A number of challenges have hindered the development of a unified theory for metazoan regeneration. To describe the full range of complex regeneration phenomena in Animalia, we suggest that metazoans that regenerate missing body parts exhibit biological attributes that are tailored along a morpho-spatial regeneration continuum, illustrated in its polar scenarios by the USA “stars and stripes” flag. Type 1 organisms (“T1, ‘stars’”) are typical colonial organisms (but contain unitary taxa) that are able to regenerate “whole new stars”, namely, whole bodies and colonial modules, through systemic induction and sometimes multiple regeneration foci (hollow regeneration spheres, resembling the blastula) that compete for dominance. They regenerate soma and germ constituents with pluripotent adult stem cells and exhibit somatic-embryogenesis mode of ontogeny. Type 2 organisms (“T2, ‘stripes’”) are capable of limited regeneration of somatic constituents via fate-restricted stem cells, and regenerate through centralized inductions that lead to a single regeneration front. T2 organisms are unitary and use preformistic mode of ontogeny. T1 and T2 organisms also differ in interpretation of what constitutes positional information. T2 organisms also execute alternative, less effective, regeneration designs ( i.e., scar formation). We assigned 15 characteristics that distinguish between T1/T2 strategies: those involving specific regeneration features and those operating on biological features at the whole-organism level. Two model organisms are discussed, representing the two strategies of T1/T2 along the regeneration continuum, the Botrylloides whole body regeneration (T1) and the mouse digit-tip regeneration (T2) phenomena. The above working hypothesis also postulates that regeneration is a primeval attribute of metazoans. As specified, the “stars and stripes” paradigm allows various combinations of the biological features assigned to T1 and T2 regeneration strategies. It does not consider any concentration gradient or thresholds and does not refer to the “epimorphosis” and “morphallaxis” terms, regeneration types across phyla or across body plans. The “stars and stripes” paradigm also ignores, at this stage of analysis, cases of regeneration loss that may obscure biological trajectories. The main advantage of the “stars and stripes” paradigm is that it allows us to compare T1/T2 regeneration, as well as other modes of regeneration, through critical determining characteristics.
References
[1]
Sanchez-Alvarado, A.; Tsonis, P.A. Bridging the regeneration gap: Genetic insights from diverse animal models. Nat. Rev. Genet. 2006, 7, 873–884.
[2]
Tanaka, E.M.; Reddien, P.W. The cellular basis for animal regeneration. Dev. Cell 2011, 21, 172–185, doi:10.1016/j.devcel.2011.06.016.
[3]
Rinkevich, Y.; Paz, G.; Rinkevich, B.; Reshef, R. Systemic bud induction and retinoic acid signaling underlie whole body regeneration in the urochordate Botrylloides leachi. PLoS Biol. 2007a, 5, e71, doi:10.1371/journal.pbio.0050071.
[4]
Sanchez-Alvarado, A. Regeneration in the metazoans: Why does it happen? Bioessays 2000, 22, 578–590, doi:10.1002/(SICI)1521-1878(200006)22:6<578::AID-BIES11>3.0.CO;2-#.
[5]
Tsonis, P.A. Regeneration of the lens in amphibians. Results Probl. Cell Differ. 2000, 31, 179–196, doi:10.1007/978-3-540-46826-4_10.
[6]
Brockes, J.P.; Kumar, A. Appendage regeneration in adult vertebrates and implications for regenerative medicine. Science 2005, 310, 1919–1923, doi:10.1126/science.1115200.
[7]
Robin, N.H.; Nadeau, J.H. Disorganization in mice and humans. Am. J. Med. Genet. 2001, 101, 334–338, doi:10.1002/1096-8628(20010715)101:4<334::AID-AJMG1233>3.0.CO;2-7.
[8]
Wolpert, L. Positional information in vertebrate limb development; an interview with Lewis Wolpert by Cheryll Tickle. Int. J. Dev. Biol. 2002, 46, 863–867.
[9]
Swalla, B.J. Building divergent body plans with similar genetic pathways. Heredity 2006, 97, 235–243, doi:10.1038/sj.hdy.6800872.
[10]
Reginelli, A.D.; Wang, Y.Q.; Sassoon, D.; Muneoka, K. Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice. Development 1995, 121, 1065–1076.
[11]
Goss, R.J.; Grimes, L.N. Tissue interactions in the regeneration of rabbit ear holes. Am. Zool. 1975, 12, 151–157.
