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J Cosmet Med 2023; 7(1): 6-8

Published online June 30, 2023

https://doi.org/10.25056/JCM.2023.7.1.6

Hair follicle stem cells and mitochondria

Chang-Deok Kim , PhD

Department of Dermatology, Chungnam National University College of Medicine, Daejeon, Rep. of Korea

Correspondence to :
Chang-Deok Kim
E-mail: cdkimd@cnu.ac.kr

Received: February 22, 2023; Revised: March 24, 2023; Accepted: April 11, 2023

© Korean Society of Korean Cosmetic Surgery & Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hair is a skin appendage that protects the skin from external factors such as physical stimuli, temperature changes, and ultraviolet light. Since hair also plays an important role aesthetically, many people are interested in hair growth and loss. Hair growth is a complex process, which is finely regulated by interactions between the various cells that make up the hair follicle. In particular, hair follicle stem cells are present in the bulge area of the hair follicle and since these cells can differentiate into various cells constituting the hair follicle, they play a pivotal role in maintaining the hair growth cycle. Hair follicle stem cells usually remain quiescent, but under certain circumstances, they become activated, start dividing, and migrate to the lower part of the bulge to form anagen hair follicle. Along with many genes involved in the process of quiescence and activation of hair follicle stem cells, energy metabolism can also affect hair follicle stem cell activity. In this regard, the role of mitochondria, energy-generating organelles, in hair follicle stem cells should be emphasized.

Keywords: energy metabolism, hair follicle stem cells, mitochondria

The hair follicle is one of the skin appendages that produce the hair shaft. The hair follicle is composed of many cells including ectodermal cells, such as keratinocytes and melanocytes, and mesodermal cells, such as fibroblasts [1]. The structure of the hair follicle is divided into the outer root sheath (ORS), which surrounds the outermost layer, and the inner root sheath, which surrounds the hair shaft, matrix, and dermal papilla. Hair growth shows cyclicity, composed of anagen (hair growing stage), catagen (regression stage), and telogen (resting stage). During the hair growth cycle, regeneration and shrinkage of hair follicle tissue periodically occur below the bulge area where the arrector pili muscle attaches, and this cyclicity indicates the existence of stem cells in the hair follicle [2]. In 1990, George Cotsarelis of the University of Pennsylvania, USA, discovered that hair follicle stem cells reside in the bulge area of the hair follicle [3]. Until this discovery, it was thought that hair follicle stem cells reside in the germinative epithelium located at the base of the hair follicle. Since it was discovered that hair follicle stem cells reside in the bulge area, various and extensive studies on hair follicle stem cells have been conducted using genetically engineered mice or cell culture systems, and many genes and cellular mechanisms regulating the hair growth cycle have been identified [4].

To understand the characteristics of hair follicle stem cells, it is first necessary to isolate hair follicle stem cells. To this end, many researchers have tried to find cell surface markers that are specifically expressed in hair follicle stem cells. As a result, various protein molecules were identified as markers of hair follicle stem cells. For example, it was found that the CD34 molecule used as a marker for hematopoietic stem cells is also expressed on the surface of hair follicle stem cells present in the bulge area, making it possible to separate and culture hair follicle stem cells using this marker. When the hair follicle cells expressing the CD34 molecule on the cell surface are isolated and cultured, it can be confirmed that the colony forming activity, one of the stem cell characters, is significantly increased compared to the cells that do not express the CD34 molecule on the cell surface [5]. Another example of a hair follicle stem cell marker is keratin 15 (KRT15). KRT15 is characterized by strong expression in hair follicle stem cells present in the bulge area of the hair follicle [6]. Therefore, if a transgenic mouse is prepared using the promoter of the KRT15 gene, it is possible to create an experimental model that expresses a specific gene only in hair follicle stem cells. In 2004, George Cotsarelis’ group produced transgenic mice using recombinant DNA in which the green fluorescent protein (GFP) gene was linked to the promoter of the KRT15 gene. Afterwards, only hair follicle stem cells could be isolated from the mouse whole epidermis using the fluorescence-activating cell sorting method, and the separated hair follicle stem cells were transplanted back into nude mice to successfully create anagen hair follicles [7]. These experimental results suggest a theoretical basis that hair follicle stem cells can be isolated, cultured in vitro to increase the amount of cells, and then transplanted into the skin to generate new hair follicles. Until now, the technology of treating hair loss by culturing and transplanting hair follicle stem cells has not been commercialized. However, it is expected that a technology capable of securing a large amount of hair follicle stem cells will be developed in the future, and it will be able to establish itself as a new tool for hair regeneration treatment.

