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Regeneration and Development in Animals

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DOI: 10.1007/s13752-011-0005-3

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Biol Theory (2011) 6:25–35
DOI 10.1007/s13752-011-0005-3
ORIGINAL PAPER
Regeneration and Development in Animals
Michel Vervoort
Received: 21 May 2011 / Accepted: 7 July 2011 / Published online: 8 November 2011
Ó Konrad Lorenz Institute 2011
Abstract Regeneration capabilities are found in most or
all animals. Whether regeneration is part of the develop-
ment of an animal or a distinct phenomenon independent
of development is a debatable question. If we consider
regeneration as a process belonging to development, sim-
ilarly to embryogenesis or metamorphosis, the existence of
regenerative capabilities in adults can be seen as an argu-
ment in favor of the theory that development continues
throughout the life of animals. Here I perform a compar-
ative analysis of regeneration versus ‘‘classical’’ develop-
mental processes in animals in order to determine to what
extent these processes are inclusive or distinct. I identify
the existence of regeneration-specific processes, i.e., pro-
cesses that occur during the regeneration, but not the initial
development, of a given structure. In addition, I find that
seemingly similar processes acting during development
and regeneration may have differential molecular and
cellular bases. I thus conclude that there are significant
differences between regeneration processes in adult ani-
mals and developmental processes occurring during earlier
phases of the life cycle. The existence of regenerative
capabilities in adult animals can therefore not be used as an
argument in favor of the idea that development spans the
whole life.
M. Vervoort (&)
Institut Jacques Monod, Université Paris Diderot and CNRS,
Paris, France
e-mail: vervoort.michel@ijm.univ-paris-diderot.fr
M. Vervoort
Institut Universitaire de France, Paris, France
Keywords Cell differentiation
Dedifferentiation

Development
Epimorphosis
Molecular mechanisms

Regeneration
Stem cells
Regeneration, the replacement of lost body parts, is a
widespread phenomenon in both animals and plants
(Birnbaum and Sánchez Alvarado 2008) that has been
studied for a long time by biologists (reviewed in Sánchez
Alvarado 2006). In this article, I focus on regeneration in
animals. Regeneration capabilities can be very extensive in
some animals, such as planarians (flatworms), which can
regenerate their entire body from small tissue fragments, or
Hydra, which is able to completely regenerate its head after
amputation. Other impressive cases of regeneration are
observed in more familiar animals, such as salamanders or
insects, which display important limb regeneration prop-
erties. More limited, yet fundamental regeneration capa-
bilities are also found in most animals, e.g., the constant
regeneration of the epithelial lining of the gut or of the
epidermis, the restoration of muscle fibers after injury, and
the constant renewal of blood cells.
Studies on animal regeneration have a quite ambiguous
position in the biological field: Although these studies are
often published in developmental biology journals or pre-
sented in developmental biology meetings, the regeneration
process itself is usually considered as a distinct phenome-
non as compared to development (Bely and Nyberg 2010),
or as an epiphenomenon of the mechanisms underlying
development (Morgan 1901; Brockes and Kumar 2008).
I think that one of the reasons for this distinction between
development and regeneration is that animal regeneration
is most often studied in adults. In the classical conception
of developmental biologists, development has a defined
temporal boundary, i.e., development stops at the time of
123
26
the acquisition of sexual maturity which defines adulthood.
Hence, regeneration occurring in adults has to be distinct
from ‘‘true’’ developmental processes. However, in the
theory that ‘‘development never ceases’’ (Gilbert 2003, Ch.
18), regeneration is seen as a bona fide developmental
process and the existence of regenerative capabilities in
adults is considered as an argument in favor of develop-
ment occurring during the whole life.
In this article, I will first discuss the meaning of the term
‘‘regeneration’’ and show that it covers significantly dif-
ferent types of processes. I will then perform a comparative
analysis of regeneration versus ‘‘classical’’ developmental
processes (I will use here development and developmental
processes in their restricted sense, i.e., processes occurring
before the transition to adulthood) in animals in order to
define to what extent they rely on similar or distinct
mechanisms and to determine whether the existence of
regenerative capabilities in adults can be considered as an
argument for a development without temporal boundaries.
I will show that there are significant differences between
regeneration processes in adult animals and developmental
processes occurring during earlier phases of the life cycle
and thus that the existence of regenerative capabilities
cannot be used as an argument in favor of development
which spans the whole life.
Definition(s) and Types of Regeneration
Not surprisingly, many different definitions of regeneration
have been proposed by various researchers in the field. One
of the oldest, yet one of the most rigorous and thorough,
was proposed by Morgan (1901, Ch. 1) in his seminal
monograph about regeneration:
The word regeneration has come to mean, in general
usage, not only the replacement of a lost part, but also
the development of a new, whole organism, or even a
part of an organism, from a piece of an adult, or of an
embryo, or of an egg. We must include also these
cases in which the part replaced is less than the part
removed, or even different in kind.
