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• W2061468450 abstract "Regeneration of a lost appendage in adult amphibians and fish is a remarkable feat of developmental patterning. Although the limb or fin may be years removed from its initial creation by an embryonic primordium, the blastema that emerges at the injury site fashions a close mimic of adult form. Central to understanding these events are revealing the cellular origins of new structures, how positional identity is maintained, and the determinants for completion. Each of these topics has been advanced recently, strengthening models for how complex tissue pattern is recalled in the adult context. Regeneration of a lost appendage in adult amphibians and fish is a remarkable feat of developmental patterning. Although the limb or fin may be years removed from its initial creation by an embryonic primordium, the blastema that emerges at the injury site fashions a close mimic of adult form. Central to understanding these events are revealing the cellular origins of new structures, how positional identity is maintained, and the determinants for completion. Each of these topics has been advanced recently, strengthening models for how complex tissue pattern is recalled in the adult context. Regeneration in the simplest terms of developmental biology means the replacement of tissue components lost by injury. Oftentimes, a regenerative response may be of little consequence in the face of a more significant repair response like scarring. For instance, the adult mammalian heart has a measurable, but severely limited, capacity to create new cardiac muscle cells after a myocardial infarction, and fibrosis is the dominant outcome (Kikuchi and Poss, 2012Kikuchi K. Poss K.D. Cardiac regenerative capacity and mechanisms.Annu. Rev. Cell Dev. Biol. 2012; 28: 719-741Crossref PubMed Scopus (210) Google Scholar, Laflamme and Murry, 2011Laflamme M.A. Murry C.E. Heart regeneration.Nature. 2011; 473: 326-335Crossref PubMed Scopus (910) Google Scholar, Senyo et al., 2013Senyo S.E. Steinhauser M.L. Pizzimenti C.L. Yang V.K. Cai L. Wang M. Wu T.D. Guerquin-Kern J.L. Lechene C.P. Lee R.T. Mammalian heart renewal by pre-existing cardiomyocytes.Nature. 2013; 493: 433-436Crossref PubMed Scopus (920) Google Scholar). Regenerative responses can be compensatory, restoring functional mass but not necessarily the structures that were lost; for example, rodent hepatic tissue is recovered in spared lobes after hepatotectomy but is not created at the injury site (Michalopoulos, 2007Michalopoulos G.K. Liver regeneration.J. Cell. Physiol. 2007; 213: 286-300Crossref PubMed Scopus (1149) Google Scholar). Additionally, spatiotemporal variables restrict many or most regenerative events, making the extent or type of injury, and the developmental stage or age of the injured animal, key variables (Poss, 2010Poss K.D. Advances in understanding tissue regenerative capacity and mechanisms in animals.Nat. Rev. Genet. 2010; 11: 710-722Crossref PubMed Scopus (285) Google Scholar). Regeneration in its most successful form restores an intricate pattern to a lost complex tissue, generating a near-perfect replica even at adult stages. An adult newt that has had one or more limbs amputated will restore skeletal muscle, bone, nerves, connective tissue, epidermis, and vasculature to a form that can be indistinguishable from its preinjury appearance. These events occur robustly whether at digit- or shoulder-level, and have been considered by many as regeneration in its truest manifestation. The Italian scholar Spallanzani initiated questions in the mid-18th century about the memory and recovery of complex adult pattern during newt limb regeneration that have remained in many ways unanswered (Spallanzani, 1768Spallanzani L. Prodromo di un’opera da imprimersi sopra la riproduzioni animali. Giovanni Montanari, Modena, Italy1768Google Scholar), and later that century bony fish were shown to regenerate amputated fins (Broussonet, 1786Broussonet P.M.A. Observations sur la regeneration de quelques parties du corps des Poissons. Hist de l’Acad Roy des Sciences, 1786Google Scholar). At the time, luminaries like Spallanzani and Bonnet debated whether regeneration is a version of preformation