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At least 19 recordsLinked to original sources
PubMed2006

Gene expression profiling gets to the root of human hair follicle stem cells.

Hair follicle stem cells sustain growth and cycling of the hair follicle and are located in the permanent portion of the follicle known as the bulge. In this issue of the JCI, Ohyama et al. report the characterization of global gene expression patterns of human hair follicle stem cells after their isolation using sophisticated laser capture techniques to microdissect out bulge cells. They discovered a panel of cell surface markers useful for isolating living hair follicle stem cells, a finding with potential therapeutic implications since isolated stem cells in mice can generate new hair follicles when transplanted to other mice. The findings of Ohyama et al. validate the use of the mouse for studying hair follicle biology but also underscore critical differences between mouse and human stem cell markers. In particular, CD34, which delineates hair follicle stem cells in the mouse, is not expressed by human hair follicle stem cells, while CD200 is expressed by stem cells in both species. Ultimately, this information will assist efforts to develop cell-based and cell-targeted treatments for skin disease.

Animals↗
PubMed2006

The pluripotency of hair follicle stem cells.

The hair follicle bulge area is an abundant, easily accessible source of actively growing, pluripotent adult stem cells. Nestin, a protein marker for neural stem cells, is also expressed in follicle stem cells as well as their immediate differentiated progeny. The nestin-expressing hair follicle stem cells differentiated into neurons, glial cells, keratinocytes and smooth muscle cells in vitro. Hair-follicle stem cells were implanted into the gap region of a severed sciatic nerve. The hair follicle stem cells greatly enhanced the rate of nerve regeneration and the restoration of nerve function. The follicle stem cells transdifferentiated largely into Schwann cells which are known to support neuron regrowth. Function of the rejoined sciatic nerve was measured by contraction of the gastrocnemius muscle upon electrical stimulation. After severing the tibial nerve and subsequent transplantation of hair-follicle stem cells, the transplanted mice recovered the ability to walk normally. These results suggest that hair-follicle stem cells provide an important accessible, autologous source of adult stem cells for regenerative medicine.

Animals↗
PubMed2004

Capturing and profiling adult hair follicle stem cells.

The hair follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of hair follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of hair loss and other disorders of skin and hair.

3T3 Cells↗
PubMed2003

Hair follicle stem cells.

The workshop on Hair Follicle Stem Cells brought together investigators who have used a variety of approaches to try to understand the biology of follicular epithelial stem cells, and the role that these cells play in regulating the hair cycle. One of the main concepts to emerge from this workshop is that follicular epithelial stem cells are multipotent, capable of giving rise not only to all the cell types of the hair, but also to the epidermis and the sebaceous gland. Furthermore, such multipotent stem cells may represent the ultimate epidermal stem cell. Another example of epithelial stem cell and transit amplifying cell plasticity, was the demonstration that adult corneal epithelium, under the influence of embryonic skin dermis could form an epidermis as well as hair follicles. With regards to the location of follicular epithelial stem cells, immunohistochemical and ultrastructural data was presented, indicating that cells with stem cell attributes were localized to the prominent bulge region of developing human fetal hair follicles. Finally, a new notion was put forth concerning the roles that the bulge-located stem cells and the hair germ cells played with respect to the hair cycle.

Animals↗
PubMed1999

Cytokeratin 15 expression in trichoepitheliomas and a subset of basal cell carcinomas suggests they originate from hair follicle stem cells.

Trichoepitheliomas and many basal cell carcinomas appear to arise from the hair follicle, and in particular from the hair follicle bulge. This histogenesis is suggested from both morphological and immunohistochemical studies on tumor cells and stroma. Epithelial stem cells are thought to be important in tumorigenesis, and we previously localized a population of stem cells to the bulge area of the outer root sheath. We recently identified an anti-CD8 monoclonal antibody (DAKO clone C8/144B) that cross-reacts with cytokeratin 15 (K15), and serves as a specific marker for the bulge. In this study, we screened a series of trichoepitheliomas (n=13), basal cell carcinomas (n=37) and a variety of other skin tumors with this antibody. All trichoepitheliomas (100%) showed keratin 15 expression, while only a subset of basal cell carcinomas (27%) was K15-positive. Epidermal tumors, including squamous cell carcinomas, were K15-negative. Tumors of follicular derivation such as proliferating trichilemmal cysts were also K15-positive, while others such as pilomatricoma were K15-negative. Expression of K15 in trichoepitheliomas, some basal cell carcinomas and other follicular tumors suggests that these tumors are related to hair follicle stem cells in the bulge.

Antibodies, Monoclonal↗
PubMed2006

[Localization and differentiation of hair follicle stem cells].