Compared to laboratory animals, there are many difficulties in studying hair follicle stem cells in humans. One of the biggest difficulties is that in the case of humans, it is difficult to accurately determine the location of the bulge where hair follicle stem cells reside [4]. In 2006, Jonathan Vogel’s group used a laser-capture microdissection method to demonstrate that human hair follicle stem cells reside in the outer layer of the hair follicle between the opening of the sebaceous gland and the junction of the arrector pili muscle. And they proposed CD200 as a marker for human hair follicle stem cells. Actually, it was proved that the CD200-expressing ORS cells present in the middle of human hair follicles show the characteristics of hair follicle stem cells [8]. In 2011, George Cotsarelis’ group studied hair follicle stem cells in the bald scalp of men with male pattern baldness using CD200 and CD34 and another hair follicle stem cell marker, integrin α6, Interestingly, hair follicle stem cells were present in the bald area showing male pattern baldness, but among these hair follicle stem cells, cells expressing both CD200 and CD34 (CD200+/CD34+ cells) were significantly reduced in the balding area compared to non-balding area [9]. This means that the cells constituting the hair follicle stem cells are very heterogenous, and male pattern baldness can be induced if the cell population exhibiting specific characteristics is reduced among them.

Mitochondria are organelles present in most eukaryotic cells and play a role in providing energy to organisms by generating adenosine triphosphate. Mitochondrial function is related to maintenance of skin homeostasis, epidermal differentiation, and hair follicle development [10]. In addition to energy production, mitochondria are important organelles involved in various cellular reactions such as fatty acid and amino acid oxidation, iron metabolism, and apoptosis [11,12]. Since hair growth is a very dynamic phenomenon accompanied by active cell division and differentiation, it can be expected that mitochondria play an important role in hair growth. However, until now, there have been few studies on how mitochondrial abnormalities affect hair follicle formation and the hair growth cycle. In order to examine how mitochondria affect the hair growth cycle, a study was conducted on CRIF1, a mitochondrial component protein. When the CRIF1 gene was removed from hair follicle stem cells using the KRT15 promoter, it was observed that the hair growth cycle was delayed compared to normal (Fig. 1) [13]. In addition, when the CRIF1 gene was removed from the epidermis, the development of hair follicles was suppressed [14]. Furthermore, deletion of mitochondrial transcription factor A in the skin epithelium using the keratin-14 promoter causes loss of function of the electron transport chain in keratinocytes, resulting in significantly reduced hair follicle density and morphogenesis [15]. From these experimental evidences, it can be seen that mitochondria play a pivotal role in maintaining the hair growth cycle. In particular, mitochondrial activity is essential during the transition from the telogen phase to the anagen phase of the hair growth cycle. Based on these experimental evidences, mitochondria activity in hair follicle stem cells can be a drug target point in the development of hair growth stimulants.

Fig. 1.KRT15-CrePR mice were crossed with CRIF1f1/fl mice to produce hair follicle stem cells-specific CRIF1 knockout mice. Mice were intraperitoneally injected with RU486 for 2 weeks from day 60 after birth. At day 120 after birth, back skins were obtained and stained with hematoxylin and eosin (×40). Normal mice are in the anagen phase where hair grows actively, whereas CRIF1 knockout mice remain in the telogen phase.

In this paper, hair follicle stem cells and mitochondria were briefly reviewed. Although hair loss is a very common disease and various treatment methods are being applied, the demand for effective drug development is still very high. If in-depth information on hair growth mechanisms is obtained through more diverse and extensive research on the characteristics of hair follicle stem cells, it is expected that more effective hair loss treatments will be developed in the future.

