regeneration in nature

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Epimorphic regeneration in Nematostella and the use of the terms “epimorphosis” and “morphallaxis” in regeneration

In a recent paper Passamaneck and Martindale show that cell proliferation is necessary for  regeneration in Nematostella ( By blocking cell proliferation the authors are able to block also regeneration, suggesting that contrary to what it has been described in Hydra, Nematostella does not appear to have any other compensatory mechanism to allow regeneration in a context of no proliferation. This finding is relevant because it shows how different cnidarian species may use very different modes of regeneration based on the classically used terms of “epimorphosis” and “morphallaxis”.

Originally, in 1901 Thomas H. Morgan wrote that “… there are known two general ways in which regeneration may take place, although the two processes are not sharply separated, and may even appear combined in the same form. In order to distinguish broadly these two modes I propose to call those cases of regeneration in which proliferation of material precedes the development of the new part, epimorphosis. The other mode, in which a part is transformed directly into a new organism, or part of an organism without proliferation at the cut surfaces, morphallaxis”. Based on this definition it appears that when regeneration requires proliferation then it would be epimorhic regeneration, whereas regeneration in the absence of proliferation would be morphallactic. A more updated use of the term “epimorphic” includes also the definition by Richard J. Goss (The natural history (and mistery) of regeneration, 1991. In A History of Regeneration Research. Milestones in the evolution of a science, Ed. C.E. Dinsmore) and that states that “Epimorphic regeneration refers to the regrowth of amputated structures from an anatomically complex stump”, and that “The first event in epimorphic regeneration is the development of a blastema, or regeneration bud, derived from dedifferentiated cells, out of which the new structure will take shape”. So, the consensus is that epimorphic regeneration requires proliferation and the formation of a blastema. But not all blastemas are derived from dedifferentiated cells as stated in Goss definition. That is valid, for instance, for amphibian limb regeneration. But in planarians, regeneration occurs mainly by cell proliferation and the formation of a blastema that is derived from adult pluripotent stem cells and not after dedifferentiation.

But whereas the idea of epimorphic regeneration is quite well-established it cannot be said probably the same for the term of “morphallaxis”. Thus, Hydra has been usually used as an example of “morphallactic” regeneration because it has been know for many years that they can regenerate in the absence of proliferation or without a significant contribution of this proliferation. However, in 2009 the laboratory of Brigitte Galliot showed that in Hydra, and after midgastric bisection, head regeneration depends on an initial apoptotic response below the wound that triggers a proliferative zone with “blastema-like” features that significantly contributes to oral regeneration ( So, in that particular context regeneration seems to be “epimorphic”. As Morgan already said in his definitions, both processes, epimorphosis and morphallaxis, are not mutually exclusive. A good example of that are freshwater planarians that have been considered to follow a mixed epimorphic/morphallactic mode of regeneration. The basis of that is that in addition to the fundamental role of pluripotent stem cells in giving rise a regenerative blastema where the missing structures are formed, there is also a remodeling of the pre-existing tissues far away from the wound that help to attain the proper body proportions during regeneration. This remodeling, considered as morphallactic, is more evident in for example in head and tail pieces regenerating a new whole planarian. Thus, if you start with a big head piece containing a big brain it regenerates not only the whole body posterior to this head (through proliferation, blastema formation and growth of the regenerated part) but at the same time the original head with its brain go through an extensive remodeling so they decrease significantly in size in order to form a smaller planarian with perfect body (head/trunk/tail) proportions. So, following Morgan’s definition of morphallaxis at the beginning of this post literally, this remodeling would not require proliferation. However, a paper from the laboratory of Alejandro Sánchez-Alvarado on the temporal and spatial dynamics of Wnt genes expression during planarian regeneration shows that “… although pre-existing cells can assess their new A/P position in the absence of stem cells, anatomical tissue remodeling in planarians depends on the presence of stem cells” ( Therefore, this data would point out that “morphallaxis” could depend somehow also on proliferation.

To solve this apparent conflict one possibility could be to restrict the term of “morphallaxis” to the first definition given by the same Morgan in 1898 in which he wrote: “Thus, the relative proportions of the planarian are attained by a remodeling of the old tissue. I would suggest that this process of transformation be called a process of morpholaxis”. Then, “morphallaxis” can be clearly associated to “remodeling of the pre-existing tissues” and this would be “proliferation dependent” or “proliferation-independent” depending on the organism (planarian/Hydra) or the specific context of regeneration.

Lens regeneration in axolotl and need for comparative studies

Two of the interesting issues on the field of regeneration are why closely related species show very distinct regenerative capacities and why some species can regenerate certain organs or structures only during specific developmental stages. Therefore, detailed comparative analyses are fundamental to answer those questions which could help to enhance the poor regenerative power showed by many species. Axolotls are a classical model for limb and tail regeneration; however, lens regeneration was supposed not to happen in these animals. This was in contrast to other amphibians such as newts and frogs. Newts can regenerate their lens no matter their age and as many times as needed; frogs can also regenerate the lens but only at pre-metamorphic stages. Another difference among newts and frogs is that whereas in newts the lens regenerates from the dorsal iris epithelium by transdifferentation, in frogs it regenerates from the cornea (also through transdifferentiation). Now a paper from the laboratory of Panagiotis Tsonis has described that axolotls can in fact regenerate the lens but only during a specific developmental period ( At stage 44 and during about two weeks, lens regeneration is permissive. Moreover, the new lens can regenerate either from the dorsal or ventral iris epithelium. Thus, we have an example of three amphibian species that show different levels of plasticity and strategies for lens regeneration. A possible next step could be then to compare the permissive and non-permissive stages for axolotl lens regeneration at gene expression and cellular levels, for instance, to determine why regeneration can take place at that particular time.