Heber-Katz, E.; Leferovich, J.M.; Bedelbaeva, K.; Gourevitch, D. Spallanzani’s mouse: A model of restoration and regeneration. Curr. Top. Microbiol. Immunol. 2004, 280, 165–189.
[14]
Henry, L.-A.; Hart, M. Regeneration from injury and resource allocation in sponges and corals—A review. Int. Rev. Hydrobiol. 2005, 90, 125–158, doi:10.1002/iroh.200410759.
[15]
Bosch, T.C.G.; David, C.N. Stem cells of Hydra magnipapillata can differentiate into somatic cells and germ line cells. Dev. Biol. 1987, 121, 182–191, doi:10.1016/0012-1606(87)90151-5.
[16]
Salo, E.; Baguna, J. Regeneration in planarians and other worms: New findings, new tools, and new perspectives. J. Exp. Zool. 2002, 292, 528–539, doi:10.1002/jez.90001.
[17]
Rinkevich, B.; Shlemberg, Z.; Fishelson, L. Whole-body protochordate regeneration from totipotent blood cells. Proc. Natl. Acad. Sci. USA 1995, 92, 7695–7699, doi:10.1073/pnas.92.17.7695.
[18]
Rinkevich, Y.; Douek, J.; Haber, O.; Rinkevich, B.; Reshef, R. Urochordate whole body regeneration inaugurates a diverse innate immune signaling profile. Dev. Biol. , 312, 131–146.
[19]
Rinkevich, Y.; Rinkevich, B.; Reshef, R. Cell signaling and transcription factor genes expressed during whole body regeneration in a colonial chordate. BMCDev. Biol. 2008, 8, 100–110, doi:10.1186/1471-213X-8-100.
[20]
Rinkevich, Y.; Rosner, A.; Rabinowitz, C.; Lapidot, Z.; Moiseeva, E.; Rinkevich, B. Piwi positive cells that line the vasculature epithelium, underlie whole body regeneration in a basal chordate. Dev. Biol. 2010, 345, 94–104, doi:10.1016/j.ydbio.2010.05.500.
[21]
Manni, L.; Zaniolo, G.; Cima, F.; Burighel, P.; Ballarin, L. Botryllus schlosseri: A model ascidian for the study of asexual reproduction. Dev. Dyn. 2007, 236, 335–352, doi:10.1002/dvdy.21037.
[22]
Voskoboynik, A.; Simon-Blecher, N.; Soen, Y.; Rinkevich, B.; De Tomaso, A.W.; Ishizuka, K.J.; Weissman, I.L. Striving for normality: Whole body regeneration through a series of abnormal generations. FASEB J. 2007, 21, 1335–1344, doi:10.1096/fj.06-7337com.
[23]
Bely, A.E.; Nyberg, K.G. Evolution of animal regeneration: Re-emergence of a field. Trends Ecol. Evol. 2010, 25, 161–170, doi:10.1016/j.tree.2009.08.005.
[24]
Poss, K.D. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat. Rev. Genet. 2010, 11, 710–722, doi:10.1038/nrg2879.
[25]
Mariani, F.V. Proximal to distal patterning during limb development and regeneration: A review of converging disciplines. Regen. Med. 2010, 5, 451–462, doi:10.2217/rme.10.27.
[26]
Morgan, T.H. Regeneration; Macmillan: New York, NY, USA, 1901.
[27]
Neufeld, D.A.; Day, F.A. Perspective: A suggested role for basement membrane structures during newt limb regeneration. Anat. Rec. 1996, 246, 155–161.
[28]
Tamura, K.; Ohgo, S.; Yokoyama, H. Limb blastema cell: A stem cell for morphological regeneration. Dev. Growth Differ. 2010, 52, 89–99.
[29]
Kragl, 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, 60–65.
[30]
Agata, K.; Saito, Y.; Nakajima, E. Unifying principles of regeneration I: Epimorphosis versus morphallaxis. Dev. Growth Differ. 2007, 49, 73–78.
[31]
Kawamura, K.; Hara, K.; Fujiwara, S. Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates. Development 1993, 117, 835–845.
[32]
Mochii, M.; Taniguchi, Y.; Shikata, I. Tail regeneration in the Xenopus tadpole. Dev. Growth Differ. 2007, 49, 155–161, doi:10.1111/j.1440-169X.2007.00912.x.