It is important to note that Morgan included in his
definition of regeneration what is often named by devel-
opmental biologists ‘‘embryonic regulation,’’ i.e., the
capability that embryos from many species have to com-
pensate for the loss of some of their cells (blastomeres)
during early development. Later authors usually neglected
embryonic regeneration, focused on adult regeneration, and
proposed rather similar definitions, such as ‘‘the creation of
a new organ after the original one has been removed’’
(Gilbert 2003, Ch. 18), ‘‘the regrowth or repair of cells,
tissues and organs’’ (Sánchez Alvarado and Tsonis 2006,
123
M. Vervoort
p. 873), ‘‘the replacement of a body part lost through
traumatic injury’’ (Bely and Nyberg 2010, p. 161), and ‘‘the
replacement of lost body parts, restoring mass and func-
tion’’ (Poss 2010, p. 710). Importantly, in most review
articles about regeneration, the existence of different types
of regeneration is pointed out. Morgan (1901, Ch. 1)
defined ‘‘physiological regeneration’’ as opposed to
‘‘restorative regeneration’’:
The term « physiological régénération » I shall use
in the ordinary sense to include such changes as the
molting and replacement of the feathers of birds, the
replacement of teeth, etc.,—changes that are a part of
the life-cycle of the individual. It is sometimes con-
venient to contrast the process of physiological
regeneration with all other kinds.
The use of the term « pathological régénération » for
the latter seems to me, as has been said, unsatisfac-
tory. The two terms proposed by Delage, « regular
régénération » and « accidental régénération » have
certain advantages, although there is nothing acci-
dental, or at least occasional, in regard to the process
itself, as it is entirely regular, although it may only
occur after an accident to the animal. For what is
known as pathological or accidental regeneration,
I propose the term « restorative régénération » and
I shall continue to use the term « physiological
régénération » as generally understood.
This is an important distinction as it emphasizes the fact
that some regenerative processes may be part of the normal
life cycle of an animal whereas others are due to external,
largely unpredictable, causes, such as injuries (see next
section for a more detailed discussion). Later authors dis-
cussed the fact that depending on the studied cases, very
different types of biological structures are regenerated, as
for example in Bely and Nyberg (2010, p. 161)—‘‘Regen-
eration can occur at multiple hierarchical levels, including
cellular, tissue, internal organ, structure, and whole-body
regeneration.’’ In this view, a subdivision should be made
between regeneration at the whole-organism level (i.e., the
regeneration of complex structures such as limbs or tails,
complete organs and organ systems, or whole-body) and
regeneration of much more limited parts of the body such as
the regeneration of the skin and the gut lining or nerve and
muscle regeneration. This latter subdivision has an obvious
connection with the one introduced by Morgan, as physio-
logical regeneration usually concerns limited sets of cells,
whereas regeneration at the whole-organism level is inclu-
ded in Morgan’s restorative regeneration category (which
obviously also includes regeneration of much more limited
group of cells in some cases). Poss (2010, p. 710) distin-
guished ‘‘homeostatic regeneration’’ which ‘‘refers to the
Regeneration and Development in Animals
natural replacement of cells lost in day-to-day minor dam-
age, cell death, and ageing’’ (thus akin to Morgan’s physi-
ological regeneration) from ‘‘injury-induced or facultative
regeneration’’ which ‘‘refers to tissue replacement after
substantial trauma like amputation or ablation’’ (including
whole-body regeneration that occurred in some animals,
and corresponding to Morgan’s restorative regeneration).
I will use Poss’ nomenclature in the next sections of this
article; beyond nomenclature questions, the important point
is to remember that regeneration may occur at many dif-
ferent levels, from single cells to whole organisms, and may
be part of the normal physiology of the animal or triggered
by external causes.
Commonly Used Arguments for the Distinction
Between Regeneration and Development
As stated above, regeneration is usually considered by
developmental biologists as being distinct from develop-
ment. What are the arguments in favor of this distinction,
beyond the aforementioned fact that regeneration can occur
in adults usually considered as a stage when development
has stopped? A first argument is that ‘‘regeneration is ini-
tiated specifically by an unpredictable injury that severs a
piece of the body, leaving a wounded, multicellular stump’’
(Bely and Nyberg 2010, pp. 161–162). In this argument,
the unpredictable nature of regeneration (due to the trig-
gering by external causes) and the predictability of devel-
opment (due to its control by internal causes such as the
genetic information contained in the cells) serve to dis-
tinguish these phenomena from one another. I would argue
against this argument at the following three main levels:
(1) This does not consider the existence of homeostatic
regeneration which is not necessarily induced by
external factors.
