A wide range of distinct biological processes contribute to the preservation of the anatomical form and functionality in adult animal organisms; these processes are acting at different levels, such as metabolism that affects the whole organism, cell turnover of organs and tissues, autophagy of specific cell types, DNA repair at the nuclear level (Rando, 2006). As human beings, we often consider that a high cell turnover is an obligatory rule to maintain the integrity of adult organisms. However, this is certainly not systematically observed across animal phyla as several species with short lifespan can be strictly post-mitotic after development, meaning that the differentiated cells can undergo cell growth but no proliferation during adulthood. The nematodes that keep their number of somatic cells constant in adulthood, provide the best example; similarly, in Drosophila all somatic adult tissues are post-mitotic except the gut. This drastic regulation of adult cell number generally impedes adult plasticity, which is required for homeostatic or regenerative mechanisms. However, in most metazoan species, the main way to protect adult organisms from physiological dysfunctions involves the removal and replacement of old or damaged differentiated cells. This ongoing physiological replacement process is named cell turnover. The adult stem cells (ASCs) play a key role in this turnover, although limited to the organ or the tissue where they reside (Wagers and Weissman, 2004; Ohlstein and Spradling, 2006; Blanpain et al., 2007). As a classical scenario, ASCs divide through asymmetric division, with one of the daughter cells keeping the “stemness” status (self-renewal) whereas the second one, no longer a stem cell, undergoes a series of cell division, providing a transient amplifying stock that will subsequently commit to one or a series of differentiated fates (Raff, 2003). As a consequence three competitive processes regulate homeostasis: cell death, cell proliferation, and cell differentiation. The study of their crosstalk in Drosophila imaginal discs showed how a coordinated cell–cell signaling tightly regulates this competition in a given tissue (Moreno and Basler, 2004). In mammalian tissues, cell turnover occurs in epidermis, intestine, lung, blood, bone marrow, thymus, testis, uterus, and mammary gland with large variations in the rate of cell turnover, from few days for the intestinal epithelium up to several months for the lung epithelium (Blanpain et al., 2007). In other organs (brain, heart, pancreas, kidney, cornea, etc.), the physiological cell turnover is likely limited and/or very slow, making difficult the in vivo monitoring of the respective behaviors of stem cells and dying cells.
Similar to cell turnover, tissue repair also allows tissue replacement but requires the damage-induced activation of programs that monitor cell proliferation and cell differentiation. Finally, regeneration of anatomical structures like appendages, represent an even more complex process with formation of a transient proliferative structure, the blastema, and activation of a developmental program that leads to restoration of original shape and function (Brockes and Kumar, 2005). Both tissue repair and regeneration that affect different tissue types and require cell replacement on a large-scale, are triggered by nonspecific and usually exogenous damage, whereas cell turnover is a process that is endogenously initiated and restricted to a fraction of cells (Pellettieri and Sanchez Alvarado, 2007).
Nevertheless one can intuitively perceive a progression from basic tissue self-renewal to tissue repair, reached by some but not all organs, to regeneration, accessed by a “happy few” elite of organs or structures. This view suggests a possible continuum between the processes that regulate each step, even though their complexity is supposed to gradually increase. To challenge the solidity of this view, we review some results recently obtained in the paradigmatic Hydra model system. But before considering the different forms of plasticity deployed in Hydra, we will first discuss the origin and the current meaning of the concept of plasticity. Indeed, this concept is widely used by biologists from different fields, but sometimes covering quite distinct meanings.
The Ambiguities of the Concept of “Plasticity”
The word “plasticity” (from Latin plasticus or Greek plastikos, ability to mold) refers to the “capacity of distortable bodies to change their shape under the action of an external force and to maintain the change after this force has ceased to act” (from Littré French dictionary, translated by Will et al., 2008). At the first look, this definition apparently applies quite well to the regenerative process, however, the usage of the word plasticity in biology is much broader, focusing on the ability of living organisms to adapt to constraints by changing their organization at a specific level, for example, evolutionary, developmental, phenotypic, synaptic, cellular, and molecular. As a consequence, the word “plasticity” should never be used alone but always be specified by the level where it applies (Pomerantz and Blau, 2004). Some scientists even proposed to apply to the concept of plasticity in biological systems a more “engineer-oriented” usage, restricting it to the contexts where lasting structural reorganization, that is, modifications of the material structure of the system (interface, connectivity network, constitutive elements), are indeed proven, leaving out of plasticity the effects of variability, flexibility, systematic variations, and vicarious (substituted) processes as these effects rather result from “operational” than structural changes (Will et al., 2008). We selected here few examples to discuss this view, certainly more rigorous or at least less metaphoric (following the words of Will et al., 2008) but as we will see, difficult to apply in some contexts.
