Morphallaxis is the regeneration of specific tissue in

a variety of organisms due to loss or death of the

existing tissue. The word comes from
the Greek allazein, which means to exchange.
The classical example of morphallaxis is that of
the Cnidarian hydra, where when the animal is
severed in two (by actively cutting it with, for example,
a surgical knife) the remaining severed sections form
two fully functional and independent hydra. The
notable feature of morphallaxis is that a large majority
of regenerated tissue comes from already-present
tissue in the organism. That is, the one severed
section of the hydra forms into a smaller version of
the original hydra, approximately the same size as the
severed section. Hence, there is an "exchange" of
tissue.
Researchers Wilson and Child showed circa 1930
that if the hydra was pulped and the disassociated
cells passed through a sieve, those cells then put into
an aqueous solution would shortly reform into the
original organism with all differentiated tissue correctly
arranged.[1]
Morphallaxis is often contrasted with epimorphosis,
which is characterized by a much greater relative
degree of cellular proliferation. Although cellular
differentiation is active in both processes, in
morphallaxis the majority of the regeneration comes
from reorganization or exchange, while
in epimorphosis the majority of the regeneration
comes from cellular differentiation. Thus, the two may
be distinguished as a measure of degree.
Epimorphosis is the regeneration of a part of an
organism by proliferation at the cut surface. For
example- in Planaria neoblasts help in regeneration.
An example of morphallaxis is in the hydra.

References[edit]
1.

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https://en.wikipedia.org/wiki/Morphallaxis

Hydra (a diploblastic polyp of the phylum Cnidarian) has been a classical model

Next, the authors used BrdU (another thymidine analog) and an antibody against

of regeneration since Abraham Trembley first studied the enormous plasticity of

mitotic cells to determine that these slow-cycling cells were in fact capable of re-

these animals already in the 18th century. Hydra are not constantly renewing

entering cell division. Previous studies have suggested that the extracellular

their cells but also are capable of regenerating a whole animal from a small piece

matrix (ECM) could provide a niche for the interstitial stem cells. Interestingly, the

of their bodies. Remarkably, they are even able to regenerate a well-patterned

authors report here that the percentage of label-retaining interstitial cells in

organism from the re-aggregation of dissociated cells. At the cellular

contact with ECM was much higher that that of cells that retained only partial

level, Hydra contains three distinct stem cell populations: the ectodermal and

labeling (dividing cells). In other systems quiescent cells are held in G0/G1 phase

endodermal myoepithelial cells are differentiated cells are also stem cells for

of the cell cycle. Recently, a study from the laboratory of Brigitte Galliot has

those specific lineages, respectively, and interstitial stem cells. The interstitial

reported that interstitial stem cells are paused at G2 phase. After one week of

stem cells are multipotent stem cells that give rise to nerve cells, gland cells,

chase for interstitial cells and 3.5 weeks for epithelial cells, most of the cells in

nematocytes and gametes. Epithelial stem cells continuously divide in the body

these compartments that retained the EdU label were in G2 phase.

column, every 3-4 days and get displaced towards the anterior (tentacles) and
posterior (basal disk or foot) tips where they terminally differentiate and
progressively get sloughed off. Interstitial stem cells divide also in the body
column but at a higher rate, every 24-30 hours and then migrate towards the tips
as progenitor cells before their final differentiation.

Finally, the authors checked the potential contribution of these slow-cycling cells
during regeneration. The authors performed midgastric amputation and analyzed
head regeneration in animals chased either for one week or 2.5-3.5 weeks. The
regenerating tips were cut at 1 and 3 hours of regeneration, macerated and then
the authors counted the number of EdU-retaining cells with complete and partial

Now, a paper from the laboratory of Yashoda Ghanekar

label. As control they used the same body region from animals in chase. The

(http://www.ncbi.nlm.nih.gov/pubmed/25432513) reports the existence of slow-

authors found a 50% decrease in the number of cells with complete label at 1h of

cycling cells within these 3 different compartments of stem cells. In various

regeneration and a concomitant increase of cells with partial label, indicating that

mammalian stem cell systems, slow-cycling or quiescent cells that do not

slow-cycling cells had entered cell division during this time.

normally go through division under normal physiological conditions have been

described. These cells normally rest in the G0 phase of the cell cycle and divide
at a very slow rate or only as a response to injury. Here, the authors report on the
presence of slow-cycling cells within Hydra stem cells.

