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Transplants from balding and hairy androgenetic alopecia scalp regrow hair comparably well on immunodeficient mice
Rozlyn A. Krajcik, PhD, Joseph H. Vogelman, DEE, Virginia L. Malloy, MS, and
Norman Orentreich, MD
DISCUSSION
The original intent of this study was to optimize the procedure of grafting human hair follicles onto immunodeficient mice to have a highly reproducible model system for evaluating treatments for Androgenetic Alopecia. To that end, various methods of transplantation were compared (data not shown), as were several strains of mice (National Institutes of Health Swiss nude and SCID) both male and female, and scalp skin from balding and hairy regions of numerous Androgenetic Alopecia male and female donors (28 males; 11 females).
What became apparent, contrary to the results reported by Van Neste et al,6 was that regardless of the method used and sex or strain of mice, grafts from
balding scalp produced pigmented terminal hairs equal in length and diameter to those produced by transplanted hair follicles from hairy, nonbalding scalp. We report here the results from 2 representative male donors in an experiment using female nude mice (Fig 3).
To minimize extraneous variables and to further verify these results, we then transplanted follicles from both the balding and hairy scalp areas from the
same individual, a female with clinically prominent Androgenetic Alopecia, to each of 7 female SCID mice. The results show that the regrowth of hair, irrespective of follicle
origin, is similar after transplantation onto immu-nodeficient mice (Fig 4). To our knowledge, this is the first study that compares the hair growth of balding and terminal scalp follicles from the same human being transplanted onto the same mouse and for both sexes with Androgenetic Alopecia.
To our knowledge, this is the first study that compares the hair growth of
balding and terminal scalp follicles from the same human being transplanted onto the same mouse and for both sexes with Androgenetic Alopecia. A key difference between this study and those previously reported6-8 appears to be the characteristics
of the pretransplantation hairs present on the selected scalp tissues. Van Neste, De Brouwer, and Dumortier6 specified the use of balding human scalp tissue only; the study then compared the growth characteristics of harvested hairs, posttransplantation, onto female nude mice, with the hairs growing in situ on the scalps of the male and female Androgenetic Alopecia donors. Information about the grade and duration of Androgenetic Alopecia in these donors was not provided. From the reported wide distribution of diameters of the hairs harvested from these balding sites,6 however, it appears that transitional scalp areas (ie, in the early process of balding yet still possessing a considerable number of terminal hairs) were the preferred sampling sites. On the basis of our observation that post-transplantation vellus hairs increase in diameter and terminal hairs decrease in diameter, a starting population of mixed hairs (vellus, terminal, thick terminal) as described6 would likely yield a final mean diameter close to the pre-transplantation mean diameter for the population, leading to the conclusion
that pretransplantation diameters are maintained. In our study, balding scalp tissue had only vellus hairs and hairy tissue had only thick, terminal hairs allowing a direct comparison of these hair types, pretransplantation and posttransplantation.
Sintov et al9 also specified balding grafts but did not report the mean diameter of the pretransplantation hairs. The pregrafted hairs probably constituted a more homogeneous population of fine, vellus hairs than those of Van Neste et al6 because at 68 days posttransplantation the grafted hairs on untreated male SCID mice had diameters from 10 to 20 m versus 30 to 40 m on antiandrogen-treated mice.9 Although this study is difficult to evaluate
relative to our data because of its shorter duration and the lack of information regarding pretransplantation diameters, it suggests that the males of some
strains of mice have systemic androgen levels high enough and/or the grafts retain sufficient 5-R activity to impede the growth of androgen-sensitive
hair follicles. In our experience, vellus hairs regrew as well on male as on female nude mice when evaluated at 6 months posttransplantation (data not
shown). Female mice were preferred because previous studies,6-8 to which we were comparing, specified females.
