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 boiling, during which time the skin was painted with iodine and hair follicles and sebaceous glands in a region of 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 adult skin are destroyed, or the entire region is centric with it. The disc included the total thickness of skin as extirpated, the new epithelium growing in from the well as the underlying panniculus carnosus. side will not regenerate these structures (14). The wire ring was now pushed through the wound into the On the basis of this concept, attempts were subcutaneous tissue and was so placed that its upward pro jecting prongs coincided with the marks on the India ink made to obtain a purely squamous sheet of epi circle. The skin was punctured at each mark with a No. 11 thelium in the rabbit for the purpose of inoculating Bard-Parker blade, thus allowing the prongs to project through it with the Shope papilloma virus. A region of skin the skin. The appearance of the anchor ring in relation to a was surgically removed from the back, and the healed wound is shown in Figure 3. The wound was protected by a glass-covered chamber wound was allowed to heal under conditions that fastened to the ring, as shown in Figure 2. The chamber con largely prevented contraction and drying. Con sisted of a heavy stainless steel ring with three projecting lugs trary to expectation, functioning hair follicles and (Fig. 1 [B]) and an ordinary chemical watch glass (Fig. 1 [A]). sebaceous glands appeared in the scars, sometimes The under surface of the ring had a shallow groove into which in great profusion. the seven prongs of the underlying wire ring were fitted. The heavy ring, placed on top of the prongs, was firmly In the experiments here reported, wounds in attached to each with 28-gauge stainless steel wire. The glass various stages of healing were studied in an at cover was then fastened in place, as shown in Figure 2, with tempt to determine the origin of the new hair 25-gauge stainless steel wire. follicles and glands. The chamber was left in place, except for temporary re The "hair follicle" is here considered a purely moval of the glass cover when observations were made or dressings applied, until the end of the experiment. Then the epithelial derivative, as defined by Cowdry (3) and animals were sacrificed with Nembutal. For microscopic by Ham (6). examination sections were cut perpendicular to the skin sur face after fixation in Bouin's solution. Whole mounts of the MATERIALS AND METHODS epithelium were prepared by the acetic acid method described Rabbits of mixed breeds weighing 2,800-3,500 gm. were by Cowdry (4). Only the epithelium of the scar separated used. They were fed commercial rabbit pellets, supplemented readily by this method. Mature hair follicles in the surround in some experiments with greens. All operations described ing skin were too deep to be pulled out. The best results below were performed under Nembutal anesthesia and as were obtained by soaking in ice-cold 1 per cent acetic acid for aseptically as possible. 2-3 days, fixing in Bouin's solution for 1 day at room tempera To obtain a uniform and large sheet of scar epithelium it ture, and then lifting off the scar epithelium. was thought desirable to hinder as much as possible the con Preparations of the dermal papillae were made after re traction of the wound during healing. For this purpose a wire moving the epithelium. Using a razor blade, a thin slice of ring was devised that could be anchored in the skin surrounding the dermal surface was shaved off and stained with hema- the wound. The ring consisted of a 22-gauge surgical stainless toxy lin. steel wire bent into the form shown in Figure 1 (C). The ring was fastened in the skin as follows: The back of the EXPERIMENTAL RESULTS rabbit was shaved with an electric clipper and was depilated Dressing of the wound and rate of healing.â€”In with a mixture of equal parts of barium sulfide and corn- starch made to a thin paste with water. The ring was placed on the first five rabbits the wound was kept moist the middle region of the back, 2 or 8 cm. from the midline. Its with vaseline gauze dressings. With this treatment outline was traced with India ink, thus forming a circle on the the wound did not develop a base that moved with skin 33 mm. in diameter. The positions of the seven prongs the skin, but remained open to the subcutaneous were marked on the circle. The ring was then sterilized by tissue until granulation from the side closed the *This investigation was supported by a research grant defect. The closure required 18-30 days and com (C-1116) from the National Cancer Institute of the National plete epithelialization several additional days. Institutes of Health, Public Health Service. Three of the wounds became infected. Received for publication April 21, 1954. Leaving the wound alone resulted in more rapid 575