(2) There are some unpredictability and controls by
external factors during development as well—for
example, fecundation can be considered as the
unpredictable encounter of gametes, the development
of the gut is crucially dependent on the presence of
bacteria whose precise number and nature is variable,
and sex determination can be controlled by environ-
mental conditions (Bäckhed et al. 2005; Janzen and
Phillips 2006; Fraune and Bosch 2010; see also
Pradeu 2011).
(3) The unpredictability of injury-induced regeneration is
questionable. We can consider that, given the con-
tinuous interaction of animals with their environment,
it is inevitable that injuries or pathologies will occur,
rendering regeneration itself inevitable and crucial
to keep the integrity of the animal. In addition, as
27
already stated by Morgan (1901)—see the quotation
in the previous section—the regeneration process
itself has nothing accidental or occasional—whatever
the causes of amputations, for example, limb
regeneration will follow a highly reproducible, thus
predictable, path.
A second argument in favor of a distinction between
development and regeneration is that ‘‘regeneration has a
unique phylogenetic distribution, different to that of other
developmental phenomena, such as embryogenesis and
asexual reproduction. It occurs in only a subset of animals,
unlike embryogenesis, which is ubiquitous’’ (Bely and
Nyberg 2010, p. 162). This is also a debatable issue and
I would argue that some kinds of regeneration are found in
all animals (see Sánchez Alvarado 2000 for many exam-
ples) and that regeneration is therefore as ‘‘ubiquitous’’ as
embryogenesis. Even organisms which are often presented
as completely devoid of any regeneration capabilities, such
as nematodes, show some sort of regeneration in adults (Wu
et al. 2007; Gabel et al. 2008). Nevertheless, regeneration at
the whole-organism level, in particular whole-body regen-
eration, is not found in all animals—phyletic analyses
suggest that the presence of extensive regenerative capa-
bilities is probably ancestral to metazoans and that these
capabilities have been lost in various evolutionary lineages
(for further details see Sánchez Alvarado 2006; Bely and
Nyberg 2010). Similar evolutionary paths can however be
observed for developmental processes: Indirect develop-
ment (i.e., development that passes through a larval stage
and involves a metamorphosis step) is widespread and
probably the ancestral developmental mode in metazoans.
Many animals do however have a direct development, thus
lacking larval stages and metamorphosis developmental
steps. The phyletic distribution of metamorphosis is there-
fore not different from that of regeneration—some species
with metamorphosis, others without—but different from
embryogenesis; yet, metamorphosis is widely considered as
a bona fide step of development. I therefore think that the
fact that regeneration at the whole-organism level does not
occur in all animals is not a relevant argument for the dis-
tinction between regeneration and development.
A third argument is that regeneration can involve
regeneration-specific features, for example, nerve depen-
dence or regeneration-specific gene expression (Bely and
Nyberg 2010). I think that this is the key putative argu-
ment—any attempt to distinguish regeneration from
development must be based on the existence of such
regeneration-specific features. I will therefore show in the
next parts of this article evidence for the existence of
regeneration-specific processes, i.e., processes that occur
during the regeneration, but not during the initial devel-
opment, of a given structure or organ. In addition, I will
123
28
highlight the existence of different molecular and cellular
bases for similar processes occurring during development
and regeneration. Before detailing my arguments, however,
I need to distinguish and explain different modes of
regeneration.
Modes of Regeneration
Two main modes of regeneration have been proposed by
Morgan (1901), based on whether active cell proliferation
is required or not, and this subdivision is still widely used
by contemporary biologists (reviewed in Sánchez Alvarado
2006; Sánchez Alvarado and Tsonis 2006). Regeneration
that does not require cell divisions is referred to as mor-
phallaxis—the restoration of the missing body part is solely
due to the remodeling of pre-existing cells and/or tissues.
There are only a few examples of morphallactic regener-
ation, such as the initial phases of head regeneration in
Hydra and of liver regeneration (after acute pancreatitis) in
mammals.
In most cases, regeneration requires cell proliferation—
this type of regeneration has been named epimorphosis.
