Regeneration in Hydra


Hydra freshwater polyps have a remarkable ability to regenerate after bisection or even after dissociation, and thus offer a unique model system to investigate the cellular and molecular basis of eumetazoan regeneration. From a single cut along the body column two different types of regeneration arise: foot regeneration from the apical part and head regeneration from the basal part. The high proportion of stem cells in the Hydra body column supports these fast and efficient processes. Grafting experiments proved that the gastric tissue in the head‐regenerating tip rapidly develops a de novo organising activity, as evidenced by the induction of an ectopic axis when transplanted onto a host. The molecular mechanisms involved in this transformation rely on the immediate activation of the mitogen activated protein kinase (MAPK) pathway and the subsequent activation of the canonical Wnt3 pathway. This early phase is followed by a patterning phase, when head regeneration requires de novo neurogenesis.

Key Concepts:

  • Hydra is a bilayered freshwater solitary polyp that belongs to Cnidaria, a phylum that also includes jellyfish, sea anemones and corals. Cnidaria as sister group to bilaterians, belongs to Eumetazoa, that is, all animals that have a differentiated gut and nervous system.

  • Hydra tissues contain three distinct stem cell populations that continuously cycle but cannot replace each other. The ectodermal and endodermal myoepithelial cells are differentiated cells that are also unipotent stem cells. These cells that cycle rather slowly provide all epithelial cells; however, these two lineages cannot replace each other. By contrast, the third lineage is multipotent, that is, the interstitial stem cells that cycle much faster (every 24–30 h) and provide nerve cells, nematocytes, gland cells as well as germinal cells.

  • Head regeneration requires a complex 3D reconstruction when foot regeneration appears much simpler, similar to tissue repair.

  • Head regeneration relies on a head organising activity that develops in several hours after bisection from the gastric tissue in the regenerating tip. This activity can be quantified at every time point of the regenerative process by lateral transplantation.

  • Successive waves of gene and protein regulations characterise each phase of head regeneration: immediate, early, early‐late and late. The immediate activation of the MAPK/RSK/CREB pathway followed by the early activation of the Wnt3 pathway participates in the establishment of the head organising activity.

  • After midgastric bisection, activation of the MAPK pathway leads to injury‐induced apoptosis of the interstitial cells, a cellular event that initiates head regeneration by activating the Wnt3 pathway in interstitial progenitors and subsequently in endodermal epithelial cells.

  • Head regeneration in Hydra is highly plastic, as it is maintained, although at a slower pace, when cell cycling is transiently inhibited or slowed down in the early phase of head regeneration. This suggests that cell proliferation is not essential for Hydra regeneration, at least during the early phase, a condition named morphallaxis.

  • Interstitial cycling cells play an important role at the early phase of head regeneration: those located at the tip receive signals from the apoptotic cells and rapidly divide, whereas those located more distantly migrate towards the wound. Both processes lead to the formation of a dense zone of progenitors in the regenerating tip.

  • Head regeneration in Hydra is highly plastic, as it is maintained after elimination of the interstitial cell lineage, indicating that epithelial cells alone can drive the head regeneration process efficiently although with a significant delay.

  • Since 2002, transgenic strategies were successfully developed in Hydra, allowing first the transient expression of reporter constructs, and since 2006 the establishment of stable transgenic lines.

Keywords: freshwater cnidarian; morphogenesis; head organiser; transplantation experiments; multipotent stem cells; plasticity of regenerative processes; MAPK/CREB signalling pathway; Wnt3/β‐catenin signalling pathway; injury‐induced cell death

Figure 1.

Diagram illustrating the anatomy and cell lineages of a Hydra. (a) Anatomy of an adult Hydra polyp (left) and enlarged view showing its bilayered tissue organisation in the body column (right). Reproduced after modifications with permission from Lenhoff and Lenhoff (). © Scientific American. (b) The different cell types in Hydra arise from three distinct stem cell populations (written in red), either multipotent as the interstitial stem cells located in the ectodermal layer (right), or unipotent as the myoepithelial stem cells located either in the endodermal (left) or ectodermal (right) layers. These stem cell populations that cannot replace each other, cycle at different paces, every 24–30 h for the interstitial cells, every 3–4 days for the myoepithelial cells. Reproduced with permission from Chera et al.. © 2011 The Authors.

Figure 2.

