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Model for self-organization of the regeneration blastema. A: Diagram of longitudinal section through an amputated limb (proximal humerus) during initial dedifferentiation. All the blastema cells inherit the proximal boundary (level of amputation) positional identity and can transform only distally. The blastema cells in contact with the wound epidermis take on the distal boundary (autopodium) identity (black cells); the adjacent blastema cells (gray cells) still have the proximal boundary (stylopodium) identity. B: The early blastema. Proliferation and intercalation of the positional identity specifying zeugopodium has taken place. C: Medium bud stage blastema. Continued intercalation generates intrasegmental PD identities. At the same time, intercalation can take place within the circumference or along the radii of the circumference to fill in any transverse positional identities that are missing. The boundary shell of blastema cells is shown in black. (Drawings by H. Nye.)
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Urodele amphibians have been widely used for studies of limb regeneration. In this article, we review studies on blastema cell proliferation and propose a model of blastemal self-organization and patterning. The model is based on local cell interactions that intercalate positional identities within circumferential and proximodistal boundaries that...
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... development of the blastema according to origin, in concert with intercalary regeneration to elimi- nate discontinuities, suggests a model for self-organization based on intercalation between boundaries (Stocum, 1980b(Stocum, , 1984(Stocum, , 1996 (Fig. 1). The model assumes that limb cells have positional identities in three-di- mensional space that constitute a "normal neighbor map" (Mittenthal, 1981). During initial dedifferentiation, before there is even a visible blas-tema, the essential outline of what is to be regenerated, consisting of cir- cumferential, proximal, and distal ...
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... status. Iron is a cofactor for many enzymes crucial to cell proliferation, including the rate-limiting enzyme for DNA replication, ribonucleotide re- ductase (Mescher and Munaim, 1988; Sussman, 1989). Transferrin is axonally transported and released distally from the sciatic nerves of regenerating axolotl hindlimbs (Kiffmeyer et al., 1991). Transection of the brachial nerves lowers the concentration of transferrin in the blastema by 50% (Mescher and Kiffmeyer, 1992). Transferrin can stimu- late blastema cell proliferation in vitro as effectively as nerve extracts (Munaim and Mescher, 1986; Albert and Boilly, 1988) and can maintain a significant level of mitotic activity when administered locally to denervated blastemas in vivo (Mescher and Kiffmeyer, 1992). The growth-promoting activity of neural extracts on organ cultures of denervated axolotl blastemas is completely removed by anti- transferrin antiserum and restored by purified axolotl transferrin (Mescher et al., 1997). Chelation of ferric ions from the extracts abolishes the mitogenic effect of the extracts; the activity is restored by adding iron back to the extract (Munaim and Mescher, 1986). To summarize, a variety of growth and trophic factors found in the AEC and the brachial nerves appear to be essential for the survival and proliferation of blastema stem cells. There are clear differences in the number and types of factors required by the regeneration blastema as opposed to the limb bud. However, the growth factors implicated (Fgf-1, -2, -8, Ggf-2) have not been as rigorously tested for mitogen status as transferrin or the growth factors of the amniote AER (Fgf-2, -4, -8). Although individual blastema cells have some developmental plasticity beyond their cell type of origin (Brockes, 1997), the developmental fate of the blastema as a whole is determined according to origin (Stocum, 1984, 1996, 2000). Numer- ous experiments have shown that the blastema is a self-organizing system, as opposed to being patterned by a set of inductive signals from the mature tissues adjacent to it. Blastemas cultured in vitro, grafted to the dorsal fin, exchanged between forelimb and hindlimb, grafted to a different PD level, or manipulated to disharmonize the anteroposterior (AP) and/or dorsoventral (DV) axes of blastema and adjacent tissues, always develop according to origin with regard to limb type, limb level, and handedness, even when the cells of the graft are forced to dedifferentiate again by reinjury (Stocum, 1968a,b, 1978b, 1980a; Stocum and Melton, 1977). When a distally derived blastema is grafted to a more proximal level, the missing intermediate structures are filled in by dedifferentiation and intercalary regeneration from the host limb level (Stocum, 1975; Iten and