Epimorphic regeneration can be further subdivided into two
broad categories, depending on whether the formation of a
regenerative blastema is involved or not (Sánchez Alvarado
2006; Sánchez Alvarado and Tsonis 2006). A blastema is a
specialized structure that forms upon amputation or injury
and which is made of two cell compartments, a superficial
layer of epithelial cells covering the whole blastema and an
inner mass of mesenchyme-like cells. Regeneration will be
achieved by the eventual differentiation of the cells of the
blastema. Whole-body regeneration of flatworms and limb/
tail regeneration in vertebrates are examples of blastemal
regeneration. Whereas blastemas themselves show surpris-
ingly similar organizations in various animals, blastema
formation can be achieved by very different ways. In some
cases, such as planarian regeneration, blastema formation is
due to the migration toward the wound of pre-existing stem
cells, named neoblasts, their proliferation, and the sub-
sequent differentiation of most of their daughter cells
(Sánchez Alvarado and Tsonis 2006). In other cases, for
example vertebrate limb regeneration after amputation,
blastema formation mainly involves the dedifferentiation of
differentiated cells of the remaining tissues, the prolifera-
tion of the dedifferentiated cells, and eventually their
redifferentiation into the original and/or other cell types—
when a cell type different from the original one is produced,
the process is named transdifferentiation (Brockes and
Kumar 2008).
Non-blastemal epimorphic regeneration is also common
and can be achieved by various manners (Sánchez Alva-
rado 2006). One manner is the transdifferentiation of parts
123
M. Vervoort
of the remaining tissue into the missing structure. This is
for example what happens during lens regeneration in
newt: Pigment epithelial cells from the tip of the dorsal iris
dedifferentiate, re-enter the cell cycle, and ultimately dif-
ferentiate into a completely different cell type to form a
lens (Tsonis 2007). Auditory hair cell regeneration in non-
mammal vertebrates, such as birds, is another example
of transdifferentiation-based regeneration (Tsonis 2007).
Transdifferentiation has also been observed during tail
regeneration in axolotl where spinal cord cells which
derive from the ectoderm dedifferentiate and produce
mesodermal-derived cell types, such as muscle and carti-
lage (Echeverri and Tanaka 2002). In other cases, non-
blastemal epimorphic regeneration is based on the prolif-
eration of the remaining differentiated cells without
dedifferentiation (Sánchez Alvarado and Tsonis 2006).
In newts, for example, after removal of a part of the heart
ventricle, adult cardiomyocytes are able to re-enter the cell
cycle and eventually repair the damaged heart. Similarly in
mammals, after partial hepatectomy, the remaining lobes of
the liver enlarge through the proliferation of all the liver
cell types, eventually replacing the missing mass of the
organ. Cases of limited dedifferentiation followed by cell
proliferation have also been observed—in the zebrafish,
recent studies showed that regenerated heart muscles come
from a subpopulation of cardiomyocytes which disassem-
ble their sarcomeric structure, proliferate, and then redif-
ferentiate into cardiomyocytes (Kikuchi et al. 2010; Jopling
et al. 2010). Finally, non-blastemal epimorphic regenera-
tion is achieved, in many cases, by stimulation of the
proliferation of resident stem cells and the differentiation
of some of their daughters—examples are the regeneration
of bones and muscles in mammals and the continuous
renewal of skin and gut cells in many animals (Sánchez
Alvarado 2000; Poss 2010).
Regeneration-Specific Processes
In order to emphasize the specificity of regeneration,
I identify 4 important processes that occur during the
regeneration of some structures or organs, but not during
their initial formation during development.
Wound Healing
A critical early response in many regeneration events, in
particular those involving blastema formation, is the
migration of epithelial cells across the plane of amputation
or tissue injury to form the wound epithelium (Brockes and
Kumar 2008). After limb amputation in newts and sala-
manders, for example, the wound epithelium has been
shown to be essential for further regeneration. Little is
Regeneration and Development in Animals
known however about the mechanism that controls the
formation of wound epithelium beyond the fact that basal
epidermal cells migration involves important morphologi-
cal changes in these cells, such as removal of desmosomes
and extension of pseudopodia, as well as extensive
extracellular matrix remodeling (Mescher 1996). Such
migration of epidermal cells and the accompanying cell
morphology changes are not found in the initial formation
of the limb.
Dedifferentiation/Transdifferentiation
As described earlier, regeneration of various structures are
thought to involve dedifferentiation and/or transdifferenti-
ation processes. Many aspects of those processes are still
under question, including the mechanisms of the dediffer-
entiation process and the nature of the dedifferentiated cells
(in particular the question about whether they are totipo-
tent/multipotent stem cells or not) (Sugimoto et al. 2011).
Nevertheless, dedifferentiation or transdifferentiation does
not occur during the initial formation of the different
structures or organs whose regeneration involves these
processes. More generally, these processes seem limited to
regeneration events and to some pathological conditions,
in particular cancer formation.
Proliferation of Differentiated Cells
During development, differentiated cells do not proliferate
and one important step in differentiation is usually cell
cycle exit (e.g., Nguyen et al. 2006; Politis et al. 2008).
During regeneration of some organs, e.g., heart in newts
and liver in mammals, fully differentiated cells enter the
cell cycle and divide (Sánchez Alvarado and Tsonis 2006),
a behavior which is not observed during the formation of
these organs during embryogenesis.