healing and only an occasional infection. This pro lium, there were other possible explanations. The cedure was adopted for the remaining 33 animals. trauma of making the wound and of affixing the The chamber allowed slow evaporation to occur, chamber may have loosened viable fragments of h. and the wound healed by scab formation and hair follicles, which could either be scattered over granulation. the wound or be carried into it by the migrating The sequence of events was as follows : As dry surface epithelium. Some parts of a follicle can ing proceeded, the upper layer of the loose sub regenerate the whole (6). cutaneous tissue became attached to the edges of To determine the distribution of the new fol the wound and moved with the skin. In 7-10 days licles and to study their structure in three dimen this membrane became thick and opaque. In 10-14 sions, whole mounts of the wound epithelium were days a brown scab covered the entire wound. The made as described above. granulation tissue growing in from the side reached Mounts prepared at various stages of healing the center in 15-22 days. Epithelialization was revealed the following sequence of events : Before usually complete several days thereafter, and the the epithelium had completely covered the wound scab separated. it had numerous bands or bars of thickening that Beginning at about the time of separation of the consisted of five or more layers of cuboidal cells. scab or several days before this occurred, vaseline Most of them were radially arranged, but many gauze dressings were applied every 3-6 days. formed a reticular pattern that connected with the When the new epithelium was not protected in radial bars. This arrangement is illustrated in Fig this way, and especially when the glass cover was ure 7 (27 days). The bars correspond to the thick left off the chamber, there was excessive drying enings of epithelium shown in cross-section in Fig and contraction of the wound with little or no ure 4. No organized structure could be seen in regeneration of hair follicles and sebaceous glands. them. Some of the bars could be traced back to Organization of the scar epithelium into hair fol hair follicles at the edge of the wound. licles and sebaceous glands.â€”Microscopic observa As epithelialization proceeded, most of the con tions were made on sections through the wounds necting bars disappeared while the radial ones per from 23 rabbits and on whole epidermal mounts sisted. Then numerous budlike projections ap from fifteen additional rabbits. peared on the bars, first at the periphery of the None of the sections showed evidence that hair wound and later near the center. This budding is follicles or sebaceous glands had been left within illustrated in Figures 8 and 9 (31 days). Each bud the wound area at the time of operation. All epi was an immature hair follicle that in cross section thelium either was confined to the surface of the would appear about as shown in Figure 5. granulation tissue or appeared to be projecting Sometimes the radial bars could be seen through from this surface epithelium into the granulation the dissecting microscope in the living animal. tissue. Radially arranged blood vessels were also some Sections of wounds not yet completely epithe- times seen under the wound epithelium. lialized showed scattered diffuse thickenings of the As the hair follicles matured and began to pro epithelium. These are illustrated in Figure 4, duce hair, the radial bars gradually disappeared, which represents a wound of 23 days. The thick leaving radially arranged rows of follicles. These ened epithelium consisted of five or more layers of rows are seen at the periphery of the scar in Figure cuboidal cells and showed no evidence of organiza 8 (31 days) and near its center in Figure 10 (33 tion. At about 30 days, when epithelialization was days). Still later, owing perhaps to local contrac usually complete, the thickened regions developed tions of the healing wounds, the linear arrange downward projections into the granulation tissue. ment disappeared entirely, as illustrated in Figure Some of these could be identified as early hair fol 11 (50 days). licles. Such a follicle is shown in Figure 5. Between It is of interest that in epidermal mounts pre F" 32 and 40 days, functioning hair follicles appeared pared from four rabbit embryos (3 weeks), the and were sometimes present in great numbers, as hair follicles arose as discrete thickenings of the illustrated in Figure 6. Once organization and epiderm, arranged in a geometrical pattern. There growth of the follicles had begun, they penetrated was no evidence of thickened epidermal bars. rapidly into the granulation tissue. In wounds of The sebaceous gland, in the region of skin under 45-55 days many of the new follicles were as deep consideration, is a derivative of the hair follicle and as those of the normal skin at the edge of the is always associated with it. Sections do not show wound. it well unless the cut is through both the gland and While these observations suggested a true re the follicle. Figure 15 (50 days) illustrates such a generation of follicles from the surface epithe gland adjacent to a regenerated follicle in a rabbit