The developmental programme is never locked in Hydra. (a) In adult polyps, active patterning processes are maintained through the coupling of differentiation and migration of cells located in the body column towards the extremities. (b) Asexual reproduction through budding is allowed to occur only in the lower part of the gastric column. (c and d) Apical or basal regeneration is observed either after bisection of the animal (c) or on reaggregation after complete dissociation of the Hydra tissues into single cells (d). In (c) the time necessary to rebuild the amputated structure depends on the level of the bisection: in Hydra vulgaris, the apex is regenerated in approximately 3 days and basal region in 1.5 days after midgastric section. Note, the head regenerating half the emergence of tentacle rudiments approximately 2 days after bisection (third image from the left at the bottom). (e) Sexual development is required for survival in less temperate natural conditions.

Figure 3.

Organising activities in intact and regenerating Hydra. (a) Intact Hydra maintain their shape thanks to two organisers, located at the apical (red) and basal (red) extremities. Upon bisection the head organiser is rapidly reestablished in the head‐regenerating tip. (b) Lateral grafting procedure to measure the presence of organising activity in heads‐regenerating tip as initially established by Browne (). (c) Level of apical‐organiser activity deduced from the observed rate of secondary head induction in the host upon transplantation of the regenerating tip (according to MacWilliams, ). The red bracket indicates the period when the organising activity is not established yet. Reproduced with permission from Galliot (). © Springer.

Figure 4.

Landmarks for cellular and molecular remodelling during Hydra head regeneration. (a) Level of apical‐organiser activity deduced from the observed rate of secondary head induction in the host upon transplantation of the regenerating tip (according to MacWilliams, ). Two distinct components were characterised. The first one, restricted to the tip region (no gradient), is detected even in absence of nerve cell differentiation, and decays over 18 h. The second one, measured as a gradient having its maxima in the tip, relies on differentiation of new nerve cells, and is still detectable after 48 h, by which time the new head had emerged. During the postcutting inhibition period, no induction of secondary head is observed. (b) Successive cellular phases displayed by head‐regenerating tip from midgastric amputation up to apical regeneration. Arrows represent the amputation plane. The ectodermal myoepithelial cells are drawn in white with light‐blue nuclei. The interstitial stem cells and progenitors as nematoblasts are depicted as green dots in the ectoderm. Under the bisection plane immediately after bisection these cells undergo apoptosis (depicted as irregular reddish cells in the bisection plane). The endodermal myoepithelial cells are digestive cells at the time of bisection (elongated, dark grey with red nuclei), which then transiently lose their epithelial organisation (roundish, blue/green nuclei) at the time they engulf the apoptotic bodies. Concomitantly, they develop an organising activity (blue nuclei) and progressively regain their original epithelial organisation (Chera et al., ). A similar transient loss of epithelial organisation also takes place during the early phase of regeneration after reaggregation (Murate et al., ). Tentacle buds become visible after 40 h, whereas the hypostome (dome surrounding the mouth opening) is being formed. (c) Molecular signalling at work during head regeneration: For each phase, genes (italic, light backgrounds) or proteins (regular, denser backgrounds) that are specifically upregulated are indicated with a colour code according to the cell lineage where they are expressed: epithelial endodermal (green), epithelial ectodermal (blue) and interstitial cells (yellow). Genes/proteins tested in functional assays are underlined. Post‐translational modifications are observed immediately after cutting (see Figure ). As observed for the development of organising activity in transplantation experiments, the timing of gene and protein regulation depends on the position of the section along the body column. Adapted with permission from Galliot et al.. © Elsevier.

Figure 5.

Immediate injury‐induced signalling after midgastric bisection in head‐regenerating tips. Interstitial cells that undergo apoptosis in the bisection plane (top) are represented in red, epithelial cells that engulf apoptotic bodies are depicted in blue. The interstitial cells (i‐cell) located either in the vicinity of the apoptotic zone and thus submitted to the WNT3 signals produced by the apoptotic cells, or at lower levels and migrating towards the wound are depicted in green. From 4 h postbisection, those i‐cells rapidly divide, whereas the adjacent epithelial cells upregulate Wnt3 expression. The injury signals that activate the MAPK in the head‐regenerating tips are currently unknown. After few hours Wnt3 is upregulated in the endodermal epithelial cells (e‐cells), this does not take place when apoptosis is inhibited suggesting some activation by the signals released by the dying cells, including Wnt3 (Chera et al., ). Scheme courtesy of Silker Reiter. © Silker Reiter.



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Further Reading

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Sarras MP Jr, Yan L, Leontovich A and Zhang JS (2002) Structure, expression, and developmental function of early divergent forms of metalloproteinases in Hydra. Cell Research 12: 163–176.

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Galliot, Brigitte(Nov 2013) Regeneration in Hydra. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001096.pub3]