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• W2073337488 abstract "We have identified some unusually persistent label-retaining cells in the hair follicles of mice, and have investigated their role in hair growth. Three-dimensional reconstruction of dorsal underfur follicles from serial sections made 14 mo after complete labeling of epidermis and hair follicles in neonatal mice disclosed the presence of highly persistent label-retaining cells associated with the first-generation follicle involved in the production of the first wave of hairs, commonly called the bulge. The label-retaining cells were most often found on the ventral surface of the first-generation follicle, five cell positions from the base, near the attachment site of the arrector pilorum muscle. No label-retaining cells were found in the hair canal, sebaceous gland, or hair germ. These label-retaining cells remained in the follicle following induction of anagen by plucking of the hairs. Surprisingly, they were not part of the first wave of mitotic activity following plucking, but instead underwent mitosis beginning 42 h after plucking. Label-retaining cells or their labeled daughters were not found in the hair germs through 48 h following induction of anagen by plucking, but instead remained in their subsebaceous follicular location even upon completion of the hair growth cycle 21 d later. These label-retaining cells are, therefore, unlikely to contribute to the formation of a new anagen follicle. We have identified some unusually persistent label-retaining cells in the hair follicles of mice, and have investigated their role in hair growth. Three-dimensional reconstruction of dorsal underfur follicles from serial sections made 14 mo after complete labeling of epidermis and hair follicles in neonatal mice disclosed the presence of highly persistent label-retaining cells associated with the first-generation follicle involved in the production of the first wave of hairs, commonly called the bulge. The label-retaining cells were most often found on the ventral surface of the first-generation follicle, five cell positions from the base, near the attachment site of the arrector pilorum muscle. No label-retaining cells were found in the hair canal, sebaceous gland, or hair germ. These label-retaining cells remained in the follicle following induction of anagen by plucking of the hairs. Surprisingly, they were not part of the first wave of mitotic activity following plucking, but instead underwent mitosis beginning 42 h after plucking. Label-retaining cells or their labeled daughters were not found in the hair germs through 48 h following induction of anagen by plucking, but instead remained in their subsebaceous follicular location even upon completion of the hair growth cycle 21 d later. These label-retaining cells are, therefore, unlikely to contribute to the formation of a new anagen follicle. label-retaining cell Although continually renewing tissues differ in organization and function, they have in common a lifelong turnover characterized by specific patterns of proliferation within morphologically defined proliferative units (Leblond, 1964Leblond C.P. Classification of cell populations on the basis of their proliferative behavior.Natl Cancer Inst Monogr. 1964; 14: 119-150PubMed Google Scholar;Lajtha, 1979Lajtha L.G. Stem cell concepts.Differentiation. 1979; 14: 23-34Crossref PubMed Scopus (385) Google Scholar;Potten, 1986Potten C.S. Cell cycles in cell hierarchies.Int J Radiat Biol. 1986; 49: 257-278Crossref Scopus (80) Google Scholar). Characteristically located within these proliferative units are stem cells possessing the following properties (Wright and Alison, 1964Wright N. Alison M. The Biology of Epithelial Cell Populations. 1. Clarendon Press, Oxford1964Google Scholar;Gilbert and Lajtha, 1965Gilbert C.W. Lajtha L.G. The importance of cell population kinetics in determining repose to irradiation of normal and malignant tissue.Cellular and Radiation Biology. Williams & Wilkins, Baltimore1965: 118-154Google Scholar;Lord, 1975Lord B.I. The relative spacial distributions of CFU-S and CFU-C in the normal mouse femur.Blood. 1975; 46: 65-75Crossref PubMed Google Scholar;Lajtha, 1979Lajtha L.G. Stem cell concepts.Differentiation. 1979; 14: 23-34Crossref PubMed Scopus (385) Google Scholar;Potten, 1986Potten C.S. Cell cycles in cell hierarchies.Int J Radiat Biol. 1986; 49: 257-278Crossref Scopus (80) Google Scholar;Hall and Watt, 1989Hall P.A. Watt F.M. Stem cells: the generation and maintenance of cellular diversity.Development. 