Appendage Regeneration in Adult Vertebrates and Implications for Regenerative Medicine

Abstract

The regeneration of complex structures in adult salamanders depends on mechanisms that offer pointers for regenerative medicine. These include the plasticity of differentiated cells and the retention in regenerative cells of local cues such as positional identity. Limb regeneration proceeds by the local formation of a blastema, a growth zone of mesenchymal stem cells on the stump. The blastema can regenerate autonomously as a self-organizing system over variable linear dimensions. Here we consider the prospects for limb regeneration in mammals from this viewpoint.T he goal of regenerative medicine is to restore cells, tissues, and structures that are lost or damaged after disease, injury, or aging. The current approaches are influenced by our understanding of embryonic development, of tissue turnover and replacement in adult animals (1-3), and by tissue engineering and stem cell biology (4). The regeneration of organs and appendages after injury occurs in diverse animal groups and provides another important viewpoint, in addition to the demonstration that complex adult tissues can be rebuilt. The lessons of biological regeneration have not been extensively assimilated, in part because this attribute appears remote and exceptional from a mammalian perspective. This Review is concerned principally with lessons from regeneration in salamanders, the species of adult vertebrates that possesses the most extensive abilities (5, 6). We identify three properties of regeneration in salamandersautonomy, scaling, and plasticity-and discuss some of the cellular and molecular mechanisms underlying them. It may be desirable to implement these properties in the context of mammalian regeneration.Regenerative medicine currently uses three approaches ( Fig. 1) (4): the implantation of stem cells to build new structures, the implantation of cells pre-primed to develop in a given direction, and the stimulation of endogenous cells to replace missing structures. Each of the different aspects identified in the first two examples-the generation of an appropriate cohort of regenerative cells, their regulated division and differentiation, and the restoration of the appropriate part of the structure-must be evoked from endogenous cells in the third approach. These processes operate in adult animals that regenerate, and in addition, the regenerative response must be initiated by signals responsive to tissue injury or removal. One candidate signal in salamanders is the local activation of thrombin, a regulator of hemostasis and other aspects of the response to injury, as well as an activator of S phase (the phase of chromosome replication) reentry in differentiated cells (7-9).A salamander can regenerate its limbs and tail, upper and lower jaws, ocular tissues such as the lens and retina, the intestine, and small sections of the heart (10-13). The various contexts for regeneration do not present an equivalent degree of difficulty. To restore the intricate and discontinuous pattern of the vertebrate limb is a different proposition from replac...

Transdetermination: Drosophila imaginal disc cells exhibit stem cell-like potency

“…Additionally, if the newly formed blastema is isolated from the disc fragment and then cultured in vivo, it is programmed to form a complete adult leg . Such a result indicates that blastema cells in the disc harbor tremendous developmental autonomy and plasticity, a property observed in vertebrate limb blastemas (Brockes & Kumar, 2005).…”

A challenge for regenerative medicine: Proper genetic programming, not cellular mimicry

“…There is a large body of research, especially from work with lower vertebrates and Drosophila, that argues strongly that transdifferentiation and dedifferentiation are not rare events in nature. Many excellent reviews cover different aspects of this fascinating field (Slack and Tosh, 2001;Brockes and Kumar, 2005;Alvarado and Tsonis, 2006;Tsonis, 2007). Thus, this topic will not be discussed in depth here.…”

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

“…Therefore, blastema tissue contains undifferentiated and proliferating cells that are able to redifferentiate to specific cell types as required (Lemischka 1999;Carlson 2007). These processes, cellular dedifferentiation and blastema formation, are especially prominent in some animals with regenerative abilities, such as hydra (Galliot et al 2006;Bosch 2007a, b), planarians (Reddien and Sánchez Alvarado 2004), zebrafish (Poss et al 2003;Poss 2007), salamanders, axolotls and newts (Odelberg 2005;Brockes and Kumar 2005). There are also several reports on limited regeneration in mammals, including the regrowth of fingertips in mouse (Han et al 2008), antlers in deer (Li et al 2014), and ear hole closure in rabbit (Goss and Grimes 1975).…”