Nerve Dependence of Many Regeneration Events
The earliest described and most intensively studied exam-
ple of nerve dependence is the regeneration of the sala-
mander limb (Brockes and Kumar 2008). The regenerating
nerve has been shown to be required to maintain prolifer-
ation of blastema cells: Indeed, denervation of the limb
causes blastema cells to cease proliferating and thus pre-
vents regeneration (Brockes and Kumar 2008). Intrigu-
ingly, when an important peripheral nerve is transected and
inserted into a skin wound, it can induce cell proliferation
and the formation of a supernumerary limb (Egar 1988;
Endo et al. 2004). This nerve dependence of cell prolifer-
ation is specific to regeneration as it is not found in the
developing limb bud. The molecular mechanism of this
29
nerve dependence is now known: Schwann cells produce a
secreted factor, nAG, as soon as the first blastema cells
divide, that stimulates cell proliferation (da Silva et al.
2002), probably through its interaction with Prod1, a cell
surface protein found in blastemal cells (Kumar et al.
2007). Neither nAG nor Prod1 seem to be involved in limb
development (Kumar et al. 2007; Brockes and Kumar
2008; Yin and Poss 2008) and no clear orthologs of these
proteins have been described in other groups of verte-
brates—Prod1 has been proposed to be the salamander
complement regulator CD59 (da Silva et al. 2002), but a
recent study convincingly showed that it is not the case
(Garza-Garcia et al. 2009). The nerve dependence of
regeneration is not limited to salamander limbs, but is also
demonstrated or suggested in many other cases, such as fin
regeneration in the teleost fish Fundulus and body part
regeneration in echinoderms, annelids, hemichordates, and
Hydra (Morgan 1902; Geraudie and Singer 1985; Candia
Carnevali and Bonasoro 2001; Miljkovic-Licina et al.
2007; Rychel and Swalla 2008)—there is no evidence for a
role for nerves in the initial formation of the corresponding
structures during development.
Differential Molecular and Cellular Bases for Similar
Processes in Development and Regeneration
Obviously, regeneration and development of structures or
organs present striking similarities and involve seemingly
common steps. Here I will review several cases of regen-
eration events and show that, although similar processes
are involved as compared to development, regeneration-
specific molecular mechanisms can be defined. The same
line of demonstration is followed by Théry (2011).
Appendage Regeneration in Urodeles and Zebrafish
The first visible signs of limb development are small bul-
ges, called limb buds, which grow out of either side of the
body wall (Towers and Tickle 2009). The early limb bud
consists of a mass of apparently homogeneous undiffer-
entiated mesenchymal cells covered by ectodermal cells,
some of which form the apical ectodermal ridge (AER)
required for bud outgrowth. It has been often suggested that
the regeneration blastema behaves like a developing limb
bud (the wound epithelium playing the role of the AER)
and therefore that limb regeneration is highly similar to
limb formation (e.g., Bryant et al. 2002; Galis et al. 2003).
This suggestion came from several different items of
experimental evidence, such as experiments in which grafts
were made between developing and regenerating urodele
limbs, upon which it was concluded that limb bud and
blastema cells behave identically (Muneoka and Bryant
123
30
1982, 1984). Other studies have shown that the expression
patterns of several genes during blastema stages of regen-
eration are comparable to those observed during limb
development (e.g., Torok et al. 1998; Galis et al. 2003).
As previously indicated, blastema formation is however
very different to limb bud formation, as it requires migration
of epidermal cells (wound healing) and dedifferentiation of
cells, processes which are not involved in limb formation.
Moreover, later phases of limb regeneration do also present
significant differences with initial limb formation. In sala-
manders, it has been shown that the blastema is not a mass
of homogeneous multipotent mesenchymal cells, but rather
a heterogeneous collection of restricted progenitor cells that
have kept to a large extent a memory of the identity of the
differentiated cells from which they arise through the
dedifferentiation event (Kragl et al. 2009). Differential gene
expressions are also observed in regeneration as compared
to development. As described in the previous section,
regeneration-specific expression of nAG and Prod1 are
found in the newt (Kumar et al. 2007; Brockes and Kumar
2008; Yin and Poss 2008). Unusual profiles of Hox gene
expression occur early during axolotl limb regeneration:
Whereas the expression of HoxA9 and HoxA13 is turned on
in a sequential manner in distinct territories in the devel-
oping limb bud, these two genes are expressed simulta-
neously during early limb regeneration and have
overlapping expression domains (Gardiner et al. 1995). The
HoxC10 gene also has different expression profiles during
regeneration and development: Whereas during develop-
ment, it is only expressed in the posterior region of the body
including hindlimbs, during regeneration, HoxC10 expres-
sion is also activated in regenerating forelimbs (Carlson
et al. 2001; Christen et al. 2003). Interesting data also
recently came from another model for vertebrate appendage
regeneration, the regeneration of fins in zebrafish. A screen
carried out to identify conditional mutations in genes that
have essential roles during the regeneration of amputated
adult fins has identified a gene, fgf20a, encoding a fibroblast
growth factor ligand and which has an essential function in
fin regeneration, but not in limb formation (Whitehead et al.