Evolutionary plasticity is certainly the best example of plasticity with structural changes leading to lasting changes. The combination of genomic, genetic, and developmental approaches over the past 20 years have definitively proven that variations in the genomic organization of the Hox gene clusters obviously lead to genetic reprogramming during development and to species-specific modifications of the body plan (Duboule, 2007). Developmental plasticity that was identified first in sea urchin embryos by Driesch in 1892, and later in vertebrate embryos, refers to the embryonic potential for regulation as the embryonic cells at early stages have the ability to change their fate to compensate for cell loss (Driesch, 1900). This potential, which accounts for the occurrence of homozygous twins, is transient but can still be observed at later stages in more specialized tissues as limb buds (Summerbell, 1981) or neural crest cells (Vaglia and Hall, 1999). Developmental plasticity, more recently named transfating (Keleher and Stent, 1990), requires the activation of the gene regulatory network (GRN) that corresponds to the new cell fate. Interestingly, in sea urchin embryo this activation apparently depends on inputs that are distinct during normal and regulative developments (Ettensohn et al., 2007). If confirmed as a general rule, this would mean that context-specific signals sensed at the “interface” of the system induce long-lasting structural reorganizations of the developing organism.
Phenotypic plasticity is “the property of a given genotype to produce different phenotypes in response to distinct environmental conditions” (Metcalf, 1906), with the first study of adaptive phenotypic plasticity described in the crustacean Daphnia. However, the different phenotypes might reveal an intrinsic “repertoire of competences” that need no structural changes to be expressed (Will et al., 2008). In the same year, 1906, the term neuroplasticity was proposed by Ernesto Lugaro, a psychiatrist, who referred to the changes in neural activity during psychic maturation, learning processes, or post-damage recovery (Berlucchi, 2002). During the first half of the 1900s, the concept of brain plasticity was rejected by the scientific community, as it was unanimously accepted that the fully developed brain reached stability at adulthood, each region of the brain performing specific function(s) that could not be modified. In the 1960s, this view started to be challenged by experiments proving activity-dependent brain plasticity (Bennett et al., 1964; Bach-y-Rita et al., 1969). Synaptic plasticity, the capability for a neuron to modify on the long term its electrophysiological activity according to the stimuli it had received, was first studied in the mollusk Aplysia (Bruner and Tauc, 1965; Kandel and Tauc, 1965). The choice of this model system was instrumental to establish the importance of plasticity in the learning and memory processes as persistent modifications of the activity of the genetic circuitry are required to sustain changes in neurophysiological activity (Barco et al., 2006).
Cellular plasticity is directly related to the questions addressed in this review, that is, what conditions of tissue homeostasis support a regenerative response. For this reason, we will discuss here only the cellular plasticity of somatic cells (Fig. 1). As a first but rather rare strategy differentiated cells can re-enter the cell cycle after injury, as exemplified by hepatocytes in mammals (Rabes et al., 1976). More frequently adult differentiated cells actually dedifferentiate upon injury before entering an active cycling phase to form a blastema (see below). But cells can also undergo metaplasia, that is, phenotypically convert from one cell or tissue type into another, a process well known by pathologists, which actually covers a variety of processes.
Figure 1. The different forms of cellular plasticity that can be observed or induced in differentiated somatic cells.
Download figure to PowerPoint
Among those, transdifferentiation is defined by the fact that stably differentiated cells irreversibly change their fate, that is, reprogram by acquiring a novel differentiated status with a specific molecular signature (Okada, 1991; Eguchi and Kodama, 1993). During that process, the cells may or may not traverse the cell cycle. Similarly cell fusion that, as transdifferentiation is also increased upon injury, might lead to reprogramming when two distinct cell types fuse (Chiu and Blau, 1984; Pomerantz and Blau, 2004). Obtaining the experimental proofs of transdifferentiation is often difficult, but at least morphological and molecular criteria as well as cell lineage relationships should clearly characterize the two cell states before and after transdifferentiation (Wagers and Weissman, 2004; Slack, 2007). In fact, the most compelling evidence is provided by the transient co-expression of markers of the two differentiated cell states (Schmid and Alder, 1984).
