Regeneration of Hair Follicles and Sebaceous Glands
from the Epithelium of Scars in the Rabbit*
CHARLESBREEDIS
(Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pa.)
It has been generally accepted that, when all the
hair follicles and sebaceous glands in a region of
adult skin are destroyed, or the entire region is
extirpated, the new epithelium growing in from the
side will not regenerate these structures (14).
On the basis of this concept, attempts were
made to obtain a purely squamous sheet of epi
thelium in the rabbit for the purpose of inoculating
it with the Shope papilloma virus. A region of skin
was surgically removed from the back, and the
wound was allowed to heal under conditions that
largely prevented contraction
and drying. Con
trary to expectation, functioning hair follicles and
sebaceous glands appeared in the scars, sometimes
in great profusion.
In the experiments
here reported, wounds in
various stages of healing were studied in an at
tempt to determine the origin of the new hair
follicles and glands.
The "hair follicle" is here considered a purely
epithelial derivative,
by Ham (6).
as defined by Cowdry (3) and
MATERIALS
AND METHODS
Rabbits of mixed breeds weighing 2,800-3,500 gm. were
used. They were fed commercial rabbit pellets, supplemented
in some experiments with greens. All operations described
below were performed under Nembutal anesthesia and as
aseptically as possible.
To obtain a uniform and large sheet of scar epithelium it
was thought desirable to hinder as much as possible the con
traction of the wound during healing. For this purpose a wire
ring was devised that could be anchored in the skin surrounding
the wound. The ring consisted of a 22-gauge surgical stainless
steel wire bent into the form shown in Figure 1 (C).
The ring was fastened in the skin as follows : The back of the
rabbit was shaved with an electric clipper and was depilated
with a mixture of equal parts of barium sulfide and cornstarch made to a thin paste with water. The ring was placed on
the middle region of the back, 2 or 8 cm. from the midline. Its
outline was traced with India ink, thus forming a circle on the
skin 33 mm. in diameter. The positions of the seven prongs
were marked on the circle. The ring was then sterilized by
*This investigation was supported by a research grant
(C-1116) from the National Cancer Institute of the National
Institutes of Health, Public Health Service.
Received for publication April 21, 1954.
boiling, during which time the skin was painted with iodine and
then washed with ether. A disc of skin about 25 mm. in diame
ter was cut with a scissors from within the circle of ink and con
centric with it. The disc included the total thickness of skin as
well as the underlying panniculus carnosus.
The wire ring was now pushed through the wound into the
subcutaneous tissue and was so placed that its upward pro
jecting prongs coincided with the marks on the India ink
circle. The skin was punctured at each mark with a No. 11
Bard-Parker blade, thus allowing the prongs to project through
the skin. The appearance of the anchor ring in relation to a
healed wound is shown in Figure 3.
The wound was protected by a glass-covered chamber
fastened to the ring, as shown in Figure 2. The chamber con
sisted of a heavy stainless steel ring with three projecting lugs
(Fig. 1 [B]) and an ordinary chemical watch glass (Fig. 1 [A]).
The under surface of the ring had a shallow groove into which
the seven prongs of the underlying wire ring were fitted.
The heavy ring, placed on top of the prongs, was firmly
attached to each with 28-gauge stainless steel wire. The glass
cover was then fastened in place, as shown in Figure 2, with
25-gauge stainless steel wire.
The chamber was left in place, except for temporary re
moval of the glass cover when observations were made or
dressings applied, until the end of the experiment. Then the
animals were sacrificed with Nembutal. For microscopic
examination sections were cut perpendicular to the skin sur
face after fixation in Bouin's solution. Whole mounts of the
epithelium were prepared by the acetic acid method described
by Cowdry (4). Only the epithelium of the scar separated
readily by this method. Mature hair follicles in the surround
ing skin were too deep to be pulled out. The best results
were obtained by soaking in ice-cold 1 per cent acetic acid for
2-3 days, fixing in Bouin's solution for 1 day at room tempera
ture, and then lifting off the scar epithelium.
Preparations of the dermal papillae were made after re
moving the epithelium. Using a razor blade, a thin slice of
the dermal surface was shaved off and stained with hematoxy lin.
EXPERIMENTAL
RESULTS
Dressing of the wound and rate of healing.—In
the first five rabbits the wound was kept moist
with vaseline gauze dressings. With this treatment
the wound did not develop a base that moved with
the skin, but remained open to the subcutaneous
tissue until granulation from the side closed the
defect. The closure required 18-30 days and com
plete epithelialization
several additional
days.