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. BREEDISâ€”Regeneration of Hair Follicles and Sebaceous Glands 577 that had also been inoculated with the Shope always associated with hair follicles, and, con papilloma virus. In the epithelial mounts the se versely, epithelial buds that could be identified as baceous gland appears as a bulbous swelling of the hair follicles always had under them dermal papil neck of the follicle near its attachment to the sur lae. Hence, it could not be determined whether or face epithelium (Fig. 12). The sebaceous gland was not one structure induced the other. Both ap first noted at about the time the follicle began to peared at about the same time and increased in produce hair. size together. The role of dermal elements in the regeneration of Regeneration of hair follicles in scars inoculated hair follicles.â€”The arrangement of the hair fol with the Shope papilloma virus.â€”The wounds of licles in the epithelial mounts and their budding five rabbits were inoculated with the Shope papil from otherwise unorganized epithelial bars argued loma virus at 21, 32, 33, 35, and 41 days, respec strongly against a possible random seeding of the tively, after removal of the disc of skin. The virus wound by hair follicle fragments. The chances suspension was inoculated over a narrow band of against repeated occurrence of the radial pattern skin and scar that extended anteroposteriorly would be enormous. However, the influence of an across the entire inside diameter of the chamber. other factor, dermis, had to be considered. The animals were sacrificed 12-15 days after in The hair follicle is in intimate contact with oculation. dermal structures, perhaps the most important of All the animals developed typical papillomas which is the dermal papilla. The papilla lies inside involving the scar epithelium, and all bore evi a cup-shaped excavation in the bulb of the hair fol dence of regeneration of hair follicles and seba licle. Several are well shown in Figure 12. In the ceous glands from this epithelium. The virus ap embryo the papilla is thought to "induce" the hair parently did not interfere with the regeneration. follicle (1, 7). Had dermal elements induced the Cells of the papilloma merged with hair follicle hair follicles in the regenerating skin? If so, how epithelium as well as with epithelium between fol had this come about? licles, and it could not be determined from what Preparations of the entire dermal surface under cell type the papilloma had arisen (see Fig. 15). lying the scar epithelium were made as described above. Six healed wounds varying from 31 to 50 DISCUSSION days in age were examined. In each case the epi The question of whether the epidermis can give thelium, which had been removed as a single rise to new hair follicles in the adult has been ar sheet, was also available for study. gued since the time of O. Hertwig (8). One of the The 31-day preparation of dermal surface was most prominent recent investigators to support that underlying the epithelium shown in Figure 8. the "new formation" hypothesis is Lacassagne As seen from this figure, hair follicles were just be (10), who has reported the redifferentiation of hair ginning to bud from the central portions of the follicles and sebaceous glands in the scars of ultra epithelial bars and were already fairly well or violet-ray burns of mice. However, the opposite ganized at the periphery. On examining the dermal opinion is so universally held that, for example, surface under this epithelium, the radial grooves one reviewer (11) has questioned the accuracy of a left by the epithelial bars were visible, and also the histological study in its entirety because the au depressions left by the buds. Condensations of cells thors mentioned the development of new hair fol that might be early dermal papillae were made out licles in scars following the total extirpation of a with some difficulty along the grooves in the cen region of skin (5). tral parts of the wound. Unquestionable early der Evidence in the literature of the origin of new mal papillae were seen near the periphery of the hair follicles has been scanty or absent. Their de wound, under the more advanced hair follicles. velopment has been difficult to observe because of Figure 13 illustrates the appearance of these early their sporadic occurrence. In the present experi papillae. ments such observation was possible only because The later preparations (34-50 days) showed an the hair follicles regenerated fairly consistently increase in size and organization of the papillae and often in profusion. that paralleled the development of the hair fol The conditions that determine whether regener licles. The mature papillae stained densely with ation of hair follicles will take place are not en hematoxylin and were clearly visible at the bottom tirely clear. At least the following factors seem to of the holes from which the hair follicles had been be involved: (a) Prevention of excessive drying pulled. Figure 14 illustrates their appearance in and contraction of the wound appear to be impor the 50-day preparation. tant, since the best regeneration, in the present In all six dermal preparations the papillae were experiments, occurred in wounds where these fac-