In summary, the authors describe here a sub-population of Hydra stem cells that
divide infrequently. These slow-cycling cells were present in the 3 stem cell
lineages, were capable of re-entering the cell cycle and were activated to divide
as a response to amputation during the first hour of regeneration.

To determine the presence of such slow-cycling cells the authors

pulsed Hydra with EdU (a thymidine analog that gets incorporated into the DNA
during cell division) for one week to ensure that all cells undergo cell division at

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least twice and then chased for several weeks in a fresh medium without EdU.
Cells that keep dividing will lose a detectable EdU signal. On the contrary cells

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that do not divide any more such as differentiated cells or quiescent stem cells
retain the Edu labeling. After one week of pulse, 94-98% of interstitial cell were
labeled as well as the 54-80% and the 46-51% of the ectodermal and
endodermal epithelial cells, respectively. After four weeks of pulse, these
percentages increased to 100% in interstitial cells and more than 90% in
epithelial cells. These results indicated that even after 4 weeks few epithelial cells
remained undivided. After a long chase (4 weeks) after the EdU pulse, a small
but significant number of EdU-positive cells were found in the body column. After
one week of pulse and up to ten days of chase around 2.6% of undifferentiated
interstitial cells showed complete EdU label. After ten days, only partial labeled
interstitial cells were detected (indicating that they were dividing). Ectodermal and

Notch signalling in Hydra head regeneration

endodermal epithelial cells retained the EdU label for much longer. Thus, after a
4 weeks chase, 2.1 and 1.8% of ectodermal and endodermal epithelia cells,

SEPTEMBER 19, 2013 6:53 AM / LEAVE A COMMENT

respectively, had complete EdU label. Considering the average cell-cycle time of
these different lineages, these results suggest that in all three there were cells

Hydra is one of the most basal animals and a classical model of regeneration.

that did not divide from approximately 8-10 cell cycles after the pulse.

These polyps display an amazing plasticity as they can regenerate a whole

animal from a tiny piece of their bodies, can reproduce asexually by budding and,
amazingly, dissociated cells can re-aggregate to form a new individual. Hydra has

a well-established oral-aboral axis. In the head (oral) region there is a hypostome

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and a ring of tentacles. Many studies have reported that the tip of the head has
an organizing activity. Thus, if this head tip is transplanted into the body column it
is able to induce a new head and a secondary axis. This organizing activity
appears to be controlled by the Wnt/Beta-catenin pathway. HyWnt3 is expressed
at the tip of the head in intact and regenerating animals. Ectopic induction of Wnt
signalling in the body column induces secondary axes all along it.
In a recent paper from the laboratory of Angelika Bttger the authors describe
how Notch signalling plays a key role in maintaining and re-establishing
the Hydra head (http://www.ncbi.nlm.nih.gov/pubmed/24012879). Notch