relying on “germs” or miniature versions of adult structures (Dinsmore, 1991Dinsmore C.E. A History of Regeneration Research: Milestones in the evolution of a science. Cambridge University Press, Cambridge, U.K.1991Google Scholar). This concept faded as experimental embryology surged a century later and when Morgan studied regeneration in various creatures prior to his better-known work in Drosophila genetics. Morgan classified appendage regeneration as an “epimorphic” process that hinges on cell proliferation at the injury site, and some of his important investigations of regeneration involved the study of pattern renewal after a series of elaborate amputation injuries to killifish fins (Morgan, 1901Morgan T.H. Regeneration. Macmillan, New York1901Google Scholar). Axolotls have become a popular model for limb regeneration, and zebrafish for fin regeneration, because of the research tools that have been developed for studying these animals. Teleost fins and urodele limbs are structurally distinct, but it is clear from years of work that they progress through similar fundamental regeneration stages. Following an amputation injury, epithelial cells migrate to cover the wound site, and a multilayered epidermis forms. Proliferation in the underlying mesenchymal compartment, which is controlled in part by influences of the wound epidermis, generates a cell mass called the blastema. Multiple structures and factors have been shown to modulate blastemal proliferation, including nerves, specialized glands, vasculature, and activators/inhibitors of classic developmental signaling pathways (Kumar and Brockes, 2012Kumar A. Brockes J.P. Nerve dependence in tissue, organ, and appendage regeneration.Trends Neurosci. 2012; 35: 691-699Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, Nacu and Tanaka, 2011Nacu E. Tanaka E.M. Limb regeneration: a new development?.Annu. Rev. Cell Dev. Biol. 2011; 27: 409-440Crossref PubMed Scopus (115) Google Scholar). In limbs, the blastema grows to a large mass that is then patterned into the upper arm, lower arm, and hand segments. In regenerating fins, new structures grow by a process that maintains a proliferative blastemal compartment in the distal region of each individual bony fin ray, while simultaneous osteoblast patterning events occur proximal to this growth to direct bone matrix deposition. In each case, pattern is restored across multiple axes to the complex structure. Appendage regeneration has been reviewed many times, and key aspects and classic experiments not covered here are examined in recent publications (Kumar and Brockes, 2012Kumar A. Brockes J.P. Nerve dependence in tissue, organ, and appendage regeneration.Trends Neurosci. 2012; 35: 691-699Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, Monaghan and Maden, 2013Monaghan J.R. Maden M. Cellular plasticity during vertebrate appendage regeneration.Curr. Top. Microbiol. Immunol. 2013; 367: 53-74Crossref PubMed Google Scholar, Nacu and Tanaka, 2011Nacu E. Tanaka E.M. Limb regeneration: a new development?.Annu. Rev. Cell Dev. Biol. 2011; 27: 409-440Crossref PubMed Scopus (115) Google Scholar, Simon and Tanaka, 2013Simon A. Tanaka E.M. Limb regeneration.Wiley Interdiscip. Rev. Dev. Biol. 2013; 2: 291-300Crossref PubMed Scopus (82) Google Scholar). We focus here on features of regeneration that arguably are most germane to the lost form that is recovered: activating the cellular sources, recalling positional identities, and slowing/stopping the process. Very recent discoveries we discuss here (and others outside the scope of this review) have established pivotal concepts and mechanisms that are anticipated to direct future investigations of appendage regeneration. Much has been learned from studies of developing embryos about how appendages first form and acquire skeletal pattern along the proximodistal (PD), anteroposterior (AP), and dorsoventral (DV) axes (Zeller et al., 2009Zeller R. Lopez-Rios J. Zuniga A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis.Nat. Rev. Genet. 