REVIEW

Fetal Skin Possesses the Ability to Regenerate Completely:
Complete Regeneration of Skin
Kazuo Kishi,1 Keisuke Okabe,1 Ruka Shimizu1 and Yoshiaki Kubota2

1Department of Plastic and Reconstructive Surgery, School of Medicine, Keio University, Tokyo, Japan
2Department of Cell Differentiation, The Sakaguchi Laboratory, Keio University, Tokyo, Japan(Received for publication on September 20, 2011)(Revised for publication on November 22, 2011)(Accepted for publication on December 16, 2011)

Until a certain developmental stage, cutaneous wounds in mammalian fetuses heal rapidly without scars
with complete regeneration of the skin. In the process of fetal wound healing, inflammatory responses,
granulation proliferation, and scar formation that are observed in adults are not seen. Numerous studies have reported the causes of fetal scarless cutaneous regeneration, including reduced expression of
TGF-β1 and higher levels of hyaluronan in the extracellular matrix, from the viewpoints of molecularbiology and cellular biology, but the mechanisms are not completely understood. Although a variety of
substances that inhibit scar formation have been investigated, currently it is almost impossible for adultcutaneous wounds to heal completely without scars. Except for a few animal species, perfect regeneration after wounding can occur only during the gestation period. By strictly comparing the stages before
and after the transition from the regeneration of skin to scarring, it will be possible to investigate themechanisms of cutaneous regeneration. (doi: 10.2302/kjm.2011-0002-IR; Keio J Med 61 (4) : 101–108,
December 2012)

Keywords: fetal, healing, regeneration, wound

Introduction
Adult mammals are not capable of regenerating defective tissue to the original state, except for a limited number of organs such as the liver. Most wounded organs,once they are injured, can heal with scar formation, butthey are not regenerated to their original state. Similarly,
in the case of the skin, the dermal structure in woundedareas is disturbed and forms scar tissues that can be definitely distinguished as scars. Unlike normal skin, scartissue of the skin exhibits characteristic features such as
disturbance of the alignment of collagen fibers, excessive dermal fibrosis, disappearance of elastic fiber andappendages, and disruption of skin texture (Fig. 1). In
contrast, if mammalian fetal skin is experimentally injured during early developmental stages, the wounds heal
rapidly without forming scars and the skin is regenerated
completely (Fig. 2).

In 1954, Hess1 was the first to show that experimentallywounded fetal skin healed very rapidly with absolutely
no scar formation. The major goals of the studies of fetal wound healing are to compare the differences between
wound healing in fetuses and adults, to investigate themechanism of fetal cutaneous regeneration, and to develop
a method of regenerating wounded adult skin by utilizing
this mechanism. Analysis of fetal wound healing is complicated because development and wound healing progress
together. The complex factors of wound healing are added
to the active processes of cell migration, cell proliferation,
cell differentiation, and apoptosis, so it is important to proceed with analysis of fetal wound healing while always
making comparisons with skin at the same developmental
stage. In this review, we introduce studies of fetal woundhealing that have been carried out on the basis of molecularand cellular biology to give an overview of fetal woundhealing and to discuss future prospects in the field.

Reprint requests to: Kazuo Kishi MD, PhD, Department of Plastic and Reconstructive Surgery, School of Medicine, Keio University 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan, E-mail: kkishi@sc.itc.keio.ac.jp
Copyright © 2012 by The Keio Journal of Medicine
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Kishi K, et al: Fetal Skin Possesses the Ability to Regenerate Completely

Differences between Fetal Wound Healing and
Adult Wound Healing
Differences between the fetal environment and theadult environment
The mechanism of cutaneous regeneration has beenstudied based on either the environment surrounding the
fetus or the fetal tissue itself. Longaker and co-workers
showed that when human fetal skin was implanted subcutaneously in nude mice and wounds were made, thelayer was closed by human fibroblasts only, resulting inscarless regeneration.2,3 Another study demonstrated thatwhen adult sheep skin was grafted on the back of a fetal
sheep and wounds were made on the implanted skin aftergrafting, grafts healed with scarring.4 These results indicate that adult cutaneous wounds heal with scarring evenin a fetal environment, whereas fetal cutaneous wounds
in an adult environment undergo regeneration without
scar formation. It has thus been shown that the fetal environment is not the main determinant of regeneration, but
the fetal tissue itself is the key to regeneration.
Inflammatory responses
It has been reported that fetal wound healing does notcause inflammatory responses. However, when an inflammatory substance was administered in fetuses during the gestation period when scarring does not occur,
macrophages were reported to be recruited to the injection sites.5,6 In addition, in E16 mouse fetuses in which
histological cutaneous regeneration is known to occur,
macrophages were recruited to the wound surface, but
Mac-1-positive activated macrophages were reported tobe limited in number.7 These findings indicate that evenat the stage when fetal cutaneous regeneration occurs, inflammatory cells exist and may respond to inflammation.
Nerve dependency

Fig. 1 The characteristics of cutaneous scar tissue.
Disturbance of the alignment of collagen fibers (arrows) (A), disappearance of appendages (B), and disruption of skin texture (arrows) (C) were observed. Bar=1mm.