Three of the wounds became infected.
Leaving the wound alone resulted in more rapid
575
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576
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Cancer Research
healing and only an occasional infection. This pro
cedure was adopted for the remaining 33 animals.
The chamber allowed slow evaporation to occur,
and the wound healed by scab formation and
granulation.
The sequence of events was as follows : As dry
ing proceeded, the upper layer of the loose sub
cutaneous tissue became attached to the edges of
the wound and moved with the skin. In 7-10 days
this membrane became thick and opaque. In 10-14
days a brown scab covered the entire wound. The
granulation tissue growing in from the side reached
the center in 15-22 days. Epithelialization
was
usually complete several days thereafter, and the
scab separated.
Beginning at about the time of separation of the
scab or several days before this occurred, vaseline
gauze dressings were applied every 3-6 days.
When the new epithelium was not protected in
this way, and especially when the glass cover was
left off the chamber, there was excessive drying
and contraction
of the wound with little or no
regeneration of hair follicles and sebaceous glands.
Organization of the scar epithelium into hair fol
licles and sebaceous glands.—Microscopic observa
tions were made on sections through the wounds
from 23 rabbits and on whole epidermal mounts
from fifteen additional rabbits.
None of the sections showed evidence that hair
follicles or sebaceous glands had been left within
the wound area at the time of operation. All epi
thelium either was confined to the surface of the
granulation
tissue or appeared to be projecting
from this surface epithelium into the granulation
tissue.
Sections of wounds not yet completely epithelialized showed scattered diffuse thickenings of the
epithelium.
These are illustrated
in Figure 4,
which represents a wound of 23 days. The thick
ened epithelium consisted of five or more layers of
cuboidal cells and showed no evidence of organiza
tion. At about 30 days, when epithelialization
was
usually complete, the thickened regions developed
downward projections into the granulation tissue.
Some of these could be identified as early hair fol
licles. Such a follicle is shown in Figure 5. Between
32 and 40 days, functioning hair follicles appeared
and were sometimes present in great numbers, as
illustrated
in Figure 6. Once organization
and
growth of the follicles had begun, they penetrated
rapidly into the granulation tissue. In wounds of
45-55 days many of the new follicles were as deep
as those of the normal skin at the edge of the
wound.
While these observations
suggested a true re
generation
of follicles from the surface epithe
lium, there were other possible explanations. The
trauma of making the wound and of affixing the
chamber may have loosened viable fragments of
hair follicles, which could either be scattered over
the wound or be carried into it by the migrating
surface epithelium.
Some parts of a follicle can
regenerate the whole (6).
To determine the distribution
of the new fol
licles and to study their structure in three dimen
sions, whole mounts of the wound epithelium were
made as described above.
Mounts prepared at various stages of healing
revealed the following sequence of events : Before
the epithelium had completely covered the wound
it had numerous bands or bars of thickening that
consisted of five or more layers of cuboidal cells.
Most of them were radially arranged, but many
formed a reticular pattern that connected with the
radial bars. This arrangement
is illustrated in Fig
ure 7 (27 days). The bars correspond to the thick
enings of epithelium shown in cross-section in Fig
ure 4. No organized structure could be seen in
them. Some of the bars could be traced back to
hair follicles at the edge of the wound.
As epithelialization
proceeded, most of the con
necting bars disappeared while the radial ones per
sisted. Then numerous budlike projections
ap
peared on the bars, first at the periphery of the
wound and later near the center. This budding is
illustrated in Figures 8 and 9 (31 days). Each bud
was an immature hair follicle that in cross section
would appear about as shown in Figure 5.
Sometimes the radial bars could be seen through
the dissecting microscope in the living animal.
Radially arranged blood vessels were also some
times seen under the wound epithelium.
As the hair follicles matured and began to pro
duce hair, the radial bars gradually disappeared,
leaving radially arranged rows of follicles. These
rows are seen at the periphery of the scar in Figure
8 (31 days) and near its center in Figure 10 (33
days). Still later, owing perhaps to local contrac
tions of the healing wounds, the linear arrange
ment disappeared entirely, as illustrated in Figure
11 (50 days).
It is of interest that in epidermal mounts pre
pared from four rabbit embryos (3 weeks), the
hair follicles arose as discrete thickenings of the
epiderm, arranged in a geometrical pattern. There
was no evidence of thickened epidermal bars.