  1. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132-42.
    Pubmed CrossRef
  2. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001;81:449-94.
    Pubmed CrossRef
  3. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61:1329-37.
    Pubmed CrossRef
  4. Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol 2006;126:1459-68.
    Pubmed CrossRef
  5. Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 2003;120:501-11.
    Pubmed CrossRef
  6. Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis G. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111(Pt 21):3179-88.
    Pubmed CrossRef
  7. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 2004;22:411-7.
    Pubmed CrossRef
  8. Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249-60.
    Pubmed KoreaMed CrossRef
  9. Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, et al. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest 2011;121:613-22.
    Pubmed KoreaMed CrossRef
  10. Sreedhar A, Aguilera-Aguirre L, Singh KK. Mitochondria in skin health, aging, and disease. Cell Death Dis 2020;11:444.
    Pubmed KoreaMed CrossRef
  11. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab 2020;32:920-37.
    Pubmed CrossRef
  12. Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: mitochondria, lipid and amino acid metabolism. Cell Mol Life Sci 2016;73:1349-63.
    Pubmed KoreaMed CrossRef
  13. Shin JM, Ko JW, Choi CW, Lee Y, Seo YJ, Lee JH, et al. Deficiency of Crif1 in hair follicle stem cells retards hair growth cycle in adult mice. PLoS One 2020;15:e0232206.
    Pubmed KoreaMed CrossRef
  14. Shin JM, Choi DK, Sohn KC, Kim JY, Im M, Lee Y, et al. Targeted deletion of Crif1 in mouse epidermis impairs skin homeostasis and hair morphogenesis. Sci Rep 2017;7:44828.
    Pubmed KoreaMed CrossRef
  15. Kloepper JE, Baris OR, Reuter K, Kobayashi K, Weiland D, Vidali S, et al. Mitochondrial function in murine skin epithelium is crucial for hair follicle morphogenesis and epithelial-mesenchymal interactions. J Invest Dermatol 2015;135:679-89.
    Pubmed CrossRef

Article

Review Article

J Cosmet Med 2023; 7(1): 6-8

Published online June 30, 2023 https://doi.org/10.25056/JCM.2023.7.1.6

Copyright © Korean Society of Korean Cosmetic Surgery & Medicine.

Hair follicle stem cells and mitochondria

Chang-Deok Kim , PhD

Department of Dermatology, Chungnam National University College of Medicine, Daejeon, Rep. of Korea

Correspondence to:Chang-Deok Kim
E-mail: cdkimd@cnu.ac.kr

Received: February 22, 2023; Revised: March 24, 2023; Accepted: April 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hair is a skin appendage that protects the skin from external factors such as physical stimuli, temperature changes, and ultraviolet light. Since hair also plays an important role aesthetically, many people are interested in hair growth and loss. Hair growth is a complex process, which is finely regulated by interactions between the various cells that make up the hair follicle. In particular, hair follicle stem cells are present in the bulge area of the hair follicle and since these cells can differentiate into various cells constituting the hair follicle, they play a pivotal role in maintaining the hair growth cycle. Hair follicle stem cells usually remain quiescent, but under certain circumstances, they become activated, start dividing, and migrate to the lower part of the bulge to form anagen hair follicle. Along with many genes involved in the process of quiescence and activation of hair follicle stem cells, energy metabolism can also affect hair follicle stem cell activity. In this regard, the role of mitochondria, energy-generating organelles, in hair follicle stem cells should be emphasized.

Keywords: energy metabolism, hair follicle stem cells, mitochondria

Introduction

The hair follicle is one of the skin appendages that produce the hair shaft. The hair follicle is composed of many cells including ectodermal cells, such as keratinocytes and melanocytes, and mesodermal cells, such as fibroblasts [1]. The structure of the hair follicle is divided into the outer root sheath (ORS), which surrounds the outermost layer, and the inner root sheath, which surrounds the hair shaft, matrix, and dermal papilla. Hair growth shows cyclicity, composed of anagen (hair growing stage), catagen (regression stage), and telogen (resting stage). During the hair growth cycle, regeneration and shrinkage of hair follicle tissue periodically occur below the bulge area where the arrector pili muscle attaches, and this cyclicity indicates the existence of stem cells in the hair follicle [2]. In 1990, George Cotsarelis of the University of Pennsylvania, USA, discovered that hair follicle stem cells reside in the bulge area of the hair follicle [3]. Until this discovery, it was thought that hair follicle stem cells reside in the germinative epithelium located at the base of the hair follicle. Since it was discovered that hair follicle stem cells reside in the bulge area, various and extensive studies on hair follicle stem cells have been conducted using genetically engineered mice or cell culture systems, and many genes and cellular mechanisms regulating the hair growth cycle have been identified [4].