Bryant, 1975; Pescitelli and Stocum, 1980). Intercalation does not take place when a proximal blastema is grafted to a more distal level (Stocum and Melton, 1977). There is, thus, a preferred polarity to the recognition of a structural discontinuity and intercalary regeneration in the PD axis. This prefer- ence would not be predicted a priori, and its basis is unknown. Likewise, when the AP or DV axis of the blastema is reversed with re- spect to the adjacent tissues, con- fronting anterior and posterior, or dorsal and ventral blastema cells, a supernumerary circumference is formed, within which intercalary regeneration along the radii takes place to generate a cross-section that grows out into a supernumerary limb (Bryant and Iten, 1976; Cameron and Fallon, 1977; Tank, 1978a; Holder and Tank, 1979; Stocum, 1980b). Both host and graft tissues contribute to the supernumerary limb to varying degrees (Stocum, 1982). Such supernumeraries are also generated after amputation of limbs in which extensor and flexor muscles or skin cuffs are rotated (Carlson, 1974, 1975). The fibroblasts of the dermis carry the information for the self-organizing pattern, as shown by experiments in which unirradiated skin (epidermis plus dermis) was grafted to irradiated limbs in axolotls (Namenwirth, 1974; Lheureux, 1975; Dunis and Namenwirth, 1977). The irradiated host muscle and cartilage tissues cannot contribute to the regeneration blastema that forms after amputation of these limbs. Nev- ertheless, the regenerate that forms, although lacking in muscle, has a normal skeletal pattern, indicating that the blastema cells derived from the dermal fibroblasts of the unirradiated skin are capable of organiz- ing the pattern. Furthermore, if tail skin is grafted onto irradiated limbs, or limb skin onto irradiated tails, the regenerates formed after amputation are entirely of graft character, demonstrating that the fibroblasts carry an appendage-specific pattern (Trampusch, 1958a,b). The development of the blastema according to origin, in concert with intercalary regeneration to elimi- nate discontinuities, suggests a model for self-organization based on intercalation between boundaries (Stocum, 1980b, 1984, 1996) (Fig. 1). The model assumes that limb cells have positional identities in three-di- mensional space that constitute a “normal neighbor map” (Mittenthal, 1981). During initial dedifferentiation, before there is even a visible blas- tema, the essential outline of what is to be regenerated, consisting of circumferential, proximal, and distal boundaries, is present at the amputation surface. All dedifferentiated cells inherit the circumferential and proximal boundaries. We postulate that the distal boundary is conferred on the distal-most blastema stem cells in contact with the AEC. There is no hard evidence that the early wound epidermis functions in estab- lishing a distal boundary, but it does confer a distal direction of PD outgrowth on the blastema. Shifting the AEC to an eccentric location by re- moving a patch of skin at the base of the blastema in Ambystoma larvae results in outgrowth of the regenerate at an angle to the stump; grafting an AEC to the base of the blastema results in production of a supernumerary limb (Thornton, 1960, 1962; Thornton and Thornton, 1965). The intermediate positional identities are then intercalated by local cell interactions until a normal neighbor map is restored. The initial interaction is between the proximal and distal boundary stem cells, which recognize the discontinuity between these boundaries. This recognition triggers cell division, which is pro- moted by growth and trophic factors from the AEC and nerves, accompanied by the progressive assignment of the intermediate positional identities to the progeny cells until a complete map is reconsti- tuted (French et al., 1976; Maden, 1977; Mittenthal, 1981; Stocum, 1978b, 1980b, 1982, 1996). The first PD identities to be established are those for each segment. This is a very early event, so that all the segments are represented by the time the initial blastema has formed. Each segment then expands by proliferation, accompanied by the intercalation of intrasegmental identities. Proximal segments of the regenerate might expand faster than distal within the blastema, or vice versa, or all could expand at equal rates. Intercalation follows three rules. First, blastema cells and their progeny can change their positional identities only in a distal direction along the PD axis and in any direction within the circumferential boundary to intercalate the missing parts of the pattern (“rule of distal and radial intercalation”). Second, given a choice of intercalating the longer or shorter number of positional identities that will restore a complete pattern, cells always choose the shorter route (“rule of shortest intercalation,” French et al., 1976). Third, when all positional