The sebaceous gland, in the region of skin under
consideration, is a derivative of the hair follicle and
is always associated with it. Sections do not show
it well unless the cut is through both the gland and
the follicle. Figure 15 (50 days) illustrates such a
gland adjacent to a regenerated follicle in a rabbit
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BREEDIS—Regeneration of Hair Follicles and Sebaceous Glands
that had also been inoculated with the Shope
papilloma virus. In the epithelial mounts the se
baceous gland appears as a bulbous swelling of the
neck of the follicle near its attachment to the sur
face epithelium (Fig. 12). The sebaceous gland was
first noted at about the time the follicle began to
produce hair.
The role of dermal elements in the regeneration of
hair follicles.—The arrangement
of the hair fol
licles in the epithelial mounts and their budding
from otherwise unorganized epithelial bars argued
strongly against a possible random seeding of the
wound by hair follicle fragments.
The chances
against repeated occurrence of the radial pattern
would be enormous. However, the influence of an
other factor, dermis, had to be considered.
The hair follicle is in intimate contact with
dermal structures, perhaps the most important of
which is the dermal papilla. The papilla lies inside
a cup-shaped excavation in the bulb of the hair fol
licle. Several are well shown in Figure 12. In the
embryo the papilla is thought to "induce" the hair
follicle (1, 7). Had dermal elements induced the
hair follicles in the regenerating skin? If so, how
had this come about?
Preparations of the entire dermal surface under
lying the scar epithelium were made as described
above. Six healed wounds varying from 31 to 50
days in age were examined. In each case the epi
thelium, which had been removed as a single
sheet, was also available for study.
The 31-day preparation of dermal surface was
that underlying the epithelium shown in Figure 8.
As seen from this figure, hair follicles were just be
ginning to bud from the central portions of the
epithelial bars and were already fairly well or
ganized at the periphery. On examining the dermal
surface under this epithelium, the radial grooves
left by the epithelial bars were visible, and also the
depressions left by the buds. Condensations of cells
that might be early dermal papillae were made out
with some difficulty along the grooves in the cen
tral parts of the wound. Unquestionable early der
mal papillae were seen near the periphery of the
wound, under the more advanced hair follicles.
Figure 13 illustrates the appearance of these early
papillae.
The later preparations
(34-50 days) showed an
increase in size and organization of the papillae
that paralleled the development
of the hair fol
licles. The mature papillae stained densely with
hematoxylin and were clearly visible at the bottom
of the holes from which the hair follicles had been
pulled. Figure 14 illustrates their appearance in
the 50-day preparation.
In all six dermal preparations the papillae were
577
always associated with hair follicles, and, con
versely, epithelial buds that could be identified as
hair follicles always had under them dermal papil
lae. Hence, it could not be determined whether or
not one structure induced the other. Both ap
peared at about the same time and increased in
size together.
Regeneration of hair follicles in scars inoculated
with the Shope papilloma virus.—The wounds of
five rabbits were inoculated with the Shope papil
loma virus at 21, 32, 33, 35, and 41 days, respec
tively, after removal of the disc of skin. The virus
suspension was inoculated over a narrow band of
skin and scar that extended anteroposteriorly
across the entire inside diameter of the chamber.
The animals were sacrificed 12-15 days after in
oculation.
All the animals developed typical papillomas
involving the scar epithelium, and all bore evi
dence of regeneration
of hair follicles and seba
ceous glands from this epithelium. The virus ap
parently did not interfere with the regeneration.
Cells of the papilloma merged with hair follicle
epithelium as well as with epithelium between fol
licles, and it could not be determined from what
cell type the papilloma had arisen (see Fig. 15).
DISCUSSION
The question of whether the epidermis can give
rise to new hair follicles in the adult has been ar
gued since the time of O. Hertwig (8). One of the
most prominent recent investigators
to support
the "new formation"
hypothesis is Lacassagne
(10), who has reported the redifferentiation
of hair
follicles and sebaceous glands in the scars of ultra
violet-ray burns of mice. However, the opposite
opinion is so universally held that, for example,
one reviewer (11) has questioned the accuracy of a
histological study in its entirety because the au
thors mentioned the development of new hair fol
licles in scars following the total extirpation of a
region of skin (5).
Evidence in the literature of the origin of new
hair follicles has been scanty or absent. Their de
velopment has been difficult to observe because of
their sporadic occurrence. In the present experi
ments such observation was possible only because
the hair follicles regenerated
fairly consistently
and often in profusion.