2009; 10: 845-858Crossref PubMed Scopus (331) Google Scholar). This information has been applied to generate molecular markers and to suggest mechanisms of various aspects of limb regeneration (Nacu and Tanaka, 2011Nacu E. Tanaka E.M. Limb regeneration: a new development?.Annu. Rev. Cell Dev. Biol. 2011; 27: 409-440Crossref PubMed Scopus (115) Google Scholar). Yet, while a limb bud forms and is patterned concomitantly with morphogenesis of other tissues in the embryo proper, a blastema emerges from cells engaged in the homeostasis and function of a differentiated adult structure, within an organism that may have reached its final developmental stage years prior to insult. Knowing which cells give rise to the blastema, and whether these cells maintain or switch lineages, is the terminus a quo for most questions in appendage regeneration. The source or sources of the blastema, and the diversity and developmental potential of its cellular constituents, have been under continual investigation for several decades. For some in the field, the term “blastema” has implied a homogeneous population of stem cells, each with an equal ability to differentiate in one of multiple directions. Additionally, the dominant view in appendage regeneration has been that blastemal cells are primarily derived from the reversion of a differentiated state—commonly referred to as “dedifferentiation,” and at its extreme is analogous to reprogramming phenomena induced by defined factors. In 2009, Kragl and colleagues examined this first idea by specifically labeling most major limb cell types in the axolotl by grafting the embryonic region that produces that limb tissue from green fluorescent protein (GFP)-labeled transgenic donors into unlabeled host embryos, or by directly grafting a specified GFP+ limb tissue to an unlabeled host (Kragl et al., 2009Kragl M. Knapp D. Nacu E. Khattak S. Maden M. Epperlein H.H. Tanaka E.M. Cells keep a memory of their tissue origin during axolotl limb regeneration.Nature. 2009; 460: 60-65Crossref PubMed Scopus (612) Google Scholar). Their analyses of labeled, regenerating limbs produced a theme of lineage restriction. That is, regenerated cell types largely retain their developmental identity as they transition through the blastemal stage, and do not normally demonstrate a potential to create diverse cell types. These findings support the idea of a compartmentalized, rather than homogeneous, blastema. Transgenic technologies have also matured rapidly for the zebrafish model system, and recent studies asked similar questions with respect to the different cell types in regenerating fins by genetic fate-mapping and mosaic transgene analysis (Knopf et al., 2011Knopf F. Hammond C. Chekuru A. Kurth T. Hans S. Weber C.W. Mahatma G. Fisher S. Brand M. Schulte-Merker S. et al.Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin.Dev. Cell. 2011; 20: 713-724Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, Singh et al., 2012Singh S.P. Holdway J.E. Poss K.D. Regeneration of amputated zebrafish fin rays from de novo osteoblasts.Dev. Cell. 2012; 22: 879-886Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Sousa et al., 2011Sousa S. Afonso N. Bensimon-Brito A. Fonseca M. Simoes M. Leon J. Roehl H. Cancela M.L. Jacinto A. Differentiated skeletal cells contribute to blastema formation during zebrafish fin regeneration.Development. 2011; 138: 3897-3905Crossref PubMed Scopus (110) Google Scholar, Stewart and Stankunas, 2012Stewart S. Stankunas K. Limited dedifferentiation provides replacement tissue during zebrafish fin regeneration.Dev. Biol. 2012; 365: 339-349Crossref PubMed Scopus (86) Google Scholar, Tu and Johnson, 2011Tu S. Johnson S.L. Fate restriction in the growing and regenerating zebrafish fin.Dev. Cell. 2011; 20: 725-732Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). These studies indicated that fin cells largely remain restricted to give rise to like cells, whether they are epidermis, endothelium, fibroblasts, or osteoblasts. Along with lineage-tracing of various cell types during mouse digit tip regeneration and even crustacean limb regeneration, the results support an evolutionarily conserved model of a compartmentalized blastema (Konstantinides and Averof, 2014Konstantinides N. Averof M. A Common Cellular Basis for Muscle Regeneration in Arthropods and Vertebrates.Science. 