identities have been filled in, intercalation stops (“rule of normal neigh- bors,” Mittenthal, 1981). The distal pattern truncation of established blastemas that are deprived of their AEC could then be explained in the same way as that for the amniote limb bud deprived of its AER, by the death of cells destined to form the distal structures. This presumably would contrast with the lack of pattern truncation in blastemas deprived of nerves, in which blastema cell division would be diminished, but apical cell death would be absent, thus preserving the PD pattern or allowing morphal- lactic regulation to produce miniature regenerates. The validity of these ideas, however, awaits a de- tailed analysis in vivo of cell death and proliferation in blastemas deprived of epidermis vs. those deprived of nerves. A similar model has been proposed for development of the embryonic urodele limb bud (Stocum and Fallon, 1982) and may be appli- cable to amniote limb buds as well. The initial limb bud cells would have a proximal default state that is con- verted to distal in those cells in contact with the AER, followed by intercalation of intermediate positional identities. Labeling studies using [ 3 H]thymidine and DiI indicate that cells representing all three segments of the limb are present very early in chick limb bud development (by stage 18 or 19) and then expand at different rates, proximal faster than distal (Stark and Searls, 1973; Dudley et al., 2002; Saunders, 2002, for review). Furthermore, the distal-most cells of stage 19 wing buds self-orga- nize into wing digital elements when grafted to the coelom or to a hind limb bud stump, indicating that they are already destined to become wing digits (Dudley et al., 2002). They are not yet determined to do so, however, because stage 20 apical mesenchyme cells (destined to form digits) form all three segments when dissociated, repacked into an ectodermal jacket, and grafted to a host embryo. Apical cells from stage 22 formed zeugopodium and autopodium, whereas stage 24 cells formed only autopodium, indicating that segmental determination takes place in a proximal-to-distal sequence (Dudley et al., 2002). These results are consistent with the findings of Chiang et al. (2001) and Litingtung et al. (2002) of an early PD ...
Citations
... These organizers are transient developmental structures with evolutionarily conserved patterning properties [15]. Similarly, regenerating blastema that form after amputation can be considered as organizing centers, which exhibit patterning properties to reconstruct the missing structure due to the molecular instructions they deliver to the surrounding cells to modify their behavior [8,[16][17][18]. Indeed, these recruitment and patterning properties can be observed by transplanting regenerative blastema. ...
Hydra head formation depends on an organizing center in which Wnt/β-catenin signaling, that plays an inductive role, positively regulates Sp5 and Zic4, with Sp5 limiting Wnt3/β-catenin expression and Zic4 triggering tentacle formation. Using transgenic lines in which the HySp5 promoter drives eGFP expression in either the epidermis or gastrodermis, we show that Sp5 promoter activity is differentially regulated in each epithelial layer. In intact animals, epidermal HySp5:GFP activity is strong apically and weak along the body column, while in the gastrodermis, it is maximal in the tentacle ring region and maintained at a high level along the upper body column. During apical regeneration, HySp5:GFP is activated early in the gastrodermis and later in the epidermis. Alsterpaullone treatment induces a shift in apical HySp5:GFP expression towards the body column where it forms transient circular figures in the epidermis. Upon β-catenin(RNAi), HySp5:GFP activity is down-regulated in the epidermis while bud-like structures expressing HySp5:GFP in the gastrodermis develop. Sp5(RNAi) reveals a negative Sp5 autoregulation in the epidermis, but not in the gastrodermis. These differential regulations in the epidermis and gastrodermis highlight the distinct architectures of the Wnt/β-catenin/TCF/Sp5/Zic4 network in the hypostome, tentacle base and body column of intact animals, as well as in the buds and apical and basal regenerating tips.
... Reptiles, the Factors preventing regeneration of appendages most ancient amniote group listed, lost only 72 such genes, also including the 27 lost in all amniotes. As outlined in Section I, the process of limb regeneration, perhaps most successful in salamanders, can be roughly categorised into two distinct stages (Muneoka & Bryant, 1982;Brockes, 1997;Nye et al., 2003;Bassat & Tanaka, 2021). The first stage involves formation of the regenerative epithelium, followed by the development of a multilayered apical cap and dedifferentiation of connective tissue cells into a multipotent state resembling the state of embryonic lateral plate cells. ...