Human hair growth is subject to both inhibitor and promoter factors, but each follicle appears to be genetically programmed to be more sensitive to one
or the other of these factors and can be transplanted without losing this donor-dominant genetic characteristic. 12-14 The hormonal environment of childhood
allows all scalp hairs to grow to normal anagen size. At sexual maturity, the hormonal environment changes, and Androgenetic Alopecia commences in the genetically
predisposed. Androgenetic Alopecia is not the result of the loss of hair follicles, but rather a systematic involution of the follicle, which results in the transformation of terminal follicles to vellus follicles with no appreciable reduction in density.15 The volume of the dermal papilla, which depends largely on its cell number
and the amount of extracellular matrix, correlates with the size of the hair fiber produced.16,17 Several reports suggest that androgen-mediated alterations
in hair size occur through interaction with the dermal papilla.18-20
In human males, dihydrotestosterone (DHT) is required for Androgenetic Alopecia to occur in the genetically predisposed. Adults with pseudohermaphroditism type 2 have normal levels of T but significantly lower levels of DHT and do not show balding as do their healthy siblings.21 Systemic treatment to inhibit the metabolism of T to DHT in combination with local therapy to reduce the conversion by 5-R of T to DHT has produced hair regrowth in bald human scalp both in length and diameter.22-24 The process, however, is slow and not necessarily effective in all individuals.
The phenomenon occurring in the xenograft experiments reported here is quite different and dramatic: hypotrophic anagen and telogen hairs from balding scalp exhibiting only vellus hairs in situ regenerate very quickly. By 6 months, the ratio of the diameters of grafted to pretransplant vellus hairs exceeds 3:1 (Fig 3). Histologic examination of posttransplantation follicles from balding scalp also shows fully developed anagen follicles at 6 months (Fig 2).
The regeneration of vellus follicles occurs just as quickly on male as on female mice (data not shown); this suggests that a factor or factors other than androgen withdrawal may be involved but does not necessarily rule out that differences in androgen levels, availability, or both between human beings and mice account in part or entirely for the rapid vellus-to-terminal transformation of balding follicles. For instance, the activity of the 5-R enzyme(s) may be greatly reduced or absent in the transplanted follicles, thereby, limiting exposure of
the follicles to DHT. The accelerated transformation of vellus follicles on immunodeficient mice might then correspond to responses seen in balding men
treated with oral finasteride24 who are exceptionally good responders. However, in our clinical experience, females with Androgenetic Alopecia, including the female in
study II, frequently have normal androgen and androgen-binding globulin levels for their age and sex.
It is difficult to argue that lower systemic androgen levels in the female mouse environment (or higher in the case of the male mice) causes the rapid regeneration of vellus hair follicles from the human female. Therefore, the existence of an inhibitor factor other than androgens, particularly in women
showing diffuse/pattern alopecia,25 that is lacking in the nude mouse seems plausible. This could be some other steroid, hormone, cytokine, neuropeptide,
or an immunologically related factor.
The one-hair-cycle reversal of the miniaturized hair follicles of Androgenetic Alopecia, as demonstrated in this study, supports the hypothesis that miniaturization does
not occur gradually over many hair cycles, as conventionally thought, but may, in fact, be an abrupt, large-step process that can potentially reverse just as
quickly.26,27 The prompted new anagen as a result of postoperative effluvium that the transplanted follicles undergo in this experimental system may be an
added advantage, accelerating or even initiating the regeneration of vellus follicles.
The data also indicate that the mouse environment is less than optimal for the growth of follicles originating from hairy scalp. The rate of increase in length of these hairs appears to be close to normal or only slightly diminished, but the mean diameter is markedly reduced. Currently, there is no explanation for the diameters of the hairs from the balding area continuing to increase, whereas those from the nonbalding area plateau after 17 weeks. It is important to note that the slope of mean diameter growth in the balding hairs diminishes at the same time that the nonbalding hair mean diameter stops increasing (Fig 5).
Nonspecific factors such as differences in temperature, protein availability, or both between human beings and mice would be expected to affect balding and nonbalding grafts equally and may account for the fact that neither type of graft produces hairs equal to that found growing in situ in optimal regions (occipital) of the scalp. However, it is also possible that a growth factor or growth promoter
originally available to the nonbalding hair follicles in situ may be lacking or reduced in these mice. The same factor that inhibits Androgenetic Alopecia follicles28 may act as a trophic factor for non-Androgenetic Alopecia follicles.
In summary, this report demonstrates that balding, miniaturized follicles possess the potential to quickly regenerate once removed from the human
scalp and that the phenomenon applies equally to follicles from both men and women with Androgenetic Alopecia. These findings expand the use of this model beyond
a tool for screening potential therapies to one that may yield insight into the mechanisms involved in Androgenetic Alopecia induction in both men and women.