Epimorphic regeneration in Nematostella and the use of the terms epimorphosis

and morphallaxis in regeneration

signalling is a well-known and highly conserved pathway that plays a role, among
other, in establishing well-defined boundaries as it can specify different cell fates
in two adjacent cells. Once Notch transmembrane receptor is bound by a ligand
the intracellular domain of the Notch receptor (NICD) is, then, cleaved and can go
to the nucleus where it works as a co-activator of target genes. DAPT is a wellknown inhibitor of the Notch pathway as it prevents cleavage of the active NICD
and it is usually used in different animal models.
Upon culturing intact Hydras in DAPT for 48h the authors saw how the tentacles
were shortened (beginning after 24h of treatment). After 48h of treatment DAPT
was removed and in the following days these polyps displayed different levels of
abnormalities in the patterning of their tentacles and heads, and even a new
secondary hypostome appeared in some of them. At the molecular level, the
expression pattern of HyWnt3 at the tip of the hypostome was not affected by
DAPT treatment. However, the expression of HyAlx (a marker or tentacle
boundary) was severely affected. Previous studies had suggested
that HyAlx might play a role in the specification of tissue for the formation of the
tentacles. The results presented here support this view and point out Notch
signalling as required for proper HyAlx expression and, therefore, differentiation
of tentacles.
Next, the authors analysed the function of Notch signalling during head
regeneration. In most of their experiments the animals were treated with DAPT
for 24h prior to amputation. After 24h of regeneration in DAPT, this inhibitor was
then removed from the medium and the animals were analyzed at different time
points of further regeneration. After 60h only 18% of the animals had regenerated
their heads. This lack of head regeneration can be explained because of the lack
of re-establishment of a new head organizer. Thus, whereas in
controls HyWnt3 is initially expressed in the regenerating tip in a broad cap-like
pattern and then it becomes restricted to the tip of the new hypostome (around
36hpa), DAPT prevented the expression of HyWnt3 for up to 48h of regeneration.
A similar result was observed for HyB-catenin. To check that DAPT really inhibits
the formation of a head organizer the authors transplanted 24h regenerating tips
of DAPT treated animals into the body column of host polyps. Only in 25% of the
transplants a secondary axis developed in sharp contrast to the 100% of
secondary axes observed when transplanting the regenerating tips of control
animals.

JANUARY 31, 2013 2:32 PM / 2 COMMENTSON EPIMORPHIC REGENERATION IN

NEMATOSTELLA AND THE USE OF THE TERMS EPIMORPHOSIS AND
MORPHALLAXIS IN REGENERATION

In a recent paper Passamaneck and Martindale show that cell proliferation is

necessary

for

regeneration

in Nematostella(http://www.ncbi.nlm.nih.gov/pubmed/23206430). By blocking cell

proliferation the authors are able to block also regeneration, suggesting that
contrary to what it has been described in Hydra, Nematostella does not appear to
have any other compensatory mechanism to allow regeneration in a context of no
proliferation. This finding is relevant because it shows how different cnidarian
species may use very different modes of regeneration based on the classically
used terms of epimorphosis and morphallaxis.
Originally, in 1901 Thomas H. Morgan wrote that there are known two general
ways in which regeneration may take place, although the two processes are not
sharply separated, and may even appear combined in the same form. In order to
distinguish broadly these two modes I propose to call those cases of
regeneration in which proliferation of material precedes the development of the
new part, epimorphosis. The other mode, in which a part is transformed directly
into a new organism, or part of an organism without proliferation at the cut
surfaces, morphallaxis. Based on this definition it appears that when
regeneration requires proliferation then it would be epimorhic regeneration,
whereas regeneration in the absence of proliferation would be morphallactic. A
more updated use of the term epimorphic includes also the definition by Richard
J. Goss (The natural history (and mistery) of regeneration, 1991. In A History of
Regeneration Research. Milestones in the evolution of a science, Ed. C.E.
Dinsmore) and that states that Epimorphic regeneration refers to the regrowth of
amputated structures from an anatomically complex stump, and that The first
event in epimorphic regeneration is the development of a blastema, or
regeneration bud, derived from dedifferentiated cells, out of which the new
structure will take shape. So, the consensus is that epimorphic regeneration
requires proliferation and the formation of a blastema. But not all blastemas are
derived from dedifferentiated cells as stated in Goss definition. That is valid, for
instance, for amphibian limb regeneration. But in planarians, regeneration occurs
mainly by cell proliferation and the formation of a blastema that is derived from
adult pluripotent stem cells and not after dedifferentiation.