[33]
Martinez, V.G.; Reddy, P.K.; Zoran, M.J. Asexual reproduction and segmental regeneration, but not morphallaxis, are inhibited by boric acid in Lumbriculus variegatus (Annelida: Clitellata: Lumbriculidae). Hydrobiologia 2003, 564, 73–86.
Wolpert, L. Positional information and the spatial pattern of cellular differentiation. J. Theor. Biol. 1969, 25, 1–47.
[36]
Jaeger, J.; Reinitz, J. On the dynamic nature of positional information. Bioessays 2006, 28, 1102–1111, doi:10.1002/bies.20494.
[37]
Sena, G.; Birnbaum, K.D. Built to rebuild: In search of organizing principles in plant regeneration. Curr. Opin. Genet. Dev. 2010, 20, 460–465, doi:10.1016/j.gde.2010.04.011.
[38]
Benazet, J.D.; Zeller, R. Vertebrate limb development: Moving from classical morphogen gradients to an integrated 4-dimensional patterning system. Cold Spring Harb. Perspect. Biol. 2009, 1, a001339, doi:10.1101/cshperspect.a001339.
[39]
Azuaje, F. Computational discrete models of tissue growth and regeneration. BriefBioinform. 2011, 12, 64–67.
[40]
Beck, C.W.; Christen, B.; Slack, J.M. Molecular pathways needed for regeneration of spinal cord and muscle in a vertebrate. Dev. Cell. 2003, 5, 429–439, doi:10.1016/S1534-5807(03)00233-8.
[41]
Han, M.; Yang, X.; Farrington, J.E.; Muneoka, K. Digit regeneration is regulated by Msx1 and BMP4 in fetal mice. Development 2003, 130, 5123–5132, doi:10.1242/dev.00710.
[42]
Tu, S.; Johnson, S.L. Fate restriction in the growing and regenerating zebrafish fin. Dev. Cell 2011, 20, 725–732, doi:10.1016/j.devcel.2011.04.013.
[43]
Gargioli, C.; Slack, J.M. Cell lineage tracing during Xenopus tail regeneration. Development 2004, 131, 2669–2679, doi:10.1242/dev.01155.
[44]
Bely, A.E.; Sikes, J.M. Latent regeneration abilities persist following recent evolutionary loss in asexual annelids. Proc. Natl. Acad. Sci. USA 2010, 107, 1464–1469, doi:10.1073/pnas.0907931107.
[45]
Martin, P.; Parkhurst, S.M. Parallels between tissue repair and embryo morphogenesis. Development 2004, 131, 3021–3034, doi:10.1242/dev.01253.
[46]
Radtke, F.; Clevers, H. Self-renewal and cancer of the gut: Two sides of a coin. Science 2005, 307, 1904–1909.
[47]
De Loof, A. All animals develop from a blastula: consequences of an undervalued definition for thinking on development. Bioessays 1992, 14, 573–575, doi:10.1002/bies.950140815.
[48]
Wilson, H.V. On some phenomena of coalescence and regeneration in sponges. J. Exp. Zool. 1907, 5, 245–258, doi:10.1002/jez.1400050204.
[49]
Shimizu, H.; Sawada, Y.; Sugiyama, T. Minimum tissue size required for hydra regeneration. Dev. Biol. 1993, 155, 287–296, doi:10.1006/dbio.1993.1028.
[50]
Rinkevich, B.; Shlemberg, Z.; Fishelson, L. Survival budding processes in the colonial tunicate Botrylloides from the Mediterranean Sea: The role of totipotent blood cells. In Invertebrate Cell Culture: Looking Towards the Twenty-First Century; Maramorosch, K., Loeb, M.J., Larfo, M.D., Eds.; Society for In Vitro Biology: San Francisco, CA, USA, 1996; pp. 1–9.
Carlson, M.R.; Bryant, S.V.; Gardiner, D.M. Expression of Msx-2 during development, regeneration, and wound healing in axolotl limbs. J. Exp. Zool. 1998, 282, 715–723, doi:10.1002/(SICI)1097-010X(19981215)282:6<715::AID-JEZ7>3.0.CO;2-F.
[53]
Lehoczky, 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, 20609–20614.
[54]
Buss, L.W. Somatic cell parasitism and the evolution of somatic tissue compatibility. Proc. Natl. Acad. Sci. USA 1982, 79, 5337–5341, doi:10.1073/pnas.79.17.5337.