This comparative approach is also stimulated in the commentary by Ashley Seifert and S Randal Voss on the paper by P. Tsonis ( and that highlights the known relationship between loss of regenerative capabilities and aging. An extreme and surprising example of that is the fact that mice up to about one week old are capable of regenerating their heart, but thereafter regeneration capacity is completely lost. But aging is not the only factor to consider when addressing the loss of regenerative capabilities shown in nature. As pointed out by Seifert and Voss, evolution, life history, physiology and ontogeny are important factors to take in account. Finally, it would become also important to search for novel models of regeneration in order to analyze and compare different mechanisms and strategies for regeneration. In this sense the finding that the African spiny mice can regenerate the skin ( means that some mammals retain higher regenerative capabilities that thought.

Gordon research Conference on Tissue Repair & Regeneration

The next Gordon Research Conference on Tissue Repair & Regeneration will be held in Colby-Sawyer College, New London, NH on June 16-21, 2013. Application deadline, May 19, 2013. For more information and registration visit the website:

follistatin and notum as organizer signaling center for planarian anterior regeneration

Following up with my previous post on polarity reestablishment during planarian regeneration a recent paper from the laboratory of Phil Newmark ( reports that follistatin through antagonizing activin signaling and together with notum and the Wnt/β-catenin pathway plays an importat role during anterior regeneration. As the authors state although increasing information is being reported about the key role of different signaling pathways in establishing axial polarity during regeneration less data addresses the issue of whether organizing centers somehow equivalent to the organizers that control body patterning during embryonic development, are conserved during planarian regeneration. Under this perspective, this study provides evidence that in planarians an organizing center based on the action of follistatin and notum would be functioning to determine anterior identity. Therefore, this study clearly suggests that conserved organizing signaling centers (based on the interaction between the BMP and Wnt/β-catenin activities) may play similar functions during body patterning along the axis in both embryonic development and regeneration. In the case of planarians further studies should determine whether and how the follistatin and notum signaling directly interact to each other at the molecular level, as well as whether and how regulate morphogenesis and cell fate beyond their role in polarity.

pbx genes on pole regeneration in planarians

One of the main questions to address during regeneration is to determine how polarity is re-established. By “polarity” meaning that an anterior-facing wound will regenerate the missing anterior structures whereas a posterior-facing wound will regenerate the missing posterior structures. For instance, just think in planarians: if you amputate an animal in 3 pieces: head, trunk and tail, the head piece will regenerate posterior trunk and tail, the trunk piece will regenerate a new head in the anterior-facing wound and a tail in the posterior-facing wound and, finally, the tail piece will regenerate new anterior trunk and head. In recent years it has been shown how the establishment of AP polarity in planarians mainly depends upon the activity of the Wnt/β-catenin pathway. Thus, the silencing of β-catenin leads to the conversion of any posterior blastema into an anterior fate and, conversely, an ectopic activity of β-catenin results in the conversion of any anterior blastema into posterior ones. That means, that multi-headed planarians can be generated after β-catenin knockdown and multi-tailed planarians develop after ectopic expression of β-catenin [Iglesias et al. (2008) Development 135: 1215-1221; Gurley et al. (2008) Science 319: 24-39; Petersen and Reddien (2008) Science 319: 327-330]. Subsequent studies have shown that the Hedgehog (Hh) pathway contributes also to the establishment of AP polarity being required for posterior identity [Rink et al. (2009) Science 326: 1406-1410; Yazawa et al. (2009) PNAS 106: 22329-22334]. Now, two papers in Development from the laboratories of Aziz Aboobaker ( and Peter Reddien ( characterize the function of a planarian pbx gene (a TALE-class homeodomain protein) that is required for the regeneration of both poles, anterior and posterior. Previous works have characterized genes that block either anterior or posterior pole regeneration [Felix and Aboobaker (2010) PLoS  Genet 6: e1000915; Hayashi et al. (2011) Development 138: 3679-3688], but pbx represents the first example of a gene required for the regeneration of both poles. In both papers the authors show a significant reduction or complete absence of patterning genes that determine or are specific markers of anterior and posterior poles. Apparently, regeneration polarity would not be completely ablated after pbx silencing but the further development and patterning of those anterior and posterior poles would be in fact blocked. Further experiment should try to determine how pbx could be interacting with different partners at both poles in order to allow the regeneration of specific anterior and posterior tissues and structures.

Scientific Meeting

The 2nd European Meeting on Planarian Biology will be held in Dresden (Germany) on September 1-4 2013. More information at

Welcome to this blog on animal regeneration

This blog aims to share and discuss the latest news on animal regeneration

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