tors were controlled. (6) The phase of the hair ate into various tissue cells of the new limb. The growth cycle may have an effect, although accord "skin blastema," similarly, is composed of undif ing to Roney et al. (15) injury at once initiates ferentiated epidermal and dermal cells. Both are growth of resting follicles in the rabbit, (c) Another derived from the edges of the wound, and both important factor is the "granulation tissue" which subsequently undergo differentiation and organi fills the skin defect, especially that part of it which zation. comes to lie immediately under the epithelium. It The experiment with the Shope papilloma virus is generally assumed that in the embryo certain was performed before it was found that hair fol elements of the dermis induce the hair follicle (1, licles could regenerate. It was hoped that scars 7). In the present experiments these elements would yield a uniform and hairless epiderm on would be derived from the dermis at the edge of which to induce papillomas for an electron micro the wound and would come to lie in the indifferent scopic comparison of the papilloma cell and its nor granulation tissue that eventually fills the wound. mal precursor. However, none of the five scars on To induce hair follicles in the overlying epithelium which the virus was inoculated turned out to be they would presumably have to lie immediately free of hair follicles. Kidd and Parsons (9) tested under this epithelium. the virus on a variety of epithelial surfaces and The importance of the dermal papilla in the found that it induced papillomas only on skin, in maintenance of the hair follicle throughout its areas that contained hair, although their results cycles of activity has been emphasized by Chase are not stated in exactly this way. (2). However, some differentiation of follicle epi Hair follicles and sebaceous glands are impor thelium into highly specialized cells can occur in tant in epidermal carcinogenesis. Simpson and its absence. Montagna et al. (13) studied mice with Cramer (16) showed that methylcholanthrene con hereditary hairlessness, which lose their ability to centrates in the sebaceous glands. Lacassagne and produce hair early in life. The hair follicle under Latarget (10) applied methylcholanthrene to scars goes a degenerative beadlike constriction in its of ultraviolet-ray burns of mice and found cancers middle portion, with eventual separation of the in regions only where there were persisting, or re bulb from the remainder of the follicle. The iso generated, hair follicles and glands. Suntzeff et al. lated external sheath cells then differentiate into (17) showed that methylcholanthrene applied to sebaceous gland cells. On the other hand, Mon the skin of young mice before the hair follicles and tagna and Chase (12) found in normal mice that, sebaceous glands had fully developed failed to pro while sebaceous glands regenerated from external duce cancer. The role of the regenerative proper sheath cells after the former were destroyed by ties of skin in carcinogenesis remains to be deter methylcholanthrene, this regeneration did not be mined. gin until the follicle began to produce hair. Appar ently, the normal hair follicle and papilla act to SUMMARY gether to prevent excessive differentiations and to Discs of skin of total skin thickness were re integrate the ones that occur. moved from the backs of rabbits. The wounds were The regeneration of skin described in the pres hindered from contracting and excessive drying by ent experiments is comparable to the regeneration means of a protective chamber and were allowed of the amphibian limb. The limb blastema (14) is to heal by scab formation and granulation. derived from the amputation stump and is com Functioning hair follicles and sebaceous glands posed of undifferentiated epidermal and deeper developed in the scars, sometimes in great pro cells. Cells of the blastema subsequently differenti fusion. It was shown that these structures arose by