1989; 106: 619-633PubMed Google Scholar). They are morphologically and biochemically undifferentiated. They are few in number compared with their transit-amplifying cell progeny. They are normally slowly cycling, yet retain the ability to proliferate in response to stimuli such as wounding during which they maintain the stem cell compartment and regenerate the transit-amplifying compartment. They are located in a well protected, highly vascularized, morphologically defined region. Identifying, characterizing, and ultimately isolating the stem cells of renewing tissues is important because of their roles in regenerative growth and in carcinogenesis, for understanding the cellular and molecular basis of growth control within the proliferative units, and because of their importance as targets in gene therapy. Hair follicles are one of the proliferative units of the cutaneous epithelium, the other being the epidermal proliferative unit (MacKenzie, 1969MacKenzie I.C. Ordered structure of the stratum corneum of mammalian skin.Nature. 1969; 222: 281Crossref Scopus (29) Google Scholar,MacKenzie, 1970MacKenzie I.C. Relationship between mitosis and the structure of the stratum corneum in mouse epidermis.Nature. 1970; 226: 653-655Crossref PubMed Scopus (139) Google Scholar;Christophers, 1971Christophers E. Cellular architecture of the stratum corneum.J Invest Dermatol. 1971; 56: 165-169Abstract Full Text PDF PubMed Scopus (114) Google Scholar;MacKenzie, 1972MacKenzie I.C. The ordered structure of mammalian epidermis.in: Maibach H.I. Rovee D.T. Epidermal Wound Healing. Year Book Medical Publishers, Chicago1972: 5-26Google Scholar;Allen and Potten, 1974Allen T.D. Potten C.S. Fine structural identification and organization of the epidermal proliferative unit.J Cell Sci. 1974; 15: 291-319PubMed Google Scholar;Potten, 1974Potten C.S. The epidermal proliferative unit (EPU). The possible role of the central basal cell.Cell Tissue Kinet. 1974; 7: 77-80PubMed Google Scholar). Hair follicles are exceedingly complex structures undergoing lifelong periods of morphogenesis, hair production, regression, and quiescence (Montagna, 1956Montagna W. The Structure and Function of the Skin. Academic Press, New York1956Google Scholar). In the adult mouse, the hair follicles are usually in the quiescent (telogen) stage. The telogen follicles are relatively simple structures, approximately one-third the length of the active follicles. The deepest part of the resting follicle lies in the upper dermis. The hairs of telogen follicles have a broad, feathered base or club (Montagna, 1956Montagna W. The Structure and Function of the Skin. Academic Press, New York1956Google Scholar). The telogen follicle consists of a two-layered epidermal sac around the club hair that is continuous with the sebaceous gland and the interfollicular epidermis. The region of the epidermal sac at the base of the club hair is composed of small, tightly compacted cells known as the hair germ. The hair germ of the telogen follicle has a flattened base where it contacts the follicular papilla, a specialized aggregation of mesenchymal cells playing a key role in the growth and morphogenesis of the follicle (Oliver, 1966Oliver R.F. Whisker growth after removal of the dermal papilla and lengths of follicle in the hooded rat.J Embryol Exp Morphol. 1966; 15: 331-347PubMed Google Scholar,Oliver, 1967Oliver R.F. The experimental induction of shisker growth in the hooded rat by implantation of dermal papillae.J Embryol Exp Morphol. 1967; 18: 43-51PubMed Google Scholar;Oliver and Jahoda, 1988Oliver R.F. Jahoda C.A. Dermal-epidermal interactions.Clin Dermatol. 1988; 6: 74-82Abstract Full Text PDF PubMed Scopus (54) Google Scholar). When the follicle is induced to grow (anagen phase), the cells of the hair germ swell, undergo mitosis, grow downwards into the deep dermis, engulfing the follicular papilla, and ultimately differentiating into the complex, multilayered structure of the hair producing bulb (Dry, 1926Dry F.W. The coat of the mouse (Mus musculus).J Genet. 1926; 16: 288-340Crossref Scopus (230) Google Scholar). Upon completion of anagen, the follicle enters the catagen phase, and the entire lower portion of the follicle undergoes apoptosis (Stenn et al., 1994Stenn K.S. Lawrence L. Veis D. Korsmeyer S. Seiberg M. Expression of the bcl-2 protooncogene in the cycling adult mouse hair follicle.J Invest Dermatol. 1994; 103: 107-111Abstract Full Text PDF PubMed Google Scholar;Seiberg et al., 1995Seiberg M. Marthinuss J. Stenn K.S. Changes in expression of apoptosis-associated genes in skin mark early catagen.J Invest Dermatol. 1995; 104: 78-82Crossref PubMed Scopus (85) Google Scholar). The follicular papilla then migrates back to the upper dermis to lie once again at the base of the new hair germ forming late in catagen (Dry, 1926Dry F.W. The coat of the mouse (Mus musculus).J Genet. 1926; 16: 288-340Crossref Scopus (230) Google Scholar), which is destined to give rise to the second-generation follicle, the companion hair of the next hair cycle (Dry, 1926Dry F.W. The coat of the mouse (Mus musculus).J Genet. 