2014; 343: 788-791Crossref PubMed Scopus (65) Google Scholar, Lehoczky et al., 2011Lehoczky J.A. Robert B. Tabin C.J. Mouse digit tip regeneration is mediated by fate-restricted progenitor cells.Proc. Natl. Acad. Sci. USA. 2011; 108: 20609-20614Crossref PubMed Scopus (149) Google Scholar, Rinkevich et al., 2011Rinkevich Y. Lindau P. Ueno H. Longaker M.T. Weissman I.L. Germ- layer and lineage-restricted stem/progenitors regenerate the mouse digit tip.Nature. 2011; 476: 409-413Crossref PubMed Scopus (296) Google Scholar). From this composite of work, several interesting questions arose, with some of these questions addressed in more recent studies. For example, to what extent are tissue origins developmentally plastic; in other words, can secondary sources be induced to replace lost cells? In fins, which contain intramembranous bone and lack skeletal muscle, osteoblasts are the primary cell type of interest, and Cre-recombinase-based fate mapping demonstrated that osteoblasts only give rise to other osteoblasts (Knopf et al., 2011Knopf F. Hammond C. Chekuru A. Kurth T. Hans S. Weber C.W. Mahatma G. Fisher S. Brand M. Schulte-Merker S. et al.Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin.Dev. Cell. 2011; 20: 713-724Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). Yet, when the vast majority of fin osteoblasts were genetically ablated, Singh et al., 2012Singh S.P. Holdway J.E. Poss K.D. Regeneration of amputated zebrafish fin rays from de novo osteoblasts.Dev. Cell. 2012; 22: 879-886Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar found that osteoblasts recovered and fins regenerated with normal rate and pattern. In this scenario, newly formed osteoblasts could not be traced to preexisting osteoblasts and ostensibly regenerated de novo from a secondary source (Singh et al., 2012Singh S.P. Holdway J.E. Poss K.D. Regeneration of amputated zebrafish fin rays from de novo osteoblasts.Dev. Cell. 2012; 22: 879-886Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Thus, there is a degree of plasticity that allows other cell types to make osteoblasts under unique conditions, although the identities of these alternative source cells remain to be uncovered by informative molecular markers and lineage-tracing. Classic experiments in salamander limbs suggest that analogous plasticity exists in amphibians (Dunis and Namenwirth, 1977Dunis D.A. Namenwirth M. The role of grafted skin in the regeneration of x-irradiated axolotl limbs.Dev. Biol. 1977; 56: 97-109Crossref PubMed Scopus (77) Google Scholar, Namenwirth, 1974Namenwirth M. The inheritance of cell differentiation during limb regeneration in the axolotl.Dev. Biol. 1974; 41: 42-56Crossref PubMed Scopus (91) Google Scholar, Thornton, 1938Thornton C.S. The histogenesis of the regenerating fore limb of larval Amblystoma after exarticulation of the humerus.J. Morphol. 1938; 62: 219-241Crossref Scopus (44) Google Scholar). As alluded to above, it is possible that lineage restriction involves dedifferentiation to enable a proliferative state, but activation of a restricted progenitor cell is also a plausible mechanism. During zebrafish fin regeneration, live imaging visualized the reduction in expression of osteocalcin, a factor secreted by differentiated osteoblasts. This change, and ultrastructural changes detectable by electron microscopy, indicated that osteoblasts undergo some degree of dedifferentiation (Knopf et al., 2011Knopf F. Hammond C. Chekuru A. Kurth T. Hans S. Weber C.W. Mahatma G. Fisher S. Brand M. Schulte-Merker S. et al.Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin.Dev. Cell. 2011; 20: 713-724Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). The key limb cell type to assess in this respect is skeletal muscle, which regenerates via a satellite cell compartment in mammals but has been investigated over many decades as a potential example of dedifferentiation in salamanders. Various studies examining histology, transplanted cells, or in vitro cultured myotubes have supported the idea that muscle dedifferentiation occurs as the newt blastema forms (Kumar et al., 2000Kumar A. Velloso C.P. Imokawa Y. Brockes J.P. Plasticity of retrovirus- labelled myotubes in the newt limb regeneration blastema.Dev. Biol. 2000; 218: 125-136Crossref PubMed Scopus (121) Google Scholar, Kumar et al., 2004Kumar A. Velloso C.P. Imokawa Y. Brockes