Fio. 1.â€”The parts of the chamber used to protect the wounds and hinder them from contracting (see text). XI. Fio. 2.â€”Chamber in place over a healed wound. The skin was depilated just before the photograph was taken. X1. Fio. 8.â€”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.â€”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.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. FIG. 5.â€”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.â€”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.â€”Wholemount of the epithelium that partly covers a healing wound at 27 days, as seen from below. The unepi- thelialized center

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Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. Fio. 8.â€”Wholeepithelial mount of a healed wound at 31 Â«lays,asseen 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. Hema- toxylin. X14. FIG. 9.â€”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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Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. FIG. 10.â€”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.â€”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.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. FIG. 12.â€”Wholeepithelial mount of Â¡ihealedwound at 35 days. The epithelial bars from which the hair follicles arose are still present but are disappearing. The bulbs of the follicle.Â«, 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. Hema- toxylin. X105. FIG. 13.â€”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.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. FIG. 14.â€”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.â€”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.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. BREEDISâ€”RegenerationofHair Follicles and Sebaceous Glands 579 budding from radially arranged bars of thickened 6. HAM,A. W. Histology. 2d ed. Philadelphia: J. B. Lippin- epithelium, at least some of which had grown or cott, 1953. 7. HARDY,M. H. The Development of Pelage Hairs and migrated from cut hair follicles at the edge of the Vibrissae from Skin in Tissue Culture. Ann. N.Y. Acad. wound. The dermal papillae formed at about the Sc., 63: 546-61, 1951. time of budding of the hair follicles and developed 8. HEHTWIG,0. Textbook of the Embryology of Man and together with them. of Mammals, p. 526. Translated from 3d German edition. The Shope virus induced papillomas on the re London: Swan Sonnenshein & Co.; New York: Macmillan Co., 1901. generating skin, but their cell of origin could not be 9. KiHD,J. G., and PASSONS,R. J. Tissue Affinity of Shope determined. Papilloma Virus. Proc. Soc. Exper. Biol. & Med., 35:438- It is concluded that scar epithelium, under the 41, 1936. conditions of the experiments, is capable of redif- 10. LACASSAONE,A.,and LATARGET,R. Methylcholanthrene ferentiating into hair follicles and sebaceous glands on Certain Scars of the Skin in Mice. Cancer Research, and that "granulation tissue" of the scar is capable 6:183-88, 1946. 11. LINDQUIST,G. The Healing of Skin Defects. An Experi of redifferentiating into dermal papillae. mental Study on the White Rat. Acta Chirurg. Scandinav., 94 (suppl. 107): 1-163, 1946. 12. MONTAGNA,W., and CHASE,H. B. Redifferentiation of ACKNOWLEDGMENTS Sebaceous Glands in the Mouse after Total Extirpation The author wishes to thank Dr. William Montagna and Dr. with Methylcholanthrene. Anat. Ree., 107:83-92, 1950. Herman B. Chase of the Department of Biology, Brown Uni 13. MONTAGNA,W.;CHASE,H. B.; and MELABAGNO,H.P. versity, for their critical examination of some of the microscopic The Skin of Hairless Mice. I. The Formation of Cysts and preparations and for helpful suggestions. the Distribution of Lipids. J. Invest. Dermatol., 19:83-94, 1952. 14. NEEDHAM,A.E. Regeneration and Wound-healing, p. 12. REFERENCES London: Methuen & Co.; New York: John Wiley & Sons, 1. BÃœTCHEB,E.O. Development of the Pilary System and the 1952. Replacement of Hair in Mammals. Ann. N.Y. Acad. Sc., 15. RONET, H. R.; COHEN,D. M.; and SCHAFFNER,I. Pat 63:508-16, 1951. terns of Hair Growth Cycles in the Colored Rabbit and 2. CHASE,H. B. Growth of the Hair. Physiol. Rev., 34:113- Their Modification by Experimental Means. J. Invest. 26, 1954. Dermatol., 21:313-30, 1953. 3. COWDBT,E. V. A Textbook of Histology, p. 554. 4th ed. 16. SIMPSON,W.L., and CRAMER,W.Fluorescence Studies of Philadelphia: Lea & Febiger, 1950. Carcinogens in Skin. I. Histological Localization of 20- 4. . Laboratory Technique in Biology and Medicine, Methylcholanthrene in Mouse Skin after a Single Applica p. 118. 3d ed. Baltimore: Williams & Wilkins, 1952. tion. Cancer Research, 3:362-69, 1943. 5. DANN,L.; GLÃœCHSMAN,A.,and TANSLEY,K.The Healing 17. SUNTZEFF,V.; CAHRUTHEHS,C.;and COWDRY,E.V. The of Untreated Experimental Wounds. Brit. J. Exper. Role of Sebaceous Glands and Hair Follicles in Epidermal Path., 22:1-9, 1941. Carcinogenesis. Cancer Research, 7:439-43, 1947.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 1954 American Association for Cancer Research. 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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