2005). Another study identified miR-133, a microRNA
producing gene, as a key regulator of zebrafish caudal fin
regeneration: miR-133 is detectable at relatively high levels
in the uninjured adult caudal fin and has to be strongly
depleted to allow regenerative outgrowth (Yin et al. 2008).
During development, miR-133 function seems limited to
muscle development and differentiation of dopaminergic
neurons (Chen et al. 2006; Yin et al. 2008).
Tail Regeneration in Amphibians
Tail regeneration has been studied in two different
amphibian subgroups, urodeles (mainly newt and axolotl)
123
M. Vervoort
and anurans (Xenopus tadpoles), and quite surprisingly
appears to be achieved in radically different ways in these
different species (Tanaka 2003; Slack et al. 2004, 2008).
In urodeles, tail regeneration proceeds through the formation
of a blastema and involves dedifferentiation of some cells
(in particular muscle cells), transdifferentiation of nerve
cells into muscle and cartilage cells, and the activation of a
pool of adult neural progenitors, radial glial cells (Egar and
Singer 1972; Echeverri et al. 2001; Echeverri and Tanaka
2002; Tanaka 2003). This has little in common with tail
formation from a tailbud that occurs during development—
however, the very limited knowledge about molecular
aspects of normal tail development in urodeles precludes
any detailed comparison with regeneration. Tail formation
and regeneration has also been extensively studied in
Xenopus. Xenopus tail regeneration does not really involve
the formation of a bona fide blastema (instead the term
regeneration bud has been used; Slack et al. 2008) as there is
no dedifferentiation and no important proliferation of
undifferentiated mesenchymal cells (reviewed in Slack et al.
2008). Rather, regeneration appears to be achieved by pro-
cesses that closely resemble those of normal tissue renewal,
cell proliferation in the ependymal layer of the spinal cord
and in the sheath region of the notochord, and renewal of
muscles from stem cells (the satellite cells) associated with
the differentiated muscle fibers. Interestingly, key differ-
ences have been observed between tail regeneration and tail
formation. A striking difference is that the end product
organs are not completely the same (Slack et al. 2008).
Indeed, the regenerated tail lack spinal ganglia and its
muscles are not segmented into myotomes and instead form
a disorganized mass of muscle fibers. The lack of spinal
ganglia is due to the absence of neural crest induction in the
regenerating tail (in contrast to what happens during
development) (Lin et al. 2007). Lack of myotomes is due to
the formation of muscle cells from satellite cells which are
released into the regeneration bud—this does not allow the
formation of myotomes which are formed during develop-
ment by the sequential generation and differentiation of
somites (Slack et al. 2008). Some differences at the molec-
ular point of view have also been shown: Whereas several
genes are similarly expressed during tail development and
regeneration, the regenerating tail has been shown to lack
the expression of two genes encoding bone morphogenetic
protein (BMP) antagonists, chordin and noggin, of sonic
hedgehog and delta-1 which encodes key signaling mole-
cules—these four genes are expressed in the tailbud during
tail development (Sugiura et al. 2004).
Muscle Regeneration in Vertebrates
Vertebrate skeletal muscle has a remarkable ability to
regenerate after various injuries, including the repeated and
Regeneration and Development in Animals
complete destruction of the tissue. This regeneration
capability is thought to be due to the presence of stem cells,
called satellite cells, that reside as quiescent cells under-
neath the basal lamina that surrounds muscle fibers, and are
able to respond to damage by giving rise to myoblasts that
develop into myofibers or fuse with pre-existing fibers
(e.g., Chargé and Rudnicki 2004; Tajbakhsh 2009). At first
sight, the production of muscle cells from satellite cells
seems similar to muscle formation that occurred during
development and similar myogenic differentiation factors
are involved in both processes (Buckingham and Montarras
2008). Recent data, however, suggest key differences. One
of these differences is that the adult satellite cells may not
share a common embryonic origin with embryonic myo-
blasts: A recent study in Xenopus showed that satellite cells
originate from the embryonic dorsolateral plate, a part of
the mesoderm distinct from the paraxial mesoderm which
produces the myoblasts (Daughters et al. 2011). Other
studies conducted in mice also suggested differential origin
for myoblasts that produce myofibers and satellite cells that
allow their regeneration (De Angelis et al. 1999; Gussoni
et al. 1999; Seale and Rudnicki 2000). In addition to a
distinct origin, adult satellite cells and embryonic muscle
progenitors also have distinct genetic requirements. For
instance, Pax3 and Pax7 have critical roles during muscle
formation but are dispensable for muscle regeneration in
the mouse (Lepper et al. 2009).