1926; 16: 288-340Crossref Scopus (230) Google Scholar). Twenty-one days after birth, the first-generation hair cycle is complete and the follicle is in telogen. At ≈7 wk of age, the second hair cycle is complete leaving the second-generation follicle. Slowly cycling, [3H]thymidine label-retaining cells (LRC) have been observed after short intervals of 4–10 wk following [3H]thymidine labeling of baby mice or of adult mice after repeated treatment with 12-O-tetradecanoylphorbol-13-acetate, to reside in the middle third of the hair follicle immediately beneath the sebaceous gland near the attachment of the arrector pilorum muscle (Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar;Morris and Potten, 1994Morris R.J. Potten C.S. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells.In Vitro. Cell Prolif. 1994; 27: 279-289Crossref PubMed Scopus (189) Google Scholar). The follicular LRC have convoluted or crenulated nuclei, reflecting their proliferative inactivity (Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar). Like the interfollicular LRC, those in the follicles respond by mitosis to topical treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, although, unlike interfollicular LRC (Morris et al., 1985Morris R.J. Fischer S.M. Slaga T.J. Evidence that centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations.J Invest Dermatol. 1985; 84: 277-281Abstract Full Text PDF PubMed Scopus (143) Google Scholar), those in the follicle require repeated treatment with 12-O-tetradecanoylphorbol-13-acetate to become activated (Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar; Morris, unpublished observations). Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar suggested that the follicular LRC may be follicular stem cells, just as the interfollicular LRC may be the stem cells of the epidermal proliferative unit. The possible role of such stem cells in the hair growth cycle has been the subject of debate (Holecek and Ackerman, 1993Holecek B.U. Ackerman A.B. Bulge-activation hypothesis: Is it valid?.Am J Dermatopathol. 1993; 15: 248-249Crossref Scopus (12) Google Scholar;Ackerman, 1994aAckerman A.B. Reply to “The bulge-activation hypothesis does not explain hair follicle cycling by may still be valid”.Am J Dermatopathol. 1994; 16: 112-115Crossref Scopus (7) Google Scholar,Ackerman, 1994bAckerman A.B. Reply to “Bulge-activation hypothesis”.Am J Dermatopathol. 1994; 16: 458-460Google Scholar;Paus and Czarnetzki, 1994aPaus R. Czarnetzki B.M. The “bulge-activation” hypothesis does not explain hair follicle cycling but may still be valid.Am J Dermatopathol. 1994; 16: 112-115Crossref Google Scholar,Paus and Czarnetzki, 1994bPaus R. Czarnetzki B.M. Bulge-activation hypothesis.Am J Dermatopathol. 1994; 16: 458-460Crossref Google Scholar). Nevertheless,Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar hypothesized that upon induction of anagen, in response to messages from the follicular papilla, a LRC divides and one of its daughters, now a transit-amplifying cell, migrates to the hair germ to initiate a new cycle of hair growth (bulge-activation hypothesis). For this to happen, one would expect the LRC to undergo mitosis upon induction of anagen and for one of its labeled daughters to migrate to the hair germ. This would result in the appearance of labeled cells in the germs of the early anagen follicle. Because the time intervals used previously in studying the follicular LRC were so short (4–10 wk;Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1803) Google Scholar;Morris and Potten, 1994Morris R.J. Potten C.S. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells.In Vitro. Cell Prolif. 1994; 27: 279-289Crossref PubMed Scopus (189) Google Scholar), and because we found so many follicular LRC at 8 wk (66% of the cells in the first-generation follicle, which is somewhat at odds with their being a rare, stem population), we wondered what would be the pattern of LRC expression 1 y following labeling. We also wondered whether we would find labeled cells in the hair germs following induction of anagen. To determine precisely the position of LRC in the follicle, we performed a detailed three-dimensional reconstruction of a number of individual hair follicles. We then determined whether these persistent LRC underwent mitosis and whether labeled cells migrated to the hair germ upon induction of anagen induced by plucking the hairs (Silver et al., 1967Silver A.F. Chase H.B. Arsenault C.T. Early anagen initiated by plucking compared with early spontaneous anagen.in: Montagna W. Dobson R.L. Adv Biol Skin. 9. Pergamon Press, New York1967: 265-286Google Scholar). BDF1 female mice bred at the Paterson Institute for Cancer Research (Manchester, U.K.) were housed under conventional conditions with food and water available ad libitum and a 12 h light cycle (lights on at 07.00 h). All animal experiments were performed under the Home Office regulations determined by the Scientific Procedures (1986) Act. Baby mice were injected subcutaneously with 10 μCi (370 kBq) of [3H]thymidine (specific activity 20 Ci per mmol (925 mBq per mmol), Du Pont NEN; Stevenage, Herts., U.K.) in 50 μl twice daily at (09.00 h and 17.00 h for 3 d beginning the third day after birth. We have previously determined that this protocol labels virtually all interfollicular and follicular epithelial cells (Morris and Potten, 1994Morris R.J. Potten C.S. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells.In Vitro. Cell Prolif. 1994; 27: 279-289Crossref PubMed Scopus (189) Google Scholar). At 14 mo of age, a group of mice was killed, the dorsal fur clipped, and the dorsum depilated with Immac (Reckitt and Colman Products, Hull, U.K.). Rectangles of skin (1.5 × 1 cm) were removed with the long axis of the rectangle parallel to the long axis of the mouse. The samples were fixed for 24 h in 10% buffered formalin and were subsequently processed for paraffin embedding. To determine whether the LRC migrated from their original position, a group of 34 mice was anesthetized with a mixture of ketamine (0.08 mg per g body weight, Parke-Davis, Pontypool, Gwent, U.K.) and Rompun (0.008 mg per g body weight, Bayer Limited, Bury St Edmunds, Suffolk, U.K.). The dorsal fur of the mice was painted with the plastic dressing, Norbecutan-038 (Bofors, Sweden), and allowed to dry. The dressing with embedded hairs was gently peeled off to induce anagen (Silver et al., 1967Silver A.F. Chase H.B. Arsenault C.T. Early anagen initiated by plucking compared with early spontaneous anagen.in: Montagna W. Dobson R.L. Adv Biol Skin. 9. Pergamon Press, New York1967: 265-286Google Scholar). Every 6 h for 48 h, groups of three or four mice were killed and pieces of the dorsal skin removed and fixed in 10% buffered formalin. In a separate experiment to determine when the LRC were induced to undergo mitosis, groups of three or four mice were twice injected with Vincristine, 0.02 mg per injection per mouse (David Ball Laboratories, Warwick, U.K.) at 3 and 6 h before being killed. Time-points were taken every 6 h through 48 h following plucking. Slides containing 10–12 serial 5 μm sections were dewaxed in xylene, rinsed in absolute ethanol, dried, and dipped in Kodak NTB-2 nuclear track emulsion (Eastman Kodak, Rochester, NY) diluted 1:1 with distilled water in a darkroom where the relative humidity was 60%–70%. Autoradiographs were exposed, desiccated at 4°C for 4 wk and were developed for 3.5 min in D-19 developer at 18°C, fixed in Kodak fixer, and were lightly stained with Ehrlich’s hematoxylin and phloxine B. Autoradiographic background was negligible. Scoring was performed with a Zeiss microscope equipped with a 63× planapochromatic objective. Nuclei with at least three grains were counted as labeled. Three-dimensional reconstruction was accomplished by imaging serial sections of individual follicles with a 40× planapochromatic objective on to an 8 × 11 inch high resolution monitor and by tracing with a fine point black marker the nuclei of the hair follicle together with associated fibroblasts on to transparent acrylic sheets 3 mm in thickness. Usually 12 serial sections were required to reconstruct completely a follicle. Each reconstruction was visualized by assembling a stack of the 12 serial sections and then by photographing through the sheets. Follicles were chosen for three-dimensional reconstruction at random if they had a good median sagittal section. Individual silver grains over epithelial nuclei were recorded in red and those over fibroblasts were recorded in green. Nuclei of fibroblasts were identified by their fusiform or spindle shape and by their slight distance from the compact, tightly packed, and basophilic epithelial nuclei of the follicle. Nine small underfur hair follicles and three follicles of guard hairs were reconstructed. Careful inspection of autoradiographs made from skins taken 1 h upon completion of the twice daily injections of [3H]thymidine for 3 d beginning the third day after birth confirmed our previously published observation that this protocol labeled virtually all cutaneous epithelial cells including those of the hair follicle (Morris and Potten, 1994Morris R.J. Potten C.S. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells.In Vitro. Cell Prolif. 