The ability to regenerate large body appendages is an ancestral trait of vertebrates, which varies across different animal groups. While anamniotes (fish and amphibians) commonly possess this ability, it is notably restricted in amniotes (reptiles, birds, and mammals). In this review, we explore the factors contributing to the loss of regenerative capabilities in amniotes. First, we analyse the potential negative impacts on appendage regeneration caused by four evolutionary innovations: advanced immunity, skin keratinization, whole-body endothermy, and increased body size. These innovations emerged as amniotes transitioned to terrestrial habitats and were correlated with a decline in regeneration capability. Second, we examine the role played by the loss of regeneration-related enhancers and genes initiated by these innovations in the fixation of an inability to regenerate body appendages at the genomic level. We propose that following the cessation of regenerative capacity, the loss of highly specific regeneration enhancers could represent an evolutionarily neutral event. Consequently, the loss of such enhancers might promptly follow the suppression of regeneration as a side effect of evolutionary innovations. By contrast, the loss of regeneration-related genes, due to their pleiotropic functions, would only take place if such loss was accompanied by additional evolutionary innovations that compensated for the loss of pleiotropic functions unrelated to regeneration, which would remain even after participation of these genes in regeneration was lost. Through a review of the literature, we provide evidence that, in many cases, the loss in amniotes of genes associated with body appendage regeneration in anamniotes was significantly delayed relative to the time when regenerative capability was lost. We hypothesise that this delay may be attributed to the necessity for evolutionary restructuring of developmental mechanisms to create conditions where the loss of these genes was a beneficial innovation for the organism. Experimental investigation of the downregulation of genes involved in the regeneration of body appendages in anamniotes but absent in amniotes offers a promising avenue to uncover evolutionary innovations that emerged from the loss of these genes. We propose that the vast majority of regeneration-related genes lost in amniotes (about 150 in humans) may be involved in regulating the early stages of limb and tail regeneration in anamniotes. Disruption of this stage, rather than the late stage, may not interfere with the mechanisms of limb and tail bud development during embryogenesis, as these mechanisms share similarities with those operating in the late stage of regeneration. Consequently, the most promising approach to restoring regeneration in humans may involve creating analogs of embryonic limb buds using stem cell-based tissue-engineering methods, followed by their transfer to the amputation stump. Due to the loss of many genes required specifically during the early stage of regeneration, this approach may be more effective than attempting to induce both early and late stages of regeneration directly in the stump itself.
... These organizers are transient developmental 51 structures with evolutionarily conserved patterning properties [15]. Similarly, regenerat-52 ing blastema that form after amputation can be considered as organizing centers, which 53 exhibit patterning properties to reconstruct the missing structure due to the molecular 54 instructions they deliver to the surrounding cells to modify their behavior [16][17][18]7]. In-55 deed, these recruitment and patterning properties can be observed by transplanting re-56 generative blastema. 57 The Hydra polyp, an animal easily maintained in the laboratory, provides a model to 58 decipher the cellular and molecular basis of regeneration. ...
The questions tackled by this study are the following: How an organizer can trigger the patterning of a new 3D shape, in Hydra a new head? What are the genetic components that carry this activity? How are these genetic components regulated in the different cell layers along the body axis of the animal and in the regenerating tips? These questions could be tackled with two main tools, (1) the transgenic lines that show specific regulations in live and fixed animals, (2) the loss-of-function assays that trigger three distinct phenotypes. These results highlight the different functions and regulations of the apical organizer in Hydra.