Rozlyn A. Krajcik, PhD, Joseph H. Vogelman, DEE, Virginia L. Malloy, MS, and
Norman Orentreich, MD
DISCUSSION
The original intent of this study was to optimize the procedure of grafting human hair follicles onto immunodeficient mice to have a highly reproducible model system for evaluating treatments for Androgenetic Alopecia. To that end, various methods of transplantation were compared (data not shown), as were several strains of mice (National Institutes of Health Swiss nude and SCID) both male and female, and scalp skin from balding and hairy regions of numerous Androgenetic Alopecia male and female donors (28 males; 11 females).
What became apparent, contrary to the results reported by Van Neste et al,6 was that regardless of the method used and sex or strain of mice, grafts from
balding scalp produced pigmented terminal hairs equal in length and diameter to those produced by transplanted hair follicles from hairy, nonbalding scalp. We report here the results from 2 representative male donors in an experiment using female nude mice (Fig 3).
To minimize extraneous variables and to further verify these results, we then transplanted follicles from both the balding and hairy scalp areas from the
same individual, a female with clinically prominent Androgenetic Alopecia, to each of 7 female SCID mice. The results show that the regrowth of hair, irrespective of follicle
origin, is similar after transplantation onto immu-nodeficient mice (Fig 4). To our knowledge, this is the first study that compares the hair growth of balding and terminal scalp follicles from the same human being transplanted onto the same mouse and for both sexes with Androgenetic Alopecia.
To our knowledge, this is the first study that compares the hair growth of
balding and terminal scalp follicles from the same human being transplanted onto the same mouse and for both sexes with Androgenetic Alopecia. A key difference between this study and those previously reported6-8 appears to be the characteristics
of the pretransplantation hairs present on the selected scalp tissues. Van Neste, De Brouwer, and Dumortier6 specified the use of balding human scalp tissue only; the study then compared the growth characteristics of harvested hairs, posttransplantation, onto female nude mice, with the hairs growing in situ on the scalps of the male and female Androgenetic Alopecia donors. Information about the grade and duration of Androgenetic Alopecia in these donors was not provided. From the reported wide distribution of diameters of the hairs harvested from these balding sites,6 however, it appears that transitional scalp areas (ie, in the early process of balding yet still possessing a considerable number of terminal hairs) were the preferred sampling sites. On the basis of our observation that post-transplantation vellus hairs increase in diameter and terminal hairs decrease in diameter, a starting population of mixed hairs (vellus, terminal, thick terminal) as described6 would likely yield a final mean diameter close to the pre-transplantation mean diameter for the population, leading to the conclusion
that pretransplantation diameters are maintained. In our study, balding scalp tissue had only vellus hairs and hairy tissue had only thick, terminal hairs allowing a direct comparison of these hair types, pretransplantation and posttransplantation.
Sintov et al9 also specified balding grafts but did not report the mean diameter of the pretransplantation hairs. The pregrafted hairs probably constituted a more homogeneous population of fine, vellus hairs than those of Van Neste et al6 because at 68 days posttransplantation the grafted hairs on untreated male SCID mice had diameters from 10 to 20 m versus 30 to 40 m on antiandrogen-treated mice.9 Although this study is difficult to evaluate
relative to our data because of its shorter duration and the lack of information regarding pretransplantation diameters, it suggests that the males of some
strains of mice have systemic androgen levels high enough and/or the grafts retain sufficient 5-R activity to impede the growth of androgen-sensitive
hair follicles. In our experience, vellus hairs regrew as well on male as on female nude mice when evaluated at 6 months posttransplantation (data not
shown). Female mice were preferred because previous studies,6-8 to which we were comparing, specified females.