J.P. The regenerative plasticity of isolated urodele myofibers and its dependence on MSX1.PLoS Biol. 2004; 2: E218Crossref PubMed Scopus (90) Google Scholar, Lo et al., 1993Lo D.C. Allen F. Brockes J.P. Reversal of muscle differentiation during urodele limb regeneration.Proc. Natl. Acad. Sci. USA. 1993; 90: 7230-7234Crossref PubMed Scopus (219) Google Scholar, McGann et al., 2001McGann C.J. Odelberg S.J. Keating M.T. Mammalian myotube dedifferentiation induced by newt regeneration extract.Proc. Natl. Acad. Sci. USA. 2001; 98: 13699-13704Crossref PubMed Scopus (189) Google Scholar). However, salamanders are known to contain a PAX7+ satellite cell population, and transplanted newt satellite cells have been shown to support new muscle regeneration (Morrison et al., 2006Morrison J.I. Loof S. He P. Simon A. Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population.J. Cell Biol. 2006; 172: 433-440Crossref PubMed Scopus (201) Google Scholar). Using Cre-loxP genetic fate mapping during limb regeneration in newts and axolotls for the first time, Guzmán and colleagues recently reassessed the endogenous contributions by these two potential sources (Sandoval-Guzmán et al., 2014Sandoval-Guzmán T. Wang H. Khattak S. Schuez M. Roensch K. Nacu E. Tazaki A. Joven A. Tanaka E.M. Simon A. Fundamental Differences in Dedifferentiation and Stem Cell Recruitment during Skeletal Muscle Regeneration in Two Salamander Species.Cell Stem Cell. 2014; 14: 174-187Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). The authors tagged differentiated muscle cell nuclei in newts via a transient transgenic genetic fate-mapping approach and then traced the labeled cells through regeneration. They found that labeled myofibers trace into the blastema after amputation, where they occasionally mark cells positive for a proliferation marker and/or negative for a contractile marker. There was no evidence that muscle satellite cells were derived from labeled myofibers (Figure 1A). At later stages of regeneration, new myofibers contained the lineage label, similarly indicating derivation from differentiated muscle cells. Surprisingly, the authors found opposing results in axolotls using a similar fate-mapping technique. In this species, whereas myofibers underwent morphological changes at the amputation plane, contributions to the regenerated limb were not detected. Instead, the authors found that PAX7+ cells are abundant in the axolotl blastema, much more so than in the newt blastema, making satellite cells a clear candidate cell type as the main source of regenerated muscle in axolotl limbs (Figure 1B). Thus, there appear to be unexpected fundamental differences in the origins of blastemal cells and regenerating tissue between two salamander species. It will be critical, as the authors point out, to directly mark and trace the endogenous satellite cell populations in axolotl and newts using the most rigorous possible methodology to determine the scope of their contributions. These intriguing findings route conversation to perhaps the most common question surrounding limb regeneration—why is it limited to a group of vertebrate species? Although the capacity for limb regeneration is unique to salamanders among tetrapods, selective pressures appear to have forged distinct paths in two species to maintain high regenerative potential. Mammals had other evolutionary priorities, but these studies imply that reawakening an ancestral program for regenerating complex muscle from an appendage stump has a flexible entry point that could include manipulation of the endogenous satellite cell machinery and/or forced myofiber dedifferentiation. Defining the origins of blastemal cells enables focused questions on how patterning information is handled during regeneration. Whether amputation occurs at the shoulder or the digit level, source cells locally maintain or quickly acquire coordinates to replace size and shape, a process typically referred to as positional memory (reviewed by Nacu and Tanaka, 2011Nacu E. Tanaka E.M. Limb regeneration: a new development?.Annu. Rev. Cell Dev. Biol. 2011; 27: 409-440Crossref PubMed Scopus (115) Google Scholar). Models for how PD identity is acquired during initial formation of the embryonic limb have evolved over the past 40 years (Duboc and Logan, 2009Duboc V. Logan M.P. Building limb morphology through integration of signalling modules.Curr. Opin. Genet. Dev. 2009; 19: 497-503Crossref PubMed Scopus (35) Google Scholar, Towers and Tickle, 2009Towers M. Tickle C. Growing models of vertebrate limb development.Development. 