1994; 27: 279-289Crossref PubMed Scopus (189) Google Scholar). Many dermal fibroblasts were also labeled by this regimen. Fourteen months after completion of continuous labeling, we identified in the hair follicles, highly persistent LRC. As is the case for older animals, virtually all of the follicles of these 14 mo old animals were in the telogen stage of the hair cycle with the exception of a very few guard hair follicles that were in anagen 2. Figure 1(b) shows a photomicrograph of a typical LRC five cell positions from the base of the first-generation follicle. These highly persistent follicular LRC usually had convoluted or crenulated nuclei attesting to their keratinocyte origin. Slightly removed from the follicle itself, small clusters of labeled fibroblasts were found in close proximity to the follicular LRC. No LRC were observed in the interfollicular epidermis or sebaceous glands 14 mo following labeling. We performed a grain count analysis of 50 consecutive follicular LRC. As shown in Figure 2, a number of cells with low grain counts was observed. Fourteen per cent of the LRC, however, were labeled with 10–19 grains, and 14% had a grain count of ≥ 20 grains, which was the grain count upon completion of the continuous labeling protocol. Because the LRC appeared, upon inspection of the serial sections, to be nonrandomly distributed, we next determined the number of highly persistent LRC in five regions of the follicle (Table 1). Persistent LRC were rarely found in the germ (defined as the layer of cells immediately above the follicular papilla), the sebaceous gland, or the hair canal: only in the first-generation and second-generation follicles where, respectively, ≈2% and 1% of the cells were LRC. It was often difficult to say precisely to which of the two follicles the LRC belonged. Sixty-four per cent of the LRC, however, were identified as associated with the first-generation follicle and 36% with the second-generation follicle. Grain count analysis disclosed that labeled cell in the first-generation follicles had more silver grains than those in the second-generation follicles. The larger tylotrich follicles of the sensory guard hairs had numerous LRC below the level of the sebaceous gland immediately above the fringed base of the club hair.Table 1Location of persistent LRC in hair follicles of mice 14 mo following completion of continuous labelingaBDF1 female mice were injected with 10 μCi of [3H]thymidine twice daily for 3 d beginning the third day after birth. Fourteen months later, labeled nuclei were identified in autoradiographs of hair follicles. The hair germ was identified as a single row of tightly compacted cells lying above the dermal papilla. The first-generation follicle was identified as a subsebaceous follicular remnant also the site of attachment of the arrector pilorum muscle. The secondary follicle was positioned immediately above the follicular papilla. In general, labeled cells in the first-generation follicle were more heavily labeled than those in the secondary follicle. Nuclei having three or more grains were scored as labeled. Values represent the average of 20 hair follicles (>2000 cells scored) from each of three mice ± standard deviation.GermFirst-generation follicleSecond-generation follicleSebaceous glandHair canalLabeling index (%)0 ± 01.8 ± 0.620.8 ± 0.450 ± 00 ± 0Percentage of total LRC0 ± 064.4 ± 5.935.6 ± 5.90 ± 00 ± 0a BDF1 female mice were injected with 10 μCi of [3H]thymidine twice daily for 3 d beginning the third day after birth. Fourteen months later, labeled nuclei were identified in autoradiographs of hair follicles. The hair germ was identified as a single row of tightly compacted cells lying above the dermal papilla. The first-generation follicle was identified as a subsebaceous follicular remnant also the site of attachment of the arrector pilorum muscle. The secondary follicle was positioned immediately above the follicular papilla. In general, labeled cells in the first-generation follicle were more heavily labeled than those in the secondary follicle. Nuclei having three or more grains were scored as labeled. Values represent the average of 20 hair follicles (>2000 cells scored) from each of three mice ± standard deviation. Open table in a new tab We next performed a detailed three-dimensional reconstruction from serial sections of nine pelage (underfur) follicles and three guard hair follicles. The reconstructions revealed that all of the follicles had at least one LRC (three silver grains were chosen as a lower limit). As shown in typical reconstructions (Figure 3a–c), LRC were usually positioned along the ventral surface of the first-generation follicle ≈5 cells from the base. This was the case in seven of nine of reconstructions of underfur follicles. The remaining two reconstructions showed LRC between the first-generation and second-generation follicles. The LRC were immediately distal to the lower limit of the sebaceous gland, near the site of attachment of the arrector pilorum muscle (Figure 3c). In four follicles, the LRC