[55]
Buss, L.W. Evolution, development, and the units of selection. Proc. Natl. Acad. Sci. USA 1983, 80, 1387–1391, doi:10.1073/pnas.80.5.1387.
[56]
Vidal, P.; Dickson, M.G. Regeneration of the distal phalanx. A case report. J. Hand Surg. 1993, 18, 230–233.
[57]
Mizell, M. Limb regeneration: induction in the newborn opossum. Science 1968, 161, 283–286.
[58]
Simon, H.G.; Nelson, C.; Goff, D.; Laufer, E.; Morgan, B.A.; Tabin, C. Differential expression of myogenic regulatory genes and Msx-1 during dedifferentiation and redifferentiation of regenerating amphibian limbs. Dev. Dyn. 1995, 202, 1–12, doi:10.1002/aja.1002020102.
[59]
Egger, B.; Gschwentner, R.; Rieger, R. Free-living flatworms under the knife: Past and present. Dev. Genes Evol. 2007, 217, 89–104, doi:10.1007/s00427-006-0120-5.
[60]
Montgomery, J.R.; Coward, S.J. On the minimal size of a planarian capable of regeneration. Trans. Am. Microsc. Soc. 1974, 93, 386–391, doi:10.2307/3225439.
[61]
Guedelhoefer, O.C.; Sánchez-Alvarado, A. Amputation induces stem cell mobilization to sites of injury during planarian regeneration. Development 2012, 139, 3510–3520.
[62]
Wenemoser, D.; Lapan, S.W.; Wilkinson, A.W.; Bell, G.W.; Reddien, P.W. A molecular wound response program associated with regeneration initiation in planarians. Genes Dev. 2012, 26, 988–1002.
[63]
Aboobaker, A.A. Planarian stem cells: A simple paradigm for regeneration. Trends Cell Biol. 2011, 21, 304–311, doi:10.1016/j.tcb.2011.01.005.
Brockes, J.P.; Kumar, A.; Velloso, C.P. Regeneration as an evolutionary variable. J. Anat. 2001, 199, 3–11, doi:10.1046/j.1469-7580.2001.19910003.x.
[66]
Somorjai, I.M.L.; Somorjai, R.L.; Garcia-Fernàndez, J.; Escrivà, H. Vertebrate-like regeneration in the invertebrate chordate amphioxus. Proc. Natl. Acad. Sci. USA 2012, 109, 517–522.
[67]
Kaneto, S.; Wada, H. Regeneration of amphioxus oral cirri and its skeletal rods: Implications for the origin of the vertebrate skeleton. J. Exp. Zool. B Mol. Dev. Evol. 2011, 316, 409–417, doi:10.1002/jez.b.21411.
[68]
Licciano, M.; Murray, J.M.; Watson, G.J.; Giangrande, A. Morphological comparison of the regeneration process in Sabella spallanzanii and Branchiomma luctuosum (Annelida, Sabellida). Invertebr. Biol. 2012, 131, 40–51.
Berrill, N.J. The development of a colonial organism: Symplegma viride. Biol. Bull. 1940, 79, 272–281, doi:10.2307/1537822.
[71]
Izzard, C.S. Development of polarity and bilateral asymmetry in the palleal bud of Botryllus schlosseri (Pallas). J. Morph. 1973, 139, 1–26, doi:10.1002/jmor.1051390102.
[72]
Mukai, H.; Watanabe, H. Relation between sexual and asexual reproduction in the compound ascidian, Botryllus primigenus. Sci. Rep. Fac. Edu. Gumma Univ. 1976, 25, 61–79.
[73]
Blackstone, N.W.; Jasker, B.D. Phylogenetic considerations of clonality, coloniality, and mode of germline development in animals. J. Exp. Zool. B Mol. Dev. Evol. 2003, 297, 35–47.
[74]
Rosner, A.; Moiseeva, E.; Rinkevich, Y.; Lapidot, Z.; Rinkevich, B. Vasa and the germ line lineage in colonial urochordate. Dev. Biol. 2009, 331, 113–128, doi:10.1016/j.ydbio.2009.04.025.
[75]
Rosner, A.; Rinkevich, B. VASA as a specific marker for germ cells lineage: In light of evolution. Trends Comp. Biochem. Physiol. 2011, 15, 1–15.
[76]
Agata, K.; Inoue, T. Survey of the differences between regenerative and non-regenerative animals. Dev. Growth Differ. 2012, 54, 143–152, doi:10.1111/j.1440-169X.2011.01323.x.