Limb regeneration in urodele amphibians is nerve
dependent, and denervated limbs are not regenerated;
therefore, nerve-driven factors are related to limb regeneration in amphibians.8 The nerve dependence of fetal
wound healing has also been reported. In lamb fetal limb
experiments, the presence of scarring was reported on
the denervated side, whereas the skin was regenerated
without scarring on the opposite enervated side.9 Fromcomparisons among cases of wound healing at various
gestational stages in mice, we suggested correlations between cutaneous regeneration and nerve regeneration;10,11
however, it is not clearly understood what nerve factors
are involved.

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103

Fig. 2 Mice embryonic day 13 cutaneous wound regenerates completely.
Under a microscope, the flank skin of fetal mice was wounded in utero, and was harvested 72 h later (A). Wounds made on embryonicday 13 healed completely, including the skin texture (B, the wound was made within the area marked by dots). The skin texture did notregenerated when wounds were made after embryonic day 14 (C). Bar=1 mm.

Molecular differences(1) Growth factors
Many studies have been conducted on the transforming
growth factor-β (TGF-β) family in relation to fibrosis. In
particular, TFG-β1 is considered to play the central rolein scarring. TGF-β1 induces fibrosis in various organs,and injection of recombinant human (rh) TGF-β1 protein
in adult skin induces fibrosis. In the adult wound healing
process, TGF-β1 (primarily secreted by macrophages) isexpressed excessively in wounds.12,13 When rhTGF-β1
protein was administered in rat wounds, scar fibrosis wasintensified, but when TGF-β1 and β2 expressed aroundrat wounds were neutralized using neutral TGF-β1 andβ2 antibodies, scars were reportedly reduced.14,15 Thereis no agreement on whether TGF-β1 in the fetal woundhealing process is expressed transiently at a very earlystage or whether it is not expressed at all. Whitby and Ferguson stated that TGF-β1 was not expressed excessively
throughout the process of fetal wound healing,12,13,16,17

whereas Martin et al. reported that it was expressed fora short time at a very early stage in the fetal wound healing process and subsequently it disappeared rapidly.18 In
any case, in fetal wound healing, TGF-β1 is not expressed
during most of the cutaneous regeneration process. WhenrhTGF-β1 was administered to fetal wounds, fibrosis was
induced and wound contraction was intensified.12,17,19,20
Among other members of the TGF-β superfamily,
TGF-β3 was shown to reduce scarring, which is the opposite effect to that of TGF-β1.21,22 When a TGF-β3(−/−)
mouse fetus is wounded, wounds heal with scarring.
When rhTGF-β3 was administered in adult wounds, scars
were reduced.23–25(2) Extracellular matrix
Hyaluronic acid is a major component of the fetal skinmatrix,26,27 and the increase in the ratio of hyaluronic
acid in fetal wounds to that in the surrounding skin was
higher than in adult wounds.27–29 When procedures fordecomposing hyaluronic acid in fetal wounds were car-

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ried out using Streptomyces hyaluronidase, fibrosis proceeded with scarring.30 In vitro wound healing experiments using a mouse fetal limb tissue culture model at
the later gestation period (i.e., when scarring can occur)
showed that formation of scars was reduced if the hyaluronic acid concentration in the culture was elevated.31 In
addition, it was reported that hyaluronic acid depresses
proliferation of fetal fibroblasts and accelerates migrationof accelerates their migration.32,33 Hyaluronic acid acts
advantageously for cellular migration and seems to inhibit inflammation, thus it regulates the microenvironment
advantageously for fetal cutaneous regeneration.34,35 Hyaluronic acid up-regulates type III collagen and TGF-β3
expression. These results suggest that TGF-β3 may promote a fetal-like cell environment that favors scarlesshealing.36
Collagen, which is a major component of extracellular matrix in adult skin, is present at lower levels in fetalskin than in adult skin, but it is more quickly deposited
in wounds during fetal wound healing than it is in adulthealing. The collagen amino-acid sequence in wounds
in fetal wound healing is the same as in normal fetal
skin.37 The quantity of collagen in fetal skin is lower thanthat in adult skin, but type I and III collagen contents inwounds increased compared to those in peripheral skinin the wound healing process.38–42 The major reason forincreases in the quantity of collagen may be that morecells migrate to wounds rather than that cells synthesize
more collagen. The ratio of type III to type I collagen inskin is higher in the fetus than in the adult.42
In addition, the relationships of syndecan-1 and -4 andtenascin with fetal wound healing have been reported.
Syndecan-1 and -4, which are transmembrane proteoglycans and have important roles as cell surface receptors during cell–cell and/or cell–matrix interactions, areexpressed strongly in the adult wound healing process,whereas they are not expressed at all in fetal wound healing.43 Tenascins, which are extracellular matrix glycoproteins, are expressed strongly in the locations to whichcells migrate. Tenascins are expressed in the peripheryof wounds both in the adult and fetus; expression occurs
early in wound healing in the fetus, but this quickly disappears. Expression is delayed in adults.44–46
When human fetal and adult skins are compared, elastin is found not to be present in the fetal dermis, whereas
it is present in adult dermis. Most of the differences between fetal and adult skin are found at the level of theexpression of dermal extracellular matrix molecules, andthe differences in the dermis may be the cause of fetal
cutaneous regeneration.47(3) Other molecules
Both PRX-2 and HOXB13 are homeobox genes, andtheir expression is enhanced in fetal fibroblasts and in fetal skin. In addition, expression of PRX-2 is enhanced in

Kishi K, et al: Fetal Skin Possesses the Ability to Regenerate Completely

fetal wound healing compared to that in normal fetal skin.
In contrast, the expression of HOXB13 in fetal wounds islower than in normal fetal skin.48 Recently, it was shownthat excision wounds healed completely without scarringin Xenopus froglets, and that mononuclear cells expressing prx1 accumulated under the new epidermis of skinwounds. These results suggest that scarless skin-woundhealing may require activation of prx1.49 Hoxd8 expression is also increased in mid-gestational wounds, suggesting that it may play a role in scarless wound repair.50
Msx-1 and Msx-2 are other homeobox genes and are expressed in the fingertips in mice. The regenerative abilityof mouse fingertips is restricted to areas in which the amputation plane is within the region of Msx1 expression.51
Msx2-null mice exhibited faster wound closure with accelerated reepithelialization. These results suggest thatMsx2 regulates the cellular competence of keratinocytes
and fibroblasts in skin injury repair.52 Increased canonical Wnt signaling is observed during postnatal cutaneous wound repair but not during fetal cutaneous wound
repair.53 However, Wnt-4 expression is increased during
fetal and postnatal wound repair (Fig. 3).54
Cellular differences
Fetal cells actually synthesize growth factors and extracellular matrix to allow tissue to be regenerated. Many
studies have explained the mechanism of cutaneous regeneration in the fetus based on the differences between
fetal cells and adult cells.
(1) Fibroblasts
Fibroblasts are assumed to play major roles in fetal
cutaneous regeneration. Fibroblasts from fetal and adultskin are different in many respects, such as the ability
to migrate in response to TGF-β signaling, collagen synthesis in response to TGF-β,55,56 responses to insulin-likegrowth factors,57 and synthesis of hyaluronic acid.58 Fetal
fibroblasts demonstrate the following characteristics thatare advantageous for regeneration. Fibroblasts from fetal
and adult skin demonstrate a difference in ability to migrate in response to migration stimulating factor (MSF)
on three-dimensional collagen.59 Adult fibroblasts show
higher expression of TGF-β1 than fetal fibroblasts do.60
Collagen gel contraction by IL-1β stimulation is significantly lower in fetal fibroblasts.61 The tyrosine kinase
Shc is expressed in fetal fibroblasts, whereas it is not expressed in adult fibroblasts.62–64 Fetal fibroblasts inhibit
inflammation and wound contraction and have characteristics that are advantageous for fibrosis inhibition. Adult
gingiva has an ability to regenerate. Comparative studies
of fibroblasts from the gum with fibroblasts from fetalskin have been carried out. Fibroblasts from the gum andfetal fibroblasts have many common features such as theability to migrate in response to cytokines. Several stud

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105

Fig. 3 Summary of fetal cutaneous regeneration.