Regeneration in Cnidarians
Cnidarians, in particular Hydra, show extensive regenera-
tion capabilities that have been studied for more than a
century (Galliot et al. 2006; Sánchez Alvarado 2000).
Whereas Hydra head regeneration is usually described
as the textbook example of morphallactic regeneration,
a recent study showed that head regeneration may follow
different paths, one of which (following midgastric bisec-
tion) involves the formation of a proliferating cell zone,
reminiscent of blastemas found in epimorphic regeneration
(Chera et al. 2009). This latter study also demonstrated that
this type of head regeneration requires the induction of
apoptosis in some of the remaining cells and that the
apoptotic cells produce Wnt3 secreted molecules that
trigger cell proliferation and head regeneration—this very
peculiar process is unlikely to occur during embryonic
development and does not happen during asexual repro-
duction (Chera et al. 2009). Very little is known about
embryonic development of Hydra. Two studies however
suggested marked differences between embryonic devel-
opment and adult regeneration (Fröbius et al. 2003; Geni-
khovich et al. 2006). In particular several genes known to
be involved in early phases of regeneration and budding are
not expressed when embryonic patterning is established
31
(Fröbius et al. 2003). In addition, a molecular screen for
genes expressed during embryogenesis revealed that many
of these genes are not (or very weakly) expressed in bud-
ding or regenerating adults (Genikhovich et al. 2006).
Another well-studied cnidarian is the sea anemone
Nematostella vectensis which also shows extensive regen-
eration and asexual reproduction properties (Reitzel et al.
2007). A comparison of Hox gene expression during
regeneration and embryonic development showed signifi-
cant differences, suggesting that at least partially distinct
mechanisms are used in these two processes (Burton and
Finnerty 2009).
Regeneration in Flatworms
Flatworms such as planarians are among the animals that
show the most impressive regeneration capabilities—an
entire organism can be regenerated from tissue fragments
as small as 1/279th of the initial body size (Morgan 1898).
Planarian regeneration is of the epimorphic type and
involves the mobilization of pre-existing multipotent stem
cells, named neoblasts (Newmark and Sánchez Alvarado
2002; Sánchez Alvarado 2006). Due to the difficulty in
obtaining and studying planarian embryos, little is known
about the development of the planarian species whose
regeneration has been the most extensively studied. Recent
data have suggested that regeneration may have a genetic
control similar to the one acting during post-embryonic
development, but radically different from that used during
embryonic development (Martı́n-Durán et al. 2010).
Another recent study focused on a non-planarian flatworm,
Macrostomum lignano (a Macrostomida), and showed
significant differences between the genetic requirement for
the function of stem cells used to build the body plan
during development and those involved in regeneration
(De Mulder et al. 2009).
Regeneration in Annelids
While annelids have been extensively studied for their
regeneration capabilities in the late 19th- and early 20th-
century (reviewed in Morgan 1901), much fewer efforts
have been made to continue investigating these animals in
more recent years and little is therefore known of the
molecular mechanisms used during their regeneration and
development. The extent of regeneration capabilities varies
from one annelid to another, as some can only regenerate
their posterior part after amputation whereas others are
capable of more extensive regenerations including head
regeneration—these extensive regeneration capacities are
usually found in annelids which also show asexual repro-
duction (Bely and Nyberg 2010; Bely and Sikes 2010).
Annelid regeneration is based on blastema formation, but it
123
32
is not completely clear whether it involves the use of
neoblast-like stem cells and/or dedifferentiation event—it
is even conceivable that different modes of blastema for-
mation may occur in different annelid species (Thouveny
and Tassava 1998; Bely and Nyberg 2010; Yoshida-Noro
and Tochinai 2010). One of the most studied cases of
annelid regeneration is that of the oligochaete worm,
Enchytraeus japonensis, whose regeneration involves
pre-existing multipotent stem cells (Myohara et al. 1999;
Yoshida-Noro and Tochinai 2010). Histochemistry analy-
ses revealed differences between development and
regeneration in this species, particularly at the level of the
nervous system, suggesting that regeneration and devel-
opment involve at least partially different regulatory
mechanisms (Myohara 2004).
Regeneration in the Hemichordate Ptychodera flava
Hemichordates are worm-like marine animals which
belong to the deuterostome group (also including verte-
brates). Ptychodera flava is a hemichordate whose anterior
structures regenerate reproducibly from posterior trunk
parts when amputated (Rychel and Swalla 2008). This
regeneration event presents several striking differences
with anterior body formation, such as probable nerve
dependence, the likely involvement of apoptosis, the
regeneration of the stomochord (one of the characteristic
features of hemichordates) by ectoderm invagination
(while the stomochord is thought to initially develop from
the endoderm), and different modes of mouth formation
(Rychel and Swalla 2008).