The conditions that determine whether regener
ation of hair follicles will take place are not en
tirely clear. At least the following factors seem to
be involved: (a) Prevention
of excessive drying
and contraction of the wound appear to be impor
tant, since the best regeneration,
in the present
experiments, occurred in wounds where these fac-
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578
Cancer Research
tors were controlled. (6) The phase of the hair
growth cycle may have an effect, although accord
ing to Roney et al. (15) injury at once initiates
growth of resting follicles in the rabbit, (c) Another
important factor is the "granulation tissue" which
fills the skin defect, especially that part of it which
comes to lie immediately under the epithelium. It
is generally assumed that in the embryo certain
elements of the dermis induce the hair follicle (1,
7). In the present experiments these elements
would be derived from the dermis at the edge of
the wound and would come to lie in the indifferent
granulation tissue that eventually fills the wound.
To induce hair follicles in the overlying epithelium
they would presumably have to lie immediately
under this epithelium.
The importance of the dermal papilla in the
maintenance of the hair follicle throughout its
cycles of activity has been emphasized by Chase
(2). However, some differentiation of follicle epi
thelium into highly specialized cells can occur in
its absence. Montagna et al. (13) studied mice with
hereditary hairlessness, which lose their ability to
produce hair early in life. The hair follicle under
goes a degenerative beadlike constriction in its
middle portion, with eventual separation of the
bulb from the remainder of the follicle. The iso
lated external sheath cells then differentiate into
sebaceous gland cells. On the other hand, Mon
tagna and Chase (12) found in normal mice that,
while sebaceous glands regenerated from external
sheath cells after the former were destroyed by
methylcholanthrene, this regeneration did not be
gin until the follicle began to produce hair. Appar
ently, the normal hair follicle and papilla act to
gether to prevent excessive differentiations and to
integrate the ones that occur.
The regeneration of skin described in the pres
ent experiments is comparable to the regeneration
of the amphibian limb. The limb blastema (14) is
derived from the amputation stump and is com
posed of undifferentiated epidermal and deeper
cells. Cells of the blastema subsequently differenti
ate into various tissue cells of the new limb. The
"skin blastema," similarly, is composed of undif
ferentiated epidermal and dermal cells. Both are
derived from the edges of the wound, and both
subsequently undergo differentiation and organi
zation.
The experiment with the Shope papilloma virus
was performed before it was found that hair fol
licles could regenerate. It was hoped that scars
would yield a uniform and hairless epiderm on
which to induce papillomas for an electron micro
scopic comparison of the papilloma cell and its nor
mal precursor. However, none of the five scars on
which the virus was inoculated turned out to be
free of hair follicles. Kidd and Parsons (9) tested
the virus on a variety of epithelial surfaces and
found that it induced papillomas only on skin, in
areas that contained hair, although their results
are not stated in exactly this way.
Hair follicles and sebaceous glands are impor
tant in epidermal carcinogenesis. Simpson and
Cramer (16) showed that methylcholanthrene con
centrates in the sebaceous glands. Lacassagne and
Latarget (10) applied methylcholanthrene to scars
of ultraviolet-ray burns of mice and found cancers
in regions only where there were persisting, or re
generated, hair follicles and glands. Suntzeff et al.
(17) showed that methylcholanthrene applied to
the skin of young mice before the hair follicles and
sebaceous glands had fully developed failed to pro
duce cancer. The role of the regenerative proper
ties of skin in carcinogenesis remains to be deter
mined.
SUMMARY
Discs of skin of total skin thickness were re
moved from the backs of rabbits. The wounds were
hindered from contracting and excessive drying by
means of a protective chamber and were allowed
to heal by scab formation and granulation.
Functioning hair follicles and sebaceous glands
developed in the scars, sometimes in great pro
fusion. It was shown that these structures arose by
Fio. 1.—The parts of the chamber used to protect the
wounds and hinder them from contracting (see text). XI.
Fio. 2.—Chamber in place over a healed wound. The
skin was depilated just before the photograph was taken. X1.
Fio. 8.—Samewound as in Figure 2, with parts A and B of
chamber removed. The outlines of the scar are not distinct
because of extensive regeneration of hair follicles. X1.4.
Fio. 4.—Healing wound at 28 days. The epithelium has
not yet reached the center of the wound, which is at the
extreme left of the photograph. Note the irregular thickenings
of the epithelium. These thickenings correspond to the radial
bars shown in Figure 7. Hematoxylin and eosin. X14.
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2
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FIG. 5.—Central part of wound at 32 days. The downward
projecting epithelial process at the left is a beginning hair
follicle. Hetnatoxylin and eosin. X105.