ies have suggested that features of fetal fibroblasts are related to the inhibition of scar formation. 59,65,66
As evidence for the fact that fetal cutaneous cells havecutaneous regeneration ability, enzymatically suspended
murine fetal mesenchymal cells and epidermal cells weremixed together and transplanted onto skin defects inimmune-deficient mice. When epidermal cells and deepfascial cells were mixed together, they did not regenerate skin. However, when dermal cells and epidermal cells
were mixed together and transplanted on the skin defects,
they regenerated complete skin, including skin appendages.67 By adding cultured human fetal cutaneous cells
to second- to third-degree burn-injured surfaces essentially requiring skin grafting, wounds prematurely close
naturally, and clinical reports have described reduced
constriction.68(2) Myofibroblasts
Myofibroblasts are assumed to play a major role inwound contraction. Myofibroblasts were not found inwounds created in the mid-gestation period, but they
were found in wounds created after the latter portionof the gestation period.69 In addition, fetal wound healing depends on when wounds are created and the sizesof wounds. As the size of a wound increase, myofibroblasts start appearing in fetal wound healing, suggesting
a possible relationship to scar formation.70 Also, the scarformation in fetal skin derived by denervation was accompanied by a-smooth muscle actin-positive cells.10(3) Inflammatory Cells
As mentioned previously, there are no inflammatory responses in fetal wound healing at an early gestation stage.
It was reported that F4/80-positive cells (monocyte-derived macrophages) were found in wounds created after
gestation day 14.5 in mice, whereas they did not appear
in wounds created before and up to gestation day 14.5.71
Mac-1 positive cells, which are markers for activatedmacrophages, do not appear in wounds created before
gestation day 16, whereas they start appearing in the latter gestation period.7 Considering that activated macrophages secrete many cytokines and growth factors thatare involved in scar formation in adult wound heating,there is a high possibility that the presence of activatedmacrophages is significantly related to scar formation.
(4) Platelets
Once wounds are made on the adult skin, platelets arebrought into contact with collagen exposed at the woundsurface, they become activated, aggregate, and thenundergo degranulation to release many cytokines andgrowth factors to start wound healing. Fetal platelets aggregate, but they aggregate poorly to collagen.72 Despite
this phenomenon, when platelets are in contact with collagen, cytokines are actually released.73 Reduced aggregation does not explain the fact that there is less inflammation in fetal wound healing; however, the amounts of
TGF-β1, TGF-β2, and PDGF-AB released by fetal platelets are much lower than those in adult healing.74 It wasalso reported that hyaluronic acid, which is the major
component of extracellular matrix in fetal tissue, inhibits
aggregation of fetal platelets.34

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Transition from Regeneration to Scar Formation

Transition from complete regeneration to disruption

It is important to determine when during the fetal gestation period fetal cutaneous regeneration changes to adultwound healing with scar formation and to identify thephenomena that change immediately before and immediately after the transition point. However, in most studiesof fetal wound healing, the mechanism of regeneration
is explored by comparing the wound healing process at
one point during the gestation period with that during theadult wound healing process. There are numerous differences in cell and tissue differentiation between fetal andadult wound healing, thus it is difficult to identify one
factor as the direct cause of regeneration.
In several studies, the changes from fetal wound healing to adult wound healing were investigated in several species to determine the transition point during
the gestation period. Wounds made on the 16th day ofgestation in rats (gestation period: 21 days) were histologically regenerated, but wounds made on the 18th dayof gestation were associated with scarring.75 In Rhesus
monkeys (Macaca mulatta, gestation period: 165 days)
wounds created on the 75th day of gestation on the lips
resulted in complete regeneration, and the collagen sequence of fetal derma was regenerated on the 85th to100th day of gestation, but hair root and sebaceous gland
were not regenerated. When wounds created on the107th day of gestation healed, histological scarring wasevident.76 Therefore, the transition point in many species of animals was found to be in the middle stage ofgestation. Monodelphis domestica, the gray, short-tailed
opossum, was selected because it gives birth when thefetus is at an early stage of development and the fetus
then grows in the mother’s pouch. Wounds were made in
Monodelphis domestica at various stages of development
after birth, and the transition point from regeneration to
healing with scarring was investigated; the transition wasobserved at about the 9th day after birth. In addition, inflammatory responses of the wounds became prominent
at the same developmental stage.77,78
Based on the studies mentioned above, the followingchanges were observed. If wounds are made at an earlystage of gestation, the skin, including appendages andpanniculus carnosus muscle (PCM), is completely regenerated. If wounds are made at a slightly later stage, thehair bulb and skin texture are no longer regenerated andvisible scarring (visible marks) remains.77,78 If wounds
are made at an even later stage, histological scarring remains. Based on the studies mentioned above, it is clearthat fetal wound healing changes to adult wound healing,
and this process is accompanied by a series of changes.

The timings of regeneration of skin texture and regeneration of the dermal pattern of extracellular matrices
have been investigated separately to clarify the transition
points, and distinct transition points were found in mice.
Until embryonic day (E) 13, murine fetuses have an ability to regenerate injured skin completely. However, when
the fetuses were injured after E14, they no longer regenerate skin texture73 (Fig. 2). The causes of regeneration canbe elucidated by investigating physical and cellular characteristics that change rapidly before and after the transition point while comparing wound healing immediately
before and after the transition point.
Conclusions
Despite the complex nature of fetal wound healing, if
comparisons can be made of the relevant processes before
and after the transition from regeneration to healing without regeneration, the mechanism of cutaneous regeneration will be elucidated in the future.
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