OBJECTIVE: To identify the localization of hair follicles stem cell (HFSC) in different stages of hair and explore the differentiating capacity of HFSC into epidermis in vitro. METHODS: HFSC were detected by K19 immunostaining in normal human skin. Then, the isolated HFSC through enzyme digestion were seeded on dermal equivalent (DE) and cultured between the air-liquid interfaces for 14 days. Skin-equivalents was harvested and used for evaluation. RESULTS: HFSC mainly located in outer root sheet in hair follicle and human anagen hair follicles containing two distinct reservoirs for K19-positive cells located in the bulge and bulb of the follicle. These two reservoirs fused in line of outer root sheets during the catagen-telogen transition phase and individualized again in the newly forming anagen hair follicle. Based on DE, growing HFSC built a multilayered and confined epidermis. CONCLUSION: HFSC located in outer root sheets can promote hair cycle and differentiate into epidermis in vitro.

Cell Differentiation↗
PubMed2005

Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves.

The hair follicle bulge area is an abundant, easily accessible source of actively growing, pluripotent adult stem cells. Nestin, a protein marker for neural stem cells, also is expressed in follicle stem cells and their immediate, differentiated progeny. The fluorescent protein GFP, whose expression is driven by the nestin regulatory element in transgenic mice, served to mark the follicle cell fate. The pluripotent nestin-driven GFP stem cells are positive for the stem cell marker CD34 but negative for keratinocyte marker keratin 15, suggesting their relatively undifferentiated state. These cells can differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In vivo studies show the nestin-driven GFP hair follicle stem cells can differentiate into blood vessels and neural tissue after transplantation to the subcutis of nude mice. Equivalent hair follicle stem cells derived from transgenic mice with beta-actin-driven GFP implanted into the gap region of a severed sciatic nerve greatly enhance the rate of nerve regeneration and the restoration of nerve function. The follicle cells transdifferentiate largely into Schwann cells, which are known to support neuron regrowth. Function of the rejoined sciatic nerve was measured by contraction of the gastrocnemius muscle upon electrical stimulation. After severing the tibial nerve and subsequent transplantation of hair follicle stem cells, walking print length and intermediate toe spread significantly recovered, indicating that the transplanted mice recovered the ability to walk normally. These results suggest that hair follicle stem cells provide an important, accessible, autologous source of adult stem cells for regenerative medicine.

Animals↗
PubMed2026

Aging of hair follicle stem cells and their niche: mechanisms and regenerative therapeutic strategies.

Hair follicles (HFs) are vital skin appendages that perform fundamental functions including protection, thermoregulation, and sensation. Orchestrated by hair follicle stem cells (HFSCs), HFs undergo cyclic regeneration throughout the lifespan. However, during chronological aging, this mini-organ experiences progressive physiological decline, clinically characterized by a marked reduction in hair density and hair graying due to pigmentation dysfunction. This aging process involves HFSC exhaustion accompanied by diminished regenerative potential and differentiation capacity, leading to degenerative changes in the bulge architecture. Concurrently, the niche supporting HFSC homeostasis undergoes multi-dimensional and systemic degradation. This niche deterioration disrupts the delicate balance between HFSC quiescence and activation, further impeding hair regeneration. In this review, we delineate the dynamic anatomical changes throughout the hair growth cycle and describe the alterations of HFSCs during aging. We specifically focus on the mechanisms underlying the multi-dimensional degradation of the HFSC niche at tissue, cellular, and molecular levels. Furthermore, we discuss various therapeutic strategies aimed at ameliorating HF aging, offering potential insights for future clinical translation in hair regeneration. Finally, we propose that integrating spatiotemporal high-resolution technologies with genomic data to further decipher the spatiotemporal behaviors of aging HFSCs and niche cells will facilitate the establishment of a robust mechanistic framework for HFSC and niche aging.

Hair Follicle↗
PubMed1998

The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells.

Stem cells are vital for the homeostasis of self-renewing tissues such as the hair follicle. Epithelial stem cells have been implicated in tumorigenesis and wound healing, and their manipulation may have wide ranging applications including gene therapy and tissue transplantation. Rodent hair follicle stem cells have been localized to an area of the follicle called the bulge, however, the identification and characterization of human hair follicle stem cells has been hampered by a lack of cellular markers for this area. We have determined that the C8/144B monoclonal antibody, originally generated against a short intracytoplasmic peptide of CD8, preferentially immunostains hair follicle bulge keratinocytes without staining the remaining hair follicle. Using expression cloning, we identified cytokeratin 15 as the keratinocyte protein recognized by the C8/144B monoclonal antibody. By delineating the bulge using this antibody, we demonstrated that bulge cells possess a stem cell phenotype characterized by their slowly-cycling nature, preferential proliferation at the onset of new hair follicle growth, high level of beta1 integrin expression, and expression of cytokeratin 19.