2009; 136: 179-190Crossref PubMed Scopus (137) Google Scholar, Zeller et al., 2009Zeller R. Lopez-Rios J. Zuniga A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis.Nat. Rev. Genet. 2009; 10: 845-858Crossref PubMed Scopus (331) Google Scholar). Recent experiments using heterotopic and recombinant limb tissue grafts indicate that skeletal patterning is determined by diffusible signals in the proximal (flank) and distal (apical ectodermal cap) regions acting on the growing appendage, as opposed to a mechanism of cell-autonomous PD determinants within limb bud cells (Cooper et al., 2011Cooper K.L. Hu J.K. ten Berge D. Fernandez-Teran M. Ros M.A. Tabin C.J. Initiation of proximal-distal patterning in the vertebrate limb by signals and growth.Science. 2011; 332: 1083-1086Crossref PubMed Scopus (123) Google Scholar, Roselló-Díez et al., 2011Roselló-Díez A. Ros M.A. Torres M. Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision.Science. 2011; 332: 1086-1088Crossref PubMed Scopus (104) Google Scholar). Whether cells in adult salamander limb blastemas are similarly specified in a progressive manner based on proximity to signaling centers, or instead sort into PD zones prior to growth and differentiation, has been for years a subject of debate. Given that the same patterning factors have been implicated in mechanisms of limb development and regeneration, a shared mode of PD specification is the most conservative model. Yet, multiple experiments have suggested that a portion of early blastemal cells quickly acquire digit tip identity. For instance, DNA electroporation-based labeling of distal portions of early blastemas tracked specifically to hand regions, and these contributions shifted to upper arm identities when the putative proximalizing factor Prod1 was introduced (Echeverri and Tanaka, 2005Echeverri K. Tanaka E.M. Proximodistal patterning during limb regeneration.Dev. Biol. 2005; 279: 391-401Crossref PubMed Scopus (111) Google Scholar). These results were consistent with a mechanism of intercalation, with distally specified blastemal cells assisting the specification and regeneration of the intermediate limb region from the stump. A recent study by Roensch and colleagues used simple, elegant immunostaining for HOXA proteins to argue that instead, regenerating axolotl limbs progressively acquire patterning signals to recreate the proximal to distal pattern (Roensch et al., 2013Roensch K. Tazaki A. Chara O. Tanaka E.M. Progressive specification rather than intercalation of segments during limb regeneration.Science. 2013; 342: 1375-1379Crossref PubMed Scopus (57) Google Scholar). During vertebrate limb development, upper arm progenitors are marked by a HoxA9+ HoxA11− HoxA13− signature; lower arm progenitors are HoxA9+ HoxA11+ HoxA13−; and hand progenitors are HoxA9+ HoxA11− HoxA13+ (Gardiner et al., 1995Gardiner D.M. Blumberg B. Komine Y. Bryant S.V. Regulation of HoxA expression in developing and regenerating axolotl limbs.Development. 1995; 121: 1731-1741PubMed Google Scholar). The authors assessed localization of HOXA9, HOXA11, and HOXA13 protein during axolotl limb regeneration at various amputation levels and days postinjury and found that regeneration recapitulated these signatures. HOXA9 protein was expressed in virtually all early blastemal cells, whereas HOXA13 levels remain low or undetectable until they appear in the distal regions of medium- to late-bud stages of upper arm blastemas and earlier in hand blastemas. Transplantation of transgenically labeled blastemal cells was also consistent with a mechanism of progressive proximal-to-distal specification. It remains to be determined how this model reconciles with the electroporation results that indicated early distal cell specification in the blastema. The kinetics and spatial determinants of regeneration, including PD specification, are a function of animal and limb size. Thus, these assays would best be performed and compared directly in size-matched animals. Moreover, Kragl et al., 2009Kragl M. Knapp D. Nacu E. Khattak S. Maden M. Epperlein H.H. Tanaka E.M. Cells keep a memory of their tissue origin during axolotl limb regeneration.Nature. 