... Researchers have developed amphibian model systems that are associated with sophisticated molecular and genomic tools based on decades of concentrated research into the molecular biology of three species-Xenopus laevis, Xenopus tropicalis, and Ambystoma mexicanum (Getwan and Lienkamp, 2017). Although these three model species scarcely capture the diversity of Amphibia (over 8,400 species;AmphibiaWeb, 2021), they have served important roles during the last half century, providing insight into tetrapod evolution (Edholm et al., 2013;Rozenblit and Gollisch, 2020), developmental biology, molecular biology, neurobiology (Dascal, 1987;Yakushiji et al., 2009;Harland and Grainger, 2011), and tissue regeneration (Nye et al., 2003;Freitas et al., 2019). Research on many other amphibian genera has made notable historical contributions to biology: e.g., Plethodon cinereus in behavioral ecology and development (Dent, 1942;Heatwole, 1962;Kleeberger and Werner, 1982;Wyman and Hawksley-Lescault, 1987;Kerney, 2011;Kerney et al., 2012); Engystomops in sexual selection (Ryan et al., 1990); Rana in cloning (Briggs and King, 1952); Rana (Lefcort et al., 1998;Bridges, 2000;Hopkins et al., 2000;Pollet and Bendell-Young, 2000) and Acris (Fleming et al., 1982;Clark et al., 1998;Reeder et al., 1998) in community ecology and toxicology. ...
We explore the feeding habits of two populations of the lizard Aspidoscelis lineattissima from two localities (Cocinas = island and Xametla = mainland) under the hypothesis that in an insular environment, there is less selection of food, because it is a relatively comfortable environment to forage due to the presence of few competitors and predators. We also examine the predator–prey size relationship in this lizard species with the intention of distinguishing possible ontogenetic changes in the choice of prey sizes in the two localities. In stomach contents of the lizards from mainland, a total of 2,616 prey items were recorded, while on the island, 1,357 prey items were found. This number of prey was divided into 18 categories for the mainland and 20 for the island. In general terms, the most important prey in the diet of lizards from both localities were Isoptera, Coleoptera (adult and larvae), Araneae, Orthoptera, Hymenoptera (ants and others), Blattodea, and Diptera. Island lizards presented a greater amount of plant material in their stomach contents. The breadth of the food niche was greater on the island than on the mainland. Although statistically there were no differences regarding food overlap between localities, the highest overlap values between groups (age classes and sexes) were found on the mainland. We found a positive relationship between morphological variables of the lizards (snout–vent length, head width, and head length) with the maximum and mean values of the prey volume in both localities. This reveals an ontogenetic change that indicates that as lizards grow, they add a greater quantity of large prey to their diet and at the same time eat smaller prey. These results showed that the diet of the lizards from both localities was similar to other species of the genus. The feeding habits of a species in contrasting environments is evidence that is helpful for understanding the foraging patterns more clearly, and the possible connection with its life history characteristics, shedding more light on the hypothesis of niche amplitude and the optimal foraging theory.
... Researchers have developed amphibian model systems that are associated with sophisticated molecular and genomic tools based on decades of concentrated research into the molecular biology of three species-Xenopus laevis, Xenopus tropicalis, and Ambystoma mexicanum (Getwan and Lienkamp, 2017). Although these three model species scarcely capture the diversity of Amphibia (over 8,400 species;AmphibiaWeb, 2021), they have served important roles during the last half century, providing insight into tetrapod evolution (Edholm et al., 2013;Rozenblit and Gollisch, 2020), developmental biology, molecular biology, neurobiology (Dascal, 1987;Yakushiji et al., 2009;Harland and Grainger, 2011), and tissue regeneration (Nye et al., 2003;Freitas et al., 2019). Research on many other amphibian genera has made notable historical contributions to biology: e.g., Plethodon cinereus in behavioral ecology and development (Dent, 1942;Heatwole, 1962;Kleeberger and Werner, 1982;Wyman and Hawksley-Lescault, 1987;Kerney, 2011;Kerney et al., 2012); Engystomops in sexual selection (Ryan et al., 1990); Rana in cloning (Briggs and King, 1952); Rana (Lefcort et al., 1998;Bridges, 2000;Hopkins et al., 2000;Pollet and Bendell-Young, 2000) and Acris (Fleming et al., 1982;Clark et al., 1998;Reeder et al., 1998) in community ecology and toxicology. ...