Hair follicle stem cells in rodent models

To understand the characteristics of hair follicle stem cells, it is first necessary to isolate hair follicle stem cells. To this end, many researchers have tried to find cell surface markers that are specifically expressed in hair follicle stem cells. As a result, various protein molecules were identified as markers of hair follicle stem cells. For example, it was found that the CD34 molecule used as a marker for hematopoietic stem cells is also expressed on the surface of hair follicle stem cells present in the bulge area, making it possible to separate and culture hair follicle stem cells using this marker. When the hair follicle cells expressing the CD34 molecule on the cell surface are isolated and cultured, it can be confirmed that the colony forming activity, one of the stem cell characters, is significantly increased compared to the cells that do not express the CD34 molecule on the cell surface [5]. Another example of a hair follicle stem cell marker is keratin 15 (KRT15). KRT15 is characterized by strong expression in hair follicle stem cells present in the bulge area of the hair follicle [6]. Therefore, if a transgenic mouse is prepared using the promoter of the KRT15 gene, it is possible to create an experimental model that expresses a specific gene only in hair follicle stem cells. In 2004, George Cotsarelis’ group produced transgenic mice using recombinant DNA in which the green fluorescent protein (GFP) gene was linked to the promoter of the KRT15 gene. Afterwards, only hair follicle stem cells could be isolated from the mouse whole epidermis using the fluorescence-activating cell sorting method, and the separated hair follicle stem cells were transplanted back into nude mice to successfully create anagen hair follicles [7]. These experimental results suggest a theoretical basis that hair follicle stem cells can be isolated, cultured in vitro to increase the amount of cells, and then transplanted into the skin to generate new hair follicles. Until now, the technology of treating hair loss by culturing and transplanting hair follicle stem cells has not been commercialized. However, it is expected that a technology capable of securing a large amount of hair follicle stem cells will be developed in the future, and it will be able to establish itself as a new tool for hair regeneration treatment.

Hair follicle stem cells in humans

Compared to laboratory animals, there are many difficulties in studying hair follicle stem cells in humans. One of the biggest difficulties is that in the case of humans, it is difficult to accurately determine the location of the bulge where hair follicle stem cells reside [4]. In 2006, Jonathan Vogel’s group used a laser-capture microdissection method to demonstrate that human hair follicle stem cells reside in the outer layer of the hair follicle between the opening of the sebaceous gland and the junction of the arrector pili muscle. And they proposed CD200 as a marker for human hair follicle stem cells. Actually, it was proved that the CD200-expressing ORS cells present in the middle of human hair follicles show the characteristics of hair follicle stem cells [8]. In 2011, George Cotsarelis’ group studied hair follicle stem cells in the bald scalp of men with male pattern baldness using CD200 and CD34 and another hair follicle stem cell marker, integrin α6, Interestingly, hair follicle stem cells were present in the bald area showing male pattern baldness, but among these hair follicle stem cells, cells expressing both CD200 and CD34 (CD200+/CD34+ cells) were significantly reduced in the balding area compared to non-balding area [9]. This means that the cells constituting the hair follicle stem cells are very heterogenous, and male pattern baldness can be induced if the cell population exhibiting specific characteristics is reduced among them.