Human hair growth is subject to both inhibitor and promoter factors, but each follicle appears to be genetically programmed to be more sensitive to one
or the other of these factors and can be transplanted without losing this donor-dominant genetic characteristic. 12-14 The hormonal environment of childhood
allows all scalp hairs to grow to normal anagen size. At sexual maturity, the hormonal environment changes, and Androgenetic Alopecia commences in the genetically
predisposed. Androgenetic Alopecia is not the result of the loss of hair follicles, but rather a systematic involution of the follicle, which results in the transformation of terminal follicles to vellus follicles with no appreciable reduction in density.15 The volume of the dermal papilla, which depends largely on its cell number
and the amount of extracellular matrix, correlates with the size of the hair fiber produced.16,17 Several reports suggest that androgen-mediated alterations
in hair size occur through interaction with the dermal papilla.18-20
In human males, dihydrotestosterone (DHT) is required for Androgenetic Alopecia to occur in the genetically predisposed. Adults with pseudohermaphroditism type 2 have normal levels of T but significantly lower levels of DHT and do not show balding as do their healthy siblings.21 Systemic treatment to inhibit the metabolism of T to DHT in combination with local therapy to reduce the conversion by 5-R of T to DHT has produced hair regrowth in bald human scalp both in length and diameter.22-24 The process, however, is slow and not necessarily effective in all individuals.
The phenomenon occurring in the xenograft experiments reported here is quite different and dramatic: hypotrophic anagen and telogen hairs from balding scalp exhibiting only vellus hairs in situ regenerate very quickly. By 6 months, the ratio of the diameters of grafted to pretransplant vellus hairs exceeds 3:1 (Fig 3). Histologic examination of posttransplantation follicles from balding scalp also shows fully developed anagen follicles at 6 months (Fig 2).
The regeneration of vellus follicles occurs just as quickly on male as on female mice (data not shown); this suggests that a factor or factors other than androgen withdrawal may be involved but does not necessarily rule out that differences in androgen levels, availability, or both between human beings and mice account in part or entirely for the rapid vellus-to-terminal transformation of balding follicles. For instance, the activity of the 5-R enzyme(s) may be greatly reduced or absent in the transplanted follicles, thereby, limiting exposure of
the follicles to DHT. The accelerated transformation of vellus follicles on immunodeficient mice might then correspond to responses seen in balding men
treated with oral finasteride24 who are exceptionally good responders. However, in our clinical experience, females with Androgenetic Alopecia, including the female in
study II, frequently have normal androgen and androgen-binding globulin levels for their age and sex.
It is difficult to argue that lower systemic androgen levels in the female mouse environment (or higher in the case of the male mice) causes the rapid regeneration of vellus hair follicles from the human female. Therefore, the existence of an inhibitor factor other than androgens, particularly in women
showing diffuse/pattern alopecia,25 that is lacking in the nude mouse seems plausible. This could be some other steroid, hormone, cytokine, neuropeptide,
or an immunologically related factor.
The one-hair-cycle reversal of the miniaturized hair follicles of Androgenetic Alopecia, as demonstrated in this study, supports the hypothesis that miniaturization does
not occur gradually over many hair cycles, as conventionally thought, but may, in fact, be an abrupt, large-step process that can potentially reverse just as
quickly.26,27 The prompted new anagen as a result of postoperative effluvium that the transplanted follicles undergo in this experimental system may be an
added advantage, accelerating or even initiating the regeneration of vellus follicles.
The data also indicate that the mouse environment is less than optimal for the growth of follicles originating from hairy scalp. The rate of increase in length of these hairs appears to be close to normal or only slightly diminished, but the mean diameter is markedly reduced. Currently, there is no explanation for the diameters of the hairs from the balding area continuing to increase, whereas those from the nonbalding area plateau after 17 weeks. It is important to note that the slope of mean diameter growth in the balding hairs diminishes at the same time that the nonbalding hair mean diameter stops increasing (Fig 5).
Nonspecific factors such as differences in temperature, protein availability, or both between human beings and mice would be expected to affect balding and nonbalding grafts equally and may account for the fact that neither type of graft produces hairs equal to that found growing in situ in optimal regions (occipital) of the scalp. However, it is also possible that a growth factor or growth promoter
originally available to the nonbalding hair follicles in situ may be lacking or reduced in these mice. The same factor that inhibits Androgenetic Alopecia follicles28 may act as a trophic factor for non-Androgenetic Alopecia follicles.
In summary, this report demonstrates that balding, miniaturized follicles possess the potential to quickly regenerate once removed from the human
scalp and that the phenomenon applies equally to follicles from both men and women with Androgenetic Alopecia. These findings expand the use of this model beyond
a tool for screening potential therapies to one that may yield insight into the mechanisms involved in Androgenetic Alopecia induction in both men and women.
:laugh: