Affiliations of authors: N. Sato, Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY; P. L. Leopold, R. G. Crystal, Division of Pulmonary and Critical Care Medicine and Institute of Genetic Medicine, Weill Medical College of Cornell University.
Correspondence to: Ronald G. Crystal, M.D., Weill Medical College of Cornell University, Institute of Genetic Medicine, 520 East 70th St., Starr 505, New York, NY 10021 (e-mail: geneticmedicine{at}med.cornell.edu).
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ABSTRACT |
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INTRODUCTION |
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We hypothesized that it may be possible to accelerate recovery of damaged hair follicles given the appropriate molecular signal(s). Hair regrowth following chemotherapy-induced alopecia is associated with hair follicle cell proliferation and active melanogenesis similar to that observed in the normal anagen phase of hair growth (7,8). Among a variety of hormones, growth factors, and development-related molecules identified as being involved in normal hair follicle growth, Sonic hedgehog (Shh) expression appears to play an important role as an initiator of hair follicle growth during both fetal hair follicle development and the postnatal hair cycle (914). Shh, first identified as Hedgehog, a segment polarity gene in Drosophila development, is involved in pattern formation of vertebrate organs, including brain, heart, lung, gut, skin, and skeleton (1523). Shh functions in association with a complex signaling pathway that includes Patched 1 (Ptc 1) and Patched 2 (Ptc 2), the Shh receptor; Smoothened (Smo; a putative transmembrane G-protein coupled receptor that interacts with Ptc); Gli 1, Gli 2, and Gli 3 (a family of transcription factors); and a variety of other signaling molecules that include the Wnt and transforming growth factor- family (2244). Previously, we demonstrated that localized, transient, enhanced expression of Shh in murine postnatal skin by the intradermal administration of an adenovirus gene transfer vector expressing the mouse Shh complementary DNA (cDNA) (AdShh) accelerates the initiation of the anagen growth phase of hair follicles (12).
Since hair follicle regeneration in chemotherapy-induced alopecia is accompanied by hair follicle growth similar to that observed in the normal anagen phase of postnatal hair growth (7), we hypothesized that overexpression of Shh in skin by the intradermal administration of AdShh may accelerate hair regrowth from chemotherapy-induced alopecia. To test this hypothesis, hair regrowth following cyclophosphamide-induced alopecia was evaluated in two murine models after administration of AdShh.
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METHODS |
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To induce expression of Shh, a replication-deficient adenovirus-5 (Ad5)-based recombinant adenovirus with E1 and E3 deletions in which the murine Shh cDNA was constructed with transgene expression under control of the cytomegalovirus (CMV) immediate-early promoter and enhancer (AdShh) (12). The control vector (AdNull) is structurally similar but contains no transgene (45). The preparation and titer determination of the adenovirus vectors were as described previously (46,47). All vectors used were free of replication-competent adenovirus (48).
Experimental Models
All of the animal experiments were approved by the Weill Medical College of Cornell University Institutional Animal Care and Use Committee pursuant to National Institutes of Health Guidelines. Two complementary experimental models for chemotherapy-induced alopecia were used: 1) chemotherapy-induced alopecia in 7-week-old mice that had previously undergone hair depilation (7); and 2) chemotherapy-induced alopecia in 3-week-old mice with previously clipped hair (49) (Table 1). In both models, the skin is in the anagen phase at the time of administration of the chemotherapeutic agent. The models differ in the mechanism of anagen phase induction. In the 7-week-old mouse model, the anagen phase is induced by a physical stimulus (depilation) (7), while in the 3-week-old mouse model, the anagen phase occurs naturally on postnatal day 28 (50). For both models, the chemotherapeutic agent was cyclophosphamide, and the AdShh or AdNull vectors were administered by intradermal injection to the mouse dorsal skin. The extent of hair follicle maturation was evaluated for histologic evidence for morphologic changes in the hair follicles in the anagen phase and for gross melanogenesis.
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Histologic Analysis
Skin was harvested, fixed in 4% paraformaldehyde in PBS (pH 7.4) and embedded in paraffin. Transverse 5-µm paraffin sections were stained with hematoxylineosin. The specimens were graded as positive for anagen phase according to the following criteria: 1) thickened dermis, 2) hair follicle invagination deep into the adipose tissue layer, and 3) evidence of melanin synthesis in the hair follicle matrix.
Gene Expression
Northern blotting in the 7-week-old model was carried out with samples from mice on experimental day 18 (day 3 after Ad vector injection) by purifying total RNA from dorsal skin taken from the area of injection (1 cm x 1 cm) by use of the TrizolTM RNA preparation kit (Life Technologies, Inc. [GIBCO BRL], Rockville, MD). Isolated RNA (10 µg/lane) was separated on a 1% agarose gel, transferred to a nylon membrane (Stratagene, La Jolla, CA) and hybridized with 32P-deoxycytidine triphosphate (dCTP)-labeled probes synthesized from cDNA by random hexamer priming (Stratagene). After detection of target RNA, filters were stripped with 0.1 x saline-sodium citrate at 95 °C and re-probed with 32P-dCTP labeled probe against glyceraldehyde phosphate dehydrogenase to ensure equal RNA loading.
Statistical Methods
Statistical evaluations employed Fisher's exact test. All P values were two-sided.
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RESULTS |
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Administration of cyclophosphamide to 7-week-old mice after depilation reliably resulted in alopecia on the depilated dorsal skin within 5 days after cyclophosphamide injection. No alopecia occurred in mice receiving only depilation, only cyclophosphamide injection, or no treatment (data not shown). The presence of alopecia was supported by histologic examination. Mouse skin was harvested 6 days after cyclophosphamide injection when all mice with depilation showed complete alopecia on the dorsal skin (data not shown). Mouse skin without treatment showed hair follicles in the telogen phase. Similarly, skin of mice without depilation, but injected with cyclophosphamide, showed hair follicles in the telogen phase without obvious tissue damage. Depilated mouse skin without cyclophosphamide injection showed growing hair follicles, indicating entry into the anagen phase. In contrast, the mouse skin treated with both depilation and cyclophosphamide showed remarkably dystrophic hair follicles and an irregular pattern of melanin deposition resulting from damage to melanocytes (data not shown).
Hair Regrowth in the 7-Week-Old Mouse Alopecia Model
In the 7-week-old mouse alopecia model, hair follicles in mouse dorsal skin typically recover normal morphology approximately 20 days after cyclophosphamide treatment (7). The potential of Shh to initiate hair follicle regeneration was evaluated by administration of AdShh to the skin of mice on experimental day 15, 6 days after cyclophosphamide treatment. To evaluate Shh gene expression in the skin after the intradermal administration of an adenovirus vector encoding Shh (AdShh), mouse skin was harvested on experimental day 18, 3 days after adenovirus vector injection. RNA was extracted and evaluated by Northern blot analysis with the use of a mouse Shh probe. Compared with controls, including naive mouse skin or skin injected with an adenovirus vector lacking an expression cassette (AdNull), the skin injected with AdShh showed a strong vector-derived Shh expression of 3.0 kilobases, as described previously (Fig. 1) (12). Consistent with the data, expression of the endogenous Patched gene (the Shh receptor gene) was increased by AdShh.
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Hair Regrowth in the 3-Week-Old Mouse Alopecia Model
To explore further the effects of AdShh on chemotherapy-induced alopecia, we examined a second alopecia model by using younger mice (3 weeks old). In this model, both male and female mice were evaluated, since a previous report that had used the same model had noted genderspecific responses (49). Mice were clipped on postnatal day 21 (experimental day 0) to aid in observing the skin color change that is associated with the telogen-to-anagen phase transition. Cyclophosphamide was administered during the second anagen phase leading to alopecia after approximately 1 week. AdShh was intradermally injected into the dorso-medial skin. A dorso-medial injection site, rather than a posterior injection site, was used because the natural hair regrowth observed in this model did not interfere with the ability to observe the effects of AdShh as was the case in the 7-week-old mouse model.