Hair follicle stem cells and mitochondria

Mitochondria are organelles present in most eukaryotic cells and play a role in providing energy to organisms by generating adenosine triphosphate. Mitochondrial function is related to maintenance of skin homeostasis, epidermal differentiation, and hair follicle development [10]. In addition to energy production, mitochondria are important organelles involved in various cellular reactions such as fatty acid and amino acid oxidation, iron metabolism, and apoptosis [11,12]. Since hair growth is a very dynamic phenomenon accompanied by active cell division and differentiation, it can be expected that mitochondria play an important role in hair growth. However, until now, there have been few studies on how mitochondrial abnormalities affect hair follicle formation and the hair growth cycle. In order to examine how mitochondria affect the hair growth cycle, a study was conducted on CRIF1, a mitochondrial component protein. When the CRIF1 gene was removed from hair follicle stem cells using the KRT15 promoter, it was observed that the hair growth cycle was delayed compared to normal (Fig. 1) [13]. In addition, when the CRIF1 gene was removed from the epidermis, the development of hair follicles was suppressed [14]. Furthermore, deletion of mitochondrial transcription factor A in the skin epithelium using the keratin-14 promoter causes loss of function of the electron transport chain in keratinocytes, resulting in significantly reduced hair follicle density and morphogenesis [15]. From these experimental evidences, it can be seen that mitochondria play a pivotal role in maintaining the hair growth cycle. In particular, mitochondrial activity is essential during the transition from the telogen phase to the anagen phase of the hair growth cycle. Based on these experimental evidences, mitochondria activity in hair follicle stem cells can be a drug target point in the development of hair growth stimulants.

Figure 1. KRT15-CrePR mice were crossed with CRIF1f1/fl mice to produce hair follicle stem cells-specific CRIF1 knockout mice. Mice were intraperitoneally injected with RU486 for 2 weeks from day 60 after birth. At day 120 after birth, back skins were obtained and stained with hematoxylin and eosin (×40). Normal mice are in the anagen phase where hair grows actively, whereas CRIF1 knockout mice remain in the telogen phase.

Conclusion

In this paper, hair follicle stem cells and mitochondria were briefly reviewed. Although hair loss is a very common disease and various treatment methods are being applied, the demand for effective drug development is still very high. If in-depth information on hair growth mechanisms is obtained through more diverse and extensive research on the characteristics of hair follicle stem cells, it is expected that more effective hair loss treatments will be developed in the future.

Conflicts of interest

The author has nothing to disclose.

Fig 1.

Figure 1.KRT15-CrePR mice were crossed with CRIF1f1/fl mice to produce hair follicle stem cells-specific CRIF1 knockout mice. Mice were intraperitoneally injected with RU486 for 2 weeks from day 60 after birth. At day 120 after birth, back skins were obtained and stained with hematoxylin and eosin (×40). Normal mice are in the anagen phase where hair grows actively, whereas CRIF1 knockout mice remain in the telogen phase.
Journal of Cosmetic Medicine 2023; 7: 6-8https://doi.org/10.25056/JCM.2023.7.1.6

References

  1. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132-42.
    Pubmed CrossRef
  2. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001;81:449-94.
    Pubmed CrossRef
  3. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61:1329-37.
    Pubmed CrossRef
  4. Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol 2006;126:1459-68.
    Pubmed CrossRef
  5. Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 2003;120:501-11.
    Pubmed CrossRef
  6. Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis G. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111(Pt 21):3179-88.
    Pubmed CrossRef
  7. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 2004;22:411-7.
    Pubmed CrossRef
  8. Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249-60.
    Pubmed KoreaMed CrossRef
  9. Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, et al. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest 2011;121:613-22.
    Pubmed KoreaMed CrossRef
  10. Sreedhar A, Aguilera-Aguirre L, Singh KK. Mitochondria in skin health, aging, and disease. Cell Death Dis 2020;11:444.
    Pubmed KoreaMed CrossRef
  11. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab 2020;32:920-37.
    Pubmed CrossRef
  12. Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: mitochondria, lipid and amino acid metabolism. Cell Mol Life Sci 2016;73:1349-63.
    Pubmed KoreaMed CrossRef
  13. Shin JM, Ko JW, Choi CW, Lee Y, Seo YJ, Lee JH, et al. Deficiency of Crif1 in hair follicle stem cells retards hair growth cycle in adult mice. PLoS One 2020;15:e0232206.
    Pubmed KoreaMed CrossRef
  14. Shin JM, Choi DK, Sohn KC, Kim JY, Im M, Lee Y, et al. Targeted deletion of Crif1 in mouse epidermis impairs skin homeostasis and hair morphogenesis. Sci Rep 2017;7:44828.
    Pubmed KoreaMed CrossRef
  15. Kloepper JE, Baris OR, Reuter K, Kobayashi K, Weiland D, Vidali S, et al. Mitochondrial function in murine skin epithelium is crucial for hair follicle morphogenesis and epithelial-mesenchymal interactions. J Invest Dermatol 2015;135:679-89.
    Pubmed CrossRef

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