Axon Regeneration in the Nematode Caenorhabditis
Nematodes are among the animals with the most limited
regeneration capabilities. However, axons of some specific
neurons are capable of regeneration after adult-stage
damage (Yanik et al. 2004; Wu et al. 2007). The mecha-
nisms underlying axon regeneration have been studied in
the case of one particular type of neuron, the so-called
AVM mechanosensory neurons (Gabel et al. 2008). Two
important differences were observed as compared to initial
axon formation: The regeneration of the axon is much less
precise that its initial formation, requiring competition and
pruning of unwanted axon branches not found during
development; axon guidance and growth also rely on dif-
ferent molecules during regeneration and development
(Gabel et al. 2008).
Taken together, the experimental data reviewed here
show that, across phyla, regeneration mechanisms can be
considered as strongly different from developmental
mechanisms.
123
M. Vervoort
Regeneration and the Temporal Boundaries
of Development
In the last two sections, I reviewed several cases of
regeneration events and showed the existence of differ-
ences when these events are compared to the corresponding
ones during development. I deliberately chose to present an
almost exhaustive analysis of regeneration versus devel-
opment differences, including cases where only scarce data
are available (annelid regeneration for example), and put
the emphasis on the observed differences. Here I would
like to insist on the fact that there are also many similarities
between development and regeneration of given structures
or organs. My point is clearly not to claim that these are
unrelated processes. From all the literature reviewed in the
previous sections, I think we can nevertheless deduce that
significant differences exist between regeneration in adult
animals and developmental processes occurring during
earlier phases of the life cycle. However, these data are not
sufficient, in my opinion, to conclude that regeneration and
development are totally distinct phenomena—more sys-
tematic comparisons between initial formation and regen-
eration of body parts or organs would be required to make
clear-cut conclusions. Nevertheless, the existence of many
differences should preclude any attempt to use the exis-
tence of regeneration capabilities in adult animals as a
master argument in favor of the claim that development is a
process that lasts the whole life.
To address at an even more abstract level the general
problem raised in the collection of articles of this thematic
section, I will add that the data I reviewed here do not
really provide decisive elements to define the existence
and/or the identity of potential temporal boundaries of
development. I would suggest that research programs
aiming at the systematic comparison of regeneration
capabilities at different stages of the life cycle may provide
crucial data to define whether temporal boundaries do exist
or not. Some data already suggest that regeneration abili-
ties may be different in early and late phases of life. In
Xenopus for example, tadpoles have hindlimb regeneration
capabilities which decline during metamorphosis—in
froglets, limb regeneration produces pattern-deficient
structures known as hypomorphic spikes whereas more
mature Xenopus individuals are unable to regenerate their
limbs (reviewed in Beck et al. 2009). Loss of regeneration
properties during the progress of the life cycle is also
observed in mammals: Adult mammalian central nervous
system axons are unable to regenerate after injury, but
immature CNS neurons regenerate axons robustly—these
differences were shown to be due in mice to the down-
regulation of transcription factors promoting axonal growth
and the up-regulation of transcription factors repressing
axonal growth, after birth (Moore et al. 2009). Fetal and
Regeneration and Development in Animals
neonatal, but not adult, mice can regenerate digit tips and
some digit regeneration has been also observed in human
children and fetuses, while not in adults (Reginelli et al.
1995; Allan et al. 2006; Yokoyama 2008). It has also
recently been shown that the hearts of neonatal mice can
regenerate after partial surgical resection, but this capacity
is lost a few days after birth and never observed in adults
(Porrello et al. 2011). I suspect that such differences may
be observed in many other cases and in different species
and I suggest that differential regenerative capabilities may
help to define stages and boundaries in the life cycle of
animals.
Conclusions
The data I report here show the existence of significant
differences between regeneration processes in adult ani-
mals and developmental processes occurring during earlier
phases of the life cycle. The existence of regenerative
capabilities in adult animals can therefore not be used as an
argument in favor of the view that development spans the
whole life. Whether development has temporal boundaries
or not, as well as the nature of these boundaries, remain
open questions. I propose that further studies on regener-
ation, in particular the comparison of regenerative abilities
at different stages of the life cycle of animals, may help to
solve this question.
Acknowledgments I am grateful to Pierre Kerner, Lucie Laplane,
Michel Morange, Antonine Nicoglou, Thomas Pradeu, and Frédérique
Théry for useful discussions and critical reading of this manuscript.
My work was supported by the CNRS and the Institut Universitaire de
France.
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