Similar to the 7-week-old mouse model, the naive and AdNull-injected skin showed dystrophic hair follicles with an extracellular distribution of melanin granules on day 27 (Fig. 3, A and B). In contrast, AdShh-injected skin contained larger growing hair follicles with a regular distribution of melanin granules in matrix cells of anagen phase hair follicles at the injection site (Fig. 3, C
). Gross morphologic analysis correlated with histologic findings (Fig. 3, DG
). The occurrence of melanogenesis and anagen phase hair follicles at the injection site was specific to AdShh-treated mice. With follow-up on experimental day 33, both male and female mice responded to AdShh treatment (melanogenesis observed: all mice naive [none of 22], AdNull [none of 22], and AdShh [19 of 22; P<.001]; mice by sexnaive [none of 12 male mice and none of 10 female mice]; AdNull [none of 12 male mice and none of 10 female mice]; AdShh [11 of 12 male mice and eight of 10 female mice; P<.001 comparing male AdShh-treated mice with either male AdNull-treated mice or male naive mice and P<.001 comparing female AdShh-treated mice with either female AdNull-treated mice or female naive mice by Fisher's exact test]). Although there was no significant difference in the response of male versus female mice to AdShh administration (P = .27), the intradermal administration of AdShh appeared to induce onset of anagen phase more rapidly in male mice compared with female mice. At experimental day 27, the majority of AdShh-treated male mice showed melanogenesis at the injection site, while only 10% of the female mice had responded.
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DISCUSSION |
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In addition to Shh, localized, transient expression of other signaling molecules may also aid in regeneration of hair follicles after chemotherapy-induced alopecia. Secreted growth factors and morphogens, such as keratinocyte growth factor (54,63), fibroblast growth factor 5 (50,64), transforming growth factors- (65), epidermal growth factor (66), and hox gene products (67), have been implicated in control of the hair follicle growth cycle. An in vitro experiment using isolated mouse dermal papilla showed that Wnt 3a, a secreted signaling molecule, induced anagen phase with subsequent hair growth after implantation in mouse skin (68). Given the ability of these gene products to control downstream gene expression, incorporation of the genes into treatments must be approached with caution. For example, constitutive expression of Shh can induce atypical morphologies in mouse and human skin that resemble basal cell nevus syndrome (69,70). In contrast, transient expression of Shh failed to produce the same pathology (12). Therefore, the timing and extent of gene expression may be critical, and the ability to achieve local, transient expression of the genes by using vectors like adenovirus may be essential to achieve constructive biologic activity of the gene products.
The present study compared Shh-induced hair follicle recovery in male and female mice. A previous report suggested that 1,25-dihydroxyvitamin D3-mediated protection against chemotherapy-induced hair loss was less effective in the female mice than in the male mice, possibly related to P450-mediated metabolism of 1,25-dihydroxyvitamin D3 (71,72). In addition, activation of estrogen receptors in the dermal papilla may slow progression into anagen phase, introducing another sex-specific variable in hair cycle biology (73), although no direct link between Shh and 1,25-dihydroxyvitamin D3 or estrogen signaling is postulated here. The differences may relate to the rate of hair follicle recovery rather than to the ability to recover. These data suggest that therapeutic intervention after chemotherapy may exhibit sex-specific pharmacokinetics.
In conclusion, the Shh signaling pathway is involved in the initiation of the hair follicle growth phase during hair follicle regeneration after chemotherapy-induced tissue injury. The present data support the idea that the Shh signaling pathway acts as a biologic switch that accelerates the initiation of the hair growth phase and that the use of transient, localized gene transfer may prove to be a useful technology for elucidating general mechanisms controlling hair regeneration in a variety of disease states.
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NOTES |
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We thank Neil R. Hackett for helpful discussions and N. Mohamed for help in preparing this manuscript.
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Manuscript received December 20, 2000; revised August 29, 2001; accepted October 9, 2001.
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