. Sunderland, MA: Sinauer Associates, Inc..

Goff R (1969) Principles of Regeneration. New York: Academic Press.

Gold DA and Jacobs DK (2013) Stem cell dynamics in Cnidaria: are there unifying principles? Development Genes and Evolution 223: 53–66.

Jeffery WR (2015c) Closing the wounds: one hundred and twenty five years of regenerative biology in the ascidian Ciona intestinalis. Genesis 53: 48–65.

Jeffery WR (2015d) The tunicate: a model system for understanding the relationship between regeneration and aging. Invertebrate Reproduction and Development 59: 17–22.

King RS and Newmark PA (2012) The cell biology of regeneration. Journal of Cell Biology 196: 553–562.

Poss KD (2010) Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature Reviews Genetics 11: 710–722.

Sánchez Alvarado A and Tsonis PA (2006) Bridging the regeneration gap: genetic insights from diverse animal models. Nature Reviews Genetics 7: 873–884.

Tanaka EM and Reddien PW (2011) The cellular basis for animal regeneration. Developmental Cell 21: 172–185.

Wolpert L and Tickle C (2010) Limb and organ regeneration. Principles of Development. Oxford, England: Oxford University Press.

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Allen, John M, Ross, Kelly G, and Zayas, Ricardo M(May 2016) Regeneration in Invertebrates: Model Systems. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001095.pub2]