Finally, the authors checked the expression of HyAlx during regeneration. In

controls HyAlx is initially expressed in the whole regenerating tip (at 24h). At 48h
this gene gets restricted to 4 or 5 rings at the sites where the tentacles will
emerge. In DAPT-treated polyps, the initial expression of HyAlx appears normal
but it never gets confined to 4 or 5 rings and it remains in the whole regenerating
tip and gets expanded, suggesting that the whole tip had characteristics of
tentacle precursors. Finally, the authors checked that upon DAPT treatment the
expression of HyNotch in the regenerating tip is not affected but that of HyHes, a
target of Notch signalling is abrogated.
Whereas in intact Hydra the authors suggest that Notch signalling is required to
define the tentacle boundary, during regeneration Notch would be required to
separate tentacle and hypostome cell fate. In their model, the Notch signalreceiving cells suppress the tentacle fate and become hypostomal cells by
stabilizing the expression of HyWnt3 and HyB-catenin. Consequently, the
inhibition of Notch signalling would allow the observed increased in tentacle cell
fate and the lack of the Wnt/beta-catenin-mediated re-establishment of the head
organizer.

But whereas the idea of epimorphic regeneration is quite well-established it

cannot be said probably the same for the term of morphallaxis. Thus, Hydra has
been usually used as an example of morphallactic regeneration because it has
been know for many years that they can regenerate in the absence of
proliferation or without a significant contribution of this proliferation. However, in
2009 the laboratory of Brigitte Galliot showed that in Hydra, and after midgastric
bisection, head regeneration depends on an initial apoptotic response below the
wound that triggers a proliferative zone with blastema-like features that
significantly

contributes

to

oral

regeneration

(http://www.ncbi.nlm.nih.gov/pubmed/19686688). So, in that particular context

regeneration seems to be epimorphic. As Morgan already said in his definitions,
both processes, epimorphosis and morphallaxis, are not mutually exclusive. A
good example of that are freshwater planarians that have been considered to
follow a mixed epimorphic/morphallactic mode of regeneration. The basis of that
is that in addition to the fundamental role of pluripotent stem cells in giving rise a
regenerative blastema where the missing structures are formed, there is also a
remodeling of the pre-existing tissues far away from the wound that help to attain
the proper body proportions during regeneration. This remodeling, considered as
morphallactic, is more evident in for example in head and tail pieces regenerating

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a new whole planarian. Thus, if you start with a big head piece containing a big
brain it regenerates not only the whole body posterior to this head (through
proliferation, blastema formation and growth of the regenerated part) but at the
same time the original head with its brain go through an extensive remodeling so
they decrease significantly in size in order to form a smaller planarian with perfect

body

of

To solve this apparent conflict one possibility could be to restrict the term of

morphallaxis at the beginning of this post literally, this remodeling would not

(head/trunk/tail)

morphallaxis to the first definition given by the same Morgan in 1898 in which

require proliferation. However, a paper from the laboratory of Alejandro Snchez-

he wrote: Thus, the relative proportions of the planarian are attained by a

Alvarado on the temporal and spatial dynamics of Wnt genes expression during

remodeling of the old tissue. I would suggest that this process of transformation

planarian regeneration shows that although pre-existing cells can assess their

be called a process of morpholaxis. Then, morphallaxis can be clearly

new A/P position in the absence of stem cells, anatomical tissue remodeling in

associated to remodeling of the pre-existing tissues and this would be

planarians

proliferation dependent or proliferation-independent depending on the

depends

proportions.

on

So,

the

following

presence

Morgans

of

definition

stem

cells

(http://www.ncbi.nlm.nih.gov/pubmed/20707997). Therefore, this data would point

out that morphallaxis could depend somehow also on proliferation.

organism (planarian/Hydra) or the specific context of regeneration.