2009; 460: 60-65Crossref PubMed Scopus (612) Google Scholar found that cartilage removed from hand structures that had been transplanted into the upper arm and stabilized in the skeleton preferentially contributed to distal structures during regeneration. These results suggest that transplanted distal cartilage and perhaps other cells can retain a memory of distal position throughout blastema formation and regeneration. In these experiments, distal HOXA signatures might be maintained in donor cells amid a sea of neighbors expressing proximal markers within the blastema, wherein intrinsic factors predominate over local environmental cues. There is a limited understanding of positional memory at the molecular level. The study of positional identity in insect imaginal discs or vertebrate embryonic limb buds has a strong history (Estella et al., 2012Estella C. Voutev R. Mann R.S. A dynamic network of morphogens and transcription factors patterns the fly leg.Curr. Top. Dev. Biol. 2012; 98: 173-198Crossref PubMed Scopus (56) Google Scholar, Towers and Tickle, 2009Towers M. Tickle C. Growing models of vertebrate limb development.Development. 2009; 136: 179-190Crossref PubMed Scopus (137) Google Scholar, Zeller et al., 2009Zeller R. Lopez-Rios J. Zuniga A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis.Nat. Rev. Genet. 2009; 10: 845-858Crossref PubMed Scopus (331) Google Scholar), and regeneration must incorporate these concepts and mechanisms while enacting an abrupt switch from day-to-day adult tissue function. Past studies have found that adult mammalian fibroblasts have unique, position-dependent properties and/or molecular profiles, despite indistinguishable morphologic appearance (Chang et al., 2002Chang H.Y. Chi J.T. Dudoit S. Bondre C. van de Rijn M. Botstein D. Brown P.O. Diversity, topographic differentiation, and positional memory in human fibroblasts.Proc. Natl. Acad. Sci. USA. 2002; 99: 12877-12882Crossref PubMed Scopus (848) Google Scholar, Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. et al.Distinct fibroblast lineages determine dermal architecture in skin development and repair.Nature. 2013; 504: 277-281Crossref PubMed Scopus (710) Google Scholar, Rinn et al., 2006Rinn J.L. Bondre C. Gladstone H.B. Brown P.O. Chang H.Y. Anatomic demarcation by positional variation in fibroblast gene expression programs.PLoS Genet. 2006; 2: e119Crossref PubMed Scopus (335) Google Scholar). The ability to detect and interpret these molecular differences increases with the application of powerful single-cell transcriptome sequencing technologies (Kalisky et al., 2011Kalisky T. Blainey P. Quake S.R. Genomic analysis at the single-cell level.Annu. Rev. Genet. 2011; 45: 431-445Crossref PubMed Scopus (157) Google Scholar, Shapiro et al., 2013Shapiro E. Biezuner T. Linnarsson S. Single-cell sequencing-based technologies will revolutionize whole-organism science.Nat. Rev. Genet. 2013; 14: 618-630Crossref PubMed Scopus (753) Google Scholar), and this type of work is revealing a new understanding of cell diversity in vertebrate tissues. Maintaining unique molecular signatures in otherwise similar cells is most likely an important component of how memory is retained and pattern is reestablished during appendage regeneration. Related to this, a recent study assessed potential components of positional information in regenerating zebrafish fins by sequencing transcriptomes from different AP regions of uninjured zebrafish pectoral fins (Nachtrab et al., 2013Nachtrab G. Kikuchi K. Tornini V.A. Poss K.D. Transcriptional components of anteroposterior positional information during zebrafish fin regeneration.Development. 2013; 140: 3754-3764" @default.
• W2061468450 created "2016-06-24" @default.
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• W2061468450 date "2014-04-01" @default.
• W2061468450 modified "2023-10-16" @default.
• W2061468450 title "Keeping at Arm’s Length during Regeneration" @default.
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