Amphibians are a clade of over 8,400 species that provide unique research opportunities and challenges. With amphibians undergoing severe global declines, we posit that assessing our current understanding of amphibians is imperative. Focusing on the past five years (2016–2020), we examine trends in amphibian research, data, and systematics. New species of amphibians continue to be described at a pace of ~150 per year. Phylogenomic studies are increasing, fueling a growing consensus in the amphibian tree of life. Over 3,000 species of amphibians are now represented by expert-curated accounts or data in AmphibiaWeb, AmphibiaChina, BIOWEB, or the Amphibian Disease Portal. Nevertheless, many species lack basic natural history data (e.g., diet records, morphological measurements, call recordings) and major gaps exist for entire amphibian clades. Genomic resources appear on the cusp of a rapid expansion, but large, repetitive amphibian genomes still pose significant challenges. Conservation continues to be a major focus for amphibian research, and threats cataloged on AmphibiaWeb for 1,261 species highlight the need to address land use change and disease using adaptive management strategies. To further promote amphibian research and conservation, we underscore the importance of database integration and suggest that other understudied or imperiled clades would benefit from similar assessments of existing data.
... | 3 embryonic steps to successfully produce a limb. As suggested, this may be accomplished by dedifferentiated fibroblasts providing an embryonic-like environment at the regeneration site and structural support with embryonic-like scaffolds as well (Nye et al., 2003). ...
Compared to other animals, the spontaneous occurrence of tumors in wild amphibians is relatively rare, generally limited to specific populations or species. The number of reports of spontaneous tumors in amphibians known up to 1986 was 491 cases in anurans and about 253 cases in urodeles. Similarly, there have been many, unsuccessful attempts to chemically or biologically induce tumors in amphibians. With these considerations, it is inevitable to wonder: do urodeles and anurans have an inherent resistance to cancer? Here, we review the spontaneous and induced occurrence of tumors in amphibians in a timeline, as well as failed attempts to induce tumors in these amphibians. Indeed, recent studies seem to indicate that there is a relationship between regeneration and cancer because regenerating tissues seem to resist tumorigenesis, as opposed to nonregenerative tissues of the same amphibian models. Although the mechanisms that allow regenerating tissues to resist tumorigenesis have not been elucidated, it is worth to note that, in addition to the apparent relationship between regeneration and cancer, amphibians possess characteristics that could contribute to their ability to resist the development of neoplastic events. The implications of these features in cancer susceptibility are discussed.
... 2) how do the differentiated cells turn into cells with an embryonic gene profile? Regarding blastema induction, classic studies clearly demonstrated that the nerves play a central role in the process [3,4]. Denervation from limbs results in no regeneration after limb amputation. ...
... 1 Research Core for Interdisciplinary Sciences (RCIS), Okayama University, 3-1-1, Tsushima-naka, Kitaku, Okayama 700-8530, Japan. 2 Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan. 3 Faculty of Science, Department of Biological Sciences, Okayama University, Okayama, Japan. 4 Division of Adaptation Physiology, Faculty of Medicine, Tottori University, Tottori, Japan. ...
Urodele amphibians, Pleurodeles waltl and Ambystoma mexicanum, have organ-level regeneration capability, such as limb regeneration. Multipotent cells are induced by an endogenous mechanism in amphibian limb regeneration. It is well known that dermal fibroblasts receive regenerative signals and turn into multipotent cells, called blastema cells. However, the induction mechanism of the blastema cells from matured dermal cells was unknown. We previously found that BMP2, FGF2, and FGF8 (B2FF) could play sufficient roles in blastema induction in urodele amphibians. Here, we show that B2FF treatment can induce dermis-derived cells that can participate in multiple cell lineage in limb regeneration. We first established a newt dermis-derived cell line and confirmed that B2FF treatment on the newt cells provided plasticity in cellular differentiation in limb regeneration. To clarify the factors that can provide the plasticity in differentiation, we performed the interspecies comparative analysis between newt cells and mouse cells and found the Pde4b gene was upregulated by B2FF treatment only in the newt cells. Blocking PDE4B signaling by a chemical PDE4 inhibitor suppressed dermis-to-cartilage transformation and the mosaic knockout animals showed consistent results. Our results are a valuable insight into how dermal fibroblasts acquire multipotency during the early phase of limb regeneration via an endogenous program in amphibian limb regeneration.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40851-022-00190-6.