More recently, it was possible to induce transdifferentiation by overexpressing one or several cell-specific transcription factors that suffice to convert one cell type to another (Slack, 2007; Eberhard and Tosh, 2008; Zhou et al., 2008). Indeed nuclear reprogramming plays an essential role in cellular plasticity and developmental biologists actually provided the first experimental evidence of this event: they showed that nuclei isolated from mature somatic cells and transplanted into enucleated Xenopus oocytes, could reprogram and orchestrate the development of a frog (Gurdon et al., 1958). This surprising finding meant that nuclei of terminally differentiated cells can become totipotent. Forty years later, the cloning of the sheep Dolly, also obtained by nuclear transfer from an adult somatic tissue, the mammary gland, confirmed this major finding in mammals (Wilmut et al., 1997). Actually, even nuclei from post-mitotic neurons can be reprogrammed to drive the complete development of mice (Eggan et al., 2004).
Finally, since 2006 reprogramming of mature somatic cells can be pushed to the point where adult differentiated cells directly reach an embryonic-like stemness thanks to the co-expression of defined transcription factors without using oocytes. Such cells, named induced pluripotent stem cells (iPSC), were obtained so far from fibroblasts (Takahashi and Yamanaka, 2006; Takahashi et al., 2007), lymphocytes (Hanna et al., 2008), keratinocytes (Aasen et al., 2008), cord blood cells (Haase et al., 2009), smooth muscle cells (Lee et al., 2010). Whatever the procedure, reprogramming relies on epigenetic changes (Loh et al., 2008; Hochedlinger and Plath, 2009), which certainly correspond to “material” changes although not necessarily “structural” changes.
Two Emerging Model Systems for Investigating Homeostasis and Regeneration
Two historical invertebrate model systems, Hydra and planarians, were long recognized to be suitable for investigating the mechanisms supporting tissue homeostasis, active maintenance of patterning in adulthood as well as complex cellular reorganization to regenerate after injury. The freshwater polyp Hydra belongs to Cnidaria, a sister phylum to bilaterians, and the flatworm planaria that belongs to Lophotrochozoa (see their respective phylogenetic positions in Fig. 2) actually share five cellular and developmental features:
An intense and continuous tissue replacement in adulthood due to a stock of mitotically active stem cells, unique in case of planarians (the neoblasts), and three-fold in case of Hydra (the ectodermal epithelial stem cells, the endodermal epithelial stem cells, and the interstitial stem cells).
A stock of adult pluripotent stem cells that produce germ cells and somatic cells throughout the life of the animals (the interstitial stem cells in Hydra; the neoblasts in planarians), a situation quite unique among most animal phyla where germ cells usually segregate during early embryonic development.
An efficient asexual reproduction mechanism, through budding in Hydra and fission in planaria.
The amazing property to regenerate almost any missing part of the body after injury.
An apparent lack of aging, at least when the animals do not enter the sexual cycle (Martinez, 1998
; Yoshida et al., 2006
; Pearson and Sanchez Alvarado, 2008
Figure 2. Wide distribution of the regenerative potentials across the animal kingdom. Phylogenetic tree of the animal species exhibiting a regenerative potential after injury.
Download figure to PowerPoint
However, Hydra and planarians are not genetically tractable. The recent development of genomic, molecular and cellular tools promoted their emergence as modern model systems where the mechanisms of homeostasis and regeneration can now be investigated thanks to RNA interference (RNAi) gene knocked down and transgenesis (see in Reddien and Sanchez Alvarado, 2004; Galliot et al., 2006; Bosch, 2007; Bottger and Alexandrova, 2007; Salo et al., 2009). Homeostasis in planarians was recently reviewed in length (Pellettieri and Sanchez Alvarado, 2007; Handberg-Thorsager et al., 2008; Rossi et al., 2008) and we will report here about the distinct forms of plasticity that take place in adult Hydra polyps, first in response to variations in the feeding diet, and second after bisection, when the animal survives the amputation stress and regenerates the missing part. Given that most gene families that control cellular and developmental behaviors are present and highly conserved in cnidarians (Putnam et al., 2007; Chapman et al., 2010), these forms of plasticity are likely not exotic and we will discuss the correspondences between these changes and those observed in various bilaterian model systems.