FIG. 6.—Samewound as in Figure 5 hut a region halfway
between the center and periphery of the wound. The hair
follicles have penetrated deeply into the granulation tissue
and are producing fine hairs. Hematoxylin and cositi. X105.
FIG. 7.—Wholemount of the epithelium that partly covers
a healing wound at 27 days, as seen from below. The unepithelialized center <ifthe wound is at the upper right. Note the
bars of thickened epithelium, most of them radially arranged.
Hematoxylin. X14.
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Fio. 8.—Whole epithelial mount of a healed wound at 31
«lays,as seen from below. The large white area is an artifact,
the epithelium having failed to separate from the underlying
granulation tissue in this region. Hair follicles are Imdding
from the radially arranged epithelial bars. They are more
advanced near the periphery than near the center. Hematoxylin. X14.
FIG. 9.—Same preparation as shown in Figure 8 but at
higher magnification. The cup-shaped depressions in the hair
follicle buds are clearly visitile. These depressions contain the
dermal papillae, which are left with the underlying dermis
when the epithelium is pulled off. Hematoxylin. X105.
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FIG. 10.—Wholeepithelial mount of a healed wound at 33
days. The large oval defect near the top of the photograph is
an artifact. The epithelial Imrs from which the hair follicles
developed have largely disappeared, hut their linear arrange
ment is still present near the center. The large coarse hairs
at the lower right- and lower left-hand corners are not derived
from the wound epithelium hut from follicles at the margin of
the wound. Hematoxylin. X14.
FIG. 11.—Wholeepithelial mount of a healed wound at 50
days. The epithelial hars and the linear arrangement of the
hair follicles have now disappeared. Many of the follicles had
grown so deeply into the regenerated dermis that their deeper
parts did not pull out when the epithelium was removed, and
so only their upper portion is present. These appear in the
photograph as short, empty cylinders attached to the epi
thelial sheet. The intact follicles have a densely staining bulb,
and a hair is growing from each. For some reason the
conditions for regeneration were not good near (lie periphery
of this wound, as most of the new follicles are in the more cen
tral regions. Hematoxylin. X14.
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11
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FIG. 12.—Wholeepithelial mount of ¡ihealed wound at 35
days. The epithelial bars from which the hair follicles arose
are still present but are disappearing. The bulbs of the follicle.«,
which contain the dermal papillae, are clearly visible. The
follicles are producili}; fine hairs, which are seen going out of
focus toward the surface of the scar. The sebaceous glands are
the bulbous swellings on the necks of the hair follicles near
their attachment to the surface epithelium of the scar. Hematoxylin. X105.
FIG. 13.—Surface of the regenerating dermis underlying
the epithelium shown in Figures 8 and 9. The densely staining
oval structures are the young dermal papillae. They are seen
best near the center of the photograph. Ilematoxylin. X 105.
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FIG. 14.—Surfaceof the dermis underlying the epithelium
shown in Figure 11 (5(1days). The dermul papillae are the
large, densely staining oval structures. They lie in the holes
left in the dermis when the hair follicles were pulled out. Note
the increase in size over the early papillae shown in Figure 13.
Hematoxylin. X105.
FIG. 15.—Sectionthrough a healed wound that had heen
inoculated with the Shope papilloma virus. The papilloma
surrounds a hair follicle. On the left side of the hair follicle
there is a sebaceous gland. Hematoxylin and eosin. X105.
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v
14
15
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BREEDIS—Regenerationof Hair Follicles and Sebaceous Glands
budding from radially arranged bars of thickened
epithelium, at least some of which had grown or
migrated from cut hair follicles at the edge of the
wound. The dermal papillae formed at about the
time of budding of the hair follicles and developed
together with them.
The Shope virus induced papillomas on the re
generating skin, but their cell of origin could not be
determined.
It is concluded that scar epithelium, under the
conditions of the experiments, is capable of redifferentiating into hair follicles and sebaceous glands
and that "granulation tissue" of the scar is capable
of redifferentiating into dermal papillae.
ACKNOWLEDGMENTS
The author wishes to thank Dr. William Montagna and Dr.
Herman B. Chase of the Department of Biology, Brown Uni
versity, for their critical examination of some of the microscopic
preparations and for helpful suggestions.
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Regeneration of Hair Follicles and Sebaceous Glands from the
Epithelium of Scars in the Rabbit
Charles Breedis
Cancer Res 1954;14:575-579.
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