... These findings, together with the follow-up intensive studies from Singer and colleagues, demonstrated the chemical nature of nerve-dependent limb regeneration, which led to the proposal of the neurotrophic hypothesis: within a given area, the number of axons, and therefore the associated neurotrophic factors, must reach a certain threshold for regeneration to occur (Singer 1952;Singer 1964;Zika and Singer 1965). In past decades, many such kinds of neurotrophic factors, secreted from injured nerves or Schwann cells and playing essential roles in nerve-dependent regeneration, have been identified, including bone morphogenetic proteins (BMPs) Makanae et al. 2016), FGFs (Mullen et al. 1996;Han et al. 2001), keratinocyte growth factor (KGF, FGF7) (Satoh et al. 2008), Substance P (Satoh et al. 2008), newt anterior gradient (nAG) (Kumar et al. 2007), Neuregulin-1 (Farkas et al. 2016), and so on, as previously reviewed (Nye et al. 2003;Mitogawa et al. 2014;Satoh et al. 2015;Satoh et al. 2016;Satoh et al. 2018). ...
... Neurons or other relevant cells (for example cells in the AEC) are sufficient to induce blastema initiation and growth. It was found that supplementing identified nerve or AEC-derived factors alone could replace the function of nerves or the AEC and rescue the regeneration defects in the absence of either nerves or the AEC (Nye et al. 2003;Mitogawa et al. 2014;Satoh et al. 2016;Satoh et al. 2018;Stocum 2019). Remarkably, a recent work using Xenopus tail regeneration model identified a new type of regeneration-organizing cells (ROCs), which are located in the AEC and function on top of different progenitors to coordinate their proliferation. ...
A successful tissue regeneration is a very complex process that requires a precise coordination of many molecular, cellular and physiological events. One of the critical steps is to convert the injury signals into regeneration signals to initiate tissue regeneration. Although many efforts have been made to investigate the mechanisms triggering tissue regeneration, the fundamental questions remain unresolved. One of the major obstacles is that the injury and the initiation of regeneration are two highly coupled processes and hard to separate from one another. In this article, we review the major events occurring at the early injury/regeneration stage in a range of species, and discuss the possible common mechanisms during initiation of tissue regeneration.
... The presence of an additional limb (polymely) is often the most cited amphibian deformity in the scientific literature although as extra limbs are particularly conspicuous they may be reported disproportionately (Ouellet, 2000). Polymely mostly results from an incomplete injury that sometimes causes a limb to both heal and regenerate (Nye et al., 2003) but it may also result from parasitic infection (Sessions & Ruth, 1990). The presence of additional limbs has been recorded in many amphibian species, but mostly from frogs and toads rather than newts (Canestrelli et al., 2006). ...
... This structure, AEC or regenerative epithelium, is an important source of molecules that are thought to be essential in recruiting cells to the injury site to form a blastema; which is defined as a mound of proliferating cells that will eventually differentiate and replace the lost limb (Campbell et al., 2011;Satoh, Bryant, & Gardiner, 2012;Satoh, Graham, et al., 2008). The blastema is a pool of heterogeneous progenitor cells with mainly restricted potential that are going to be the source of the cells to re-establish the tissues that form the limb (Gardiner, Muneoka, & Bryant, 1986;Kragl et al., 2013;Muneoka, Fox, & Bryant, 1986;Nye, Cameron, Chernoff, & Stocum, 2003;. One of the big questions in the field is, what are the main cellular and molecular mechanism that contribute to the generation of the progenitor cells that form the blastema? ...
Salamanders are recognized for their ability to regenerate a broad range of tissues. They have also have been used for hundreds of years for classical developmental biology studies because of their large accessible embryos. The range of tissues these animals can regenerate is fascinating, from full limbs to parts of the brain or heart, a potential that is missing in humans. Many promising research efforts are working to decipher the molecular blueprints shared across the organisms that naturally have the capacity to regenerate different tissues and organs. Salamanders are an excellent example of a vertebrate that can functionally regenerate a wide range of tissue types. In this review, we outline some of the significant insights that have been made that are aiding in understanding the cellular and molecular mechanisms of tissue regeneration in salamanders and discuss why salamanders are a worthy model in which to study regenerative biology and how this may benefit research fields like regenerative medicine to develop therapies for humans in the future.