were found in both locations. As shown in Figure 3(b), some hair follicles had as many as four LRC. The follicular LRC were often positioned near a cluster of heavily labeled fibroblasts, identified by their fusiform shape and by their slight distance from the follicle. The three-dimensional reconstructions (Figure 3) revealed three aggregations of label-retaining fibroblasts associated with the ventral aspect of the follicle and the lower sebaceous gland. The pattern of persistent LRC in the guard hairs differed from that of the smaller, pelage follicles (Figure 3d). Three-dimensional reconstruction disclosed that the LRC were located in two clusters located on both the dorsal and ventral surfaces of the guard follicle just above the fringed club hair. In contrast to the one to four LRC present in the small follicles, the follicles of guard hairs had from 17 to 45 LRC clustered on the dorsal and ventral surfaces. To determine whether the LRC actually divided following induction of anagen by plucking, mitotic figures were accumulated for 6 h intervals with Vincristine through 48 h following plucking. Mitotic figures in general were rare at times less than 18–24 h following plucking, but after this interval, were observed throughout the follicle. Surprisingly, mitotic LRC were not observed until 42 and 48 h following plucking (Figure 1c) when many of the follicles had entered anagen stage 2. Label-retaining fibroblasts were not observed to divide, even with 6 h accumulations with Vincristine, nor was there any obvious reduction in the grain count of the fibroblasts at 22 d after plucking suggesting their division. Table 2We then investigated whether or not anagen induced by plucking resulted in LRC migrating to the germ as proposed by the bulge-activation hypothesis. Figure 1(b) shows a LRC remaining in the follicle immediately following plucking of the club hairs of both the first-generation and second-generation follicles. As shown in I, we rarely found LRC in the hair germs (defined as the layer of cells immediately above the follicular papilla) through 48 h following plucking despite the fact that many of the follicles were morphologically in anagen stage 1 at 18 h and in anagen stage 2 by 42 h following plucking. LRC or their labeled daughters were indeed present in the follicles throughout this interval, but remained positioned beneath the sebaceous gland. The relatively high grain counts of many of the original LRC should have allowed labeled daughters to be clearly identified and hence any migration to be observed. By the time of anagen 2, the bulb of the follicle had begun to engulf the follicular papilla.Table 2I. Labeled cells are rarely found in the hair germs following induction of anagen by pluckingHours after plucking aBDF1 female mice were injected with 10 μCi of [3H]thymidine twice daily for 3 d beginning the third day after birth. Fourteen months later, the mice were plucked by removing the dorsal hairs enmeshed in a plastic dressing (Norbecutan). At 6 h intervals thereafter, groups of three mice were killed and pieces of dorsal skin were excised, were fixed in formalin, and were embedded in paraffin. Slides containing 10–12 5 μm serial sections were then prepared for light microscopic autoradiography.Label-retaining cells in hair germs bAverage percentage ± SD of 20 hair follicles (>100 cells scored) from the hair germs from each of three or four mice.Estimated stage of the hair growth cycle cThe stage of the hair growth cycle was estimated according toMontagna (1956).Unplucked0 ± 0telogen60 ± 0telogen120 ± 0telogen180 ± 0anagen 1240.3 ± 0.5anagen 1300 ± 0anagen 1360 ± 0anagens 1 and 2420.3 ± 0.6anagen 2480 ± 0anagen 2a BDF1 female mice were injected with 10 μCi of [3H]thymidine twice daily for 3 d beginning the third day after birth. Fourteen months later, the mice were plucked by removing the dorsal hairs enmeshed in a plastic dressing (Norbecutan). At 6 h intervals thereafter, groups of three mice were killed and pieces of dorsal skin were excised, were fixed in formalin, and were embedded in paraffin. Slides containing 10–12 5 μm serial sections were then prepared for light microscopic autoradiography.b Average percentage ± SD of 20 hair follicles (>100 cells scored) from the hair germs from" @default.
• W2073337488 created "2016-06-24" @default.
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• W2073337488 date "1999-04-01" @default.
• W2073337488 modified "2023-10-14" @default.
• W2073337488 title "Highly Persistent Label-Retaining Cells in the Hair Follicles of Mice and Their Fate Following Induction of Anagen" @default.
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• W2073337488 doi "https://doi.org/10.1046/j.1523-1747.1999.00537.x" @default.
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