Adult↗
PubMed1991

Hair follicle stem cells? A distinct germinative epidermal cell population is activated in vitro by the presence of hair dermal papilla cells.

Germinative epidermal cells in the lower end bulb region of anagen hair follicles are highly active, and give rise to hair fibres through rapid proliferation and complex differentiation. They have often been termed hair follicle stem cells, but owing to difficulties in isolation and identification their properties have previously only been clearly documented in vivo. We aimed to isolate and culture germinative cells in vitro, and used microdissection methods to dissect a small but identifiable group of cells from complete follicles. Transmission electron microscopy confirmed that the isolated cells were identical to germinative epidermal cells in situ. SDS-PAGE was used to show that they did not have the same protein composition as epidermis from their immediate proximity (overlying hair matrix), or from other follicular (outer root sheath) and interfollicular (skin basal) regions. Moreover, the germinative cells were found to display morphology and in vitro behaviour that distinguished them from comparative epidermal cells. When cultured in media and on substrata normally conducive to epidermal cell growth they remained in a quiescent state, and did not divide or differentiate. In contrast to other epidermal cells that formed typical pavement-like arrangements, germinative cells remained uniformly small, round and closely packed. However, when cultured in association with hair follicle dermal papilla cells they were radically stimulated into proliferative and aggregative behaviour. Furthermore, they were able to form organotypic-like structures, and exceptionally for skin-derived cell recombinations, a distinct basal lamina at the papilla-germinative cell junction. These results provide evidence that hair follicle germinative cells have intriguing properties that distinguish them from other follicular epidermis. The finding that they can be activated by dermal papilla cells reflects the intimate nature of the papilla-germinative cell relationship in situ, and should facilitate research into hair growth control mechanisms. The nature of germinative cells is discussed in the wider context of hair follicle stem-cell terminology.

Animals↗
PubMed2006

[Skin construction by hair follicle stem cells and fibroblasts].

OBJECTIVE: To establish a method of constructing skin-equivalents (SE) by the hair follicle stem cells (HFSC) and the fibroblasts. METHODS: The K19 immunostaining was employed to localize the HFSC in the human scalp from the cosmetic surgery. The isolated HFSC through the enzyme digestion were seeded on the dermal equivalent (DE) formed by polymerization of the fibroblasts and collagen. After being cultured between the air-liquid interface for 14 days, SE were harvested and used for an evaluation. RESULTS: HFSC were located mainly in the outer root sheath in the hair follicle. Based on DE, the growing HFSC could build a fully-developed and multi-layered epidermis with the basal membrane formed between the epidermis and the dermis. The fibroblasts were active and spread evenly in the collagen matrix. CONCLUSION: The hair follicle stem cells located in the outer root sheath can be successfully used to construct skin-equivalents in vitro and have a promising clinical use in the treatment.

Animals↗
PubMed2004

Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen.

The lowermost portion of the resting (telogen) follicle consists of the bulge and secondary hair germ. We previously showed that the progeny of stem cells in the bulge form the lower follicle and hair, but the relationship of the bulge cells with the secondary hair germ cells, which are also involved in the generation of the new hair at the onset of the hair growth cycle (anagen), remains unclear. Here we address whether secondary hair germ cells are derived directly from epithelial stem cells in the adjacent bulge or whether they arise from cells within the lower follicle that survive the degenerative phase of the hair cycle (catagen). We use 5-bromo-2'-deoxyuridine to label bulge cells at anagen onset, and demonstrate that the lowermost portion of the bulge collapses around the hair and forms the secondary hair germ during late catagen. During the first six days of anagen onset bulge cells proliferate and self-renew. Bulge cell proliferation at this time also generates cells that form the future secondary germ. As bulge cells form the secondary germ cells at the end of catagen, they lose expression of a biochemical marker, S100A6. Remarkably, however, following injury of bulge cells by hair depilation, progenitor cells in the secondary hair germ repopulate the bulge and re-express bulge cell markers. These findings support the notion that keratinocytes can "dedifferentiate" to a stem cell state in response to wounding, perhaps related to signals from the stem cell niche. Finally, we also present evidence that quiescent bulge cells undergo apoptosis during follicle remodeling in catagen, indicating that a subpopulation of bulge cells is not permanent.

Animals↗
PubMed2005

Conditional telomerase induction causes proliferation of hair follicle stem cells.

TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.

Animals↗
PubMed1993

Mouse skin is particularly susceptible to tumor initiation during early anagen of the hair cycle: possible involvement of hair follicle stem cells.

Stem cells are believed to be a necessary target of chemical carcinogens. Based on autoradiographic, ultrastructural, and biologic criteria, we have recently proposed that hair follicle stem cells reside not in the bulb, but in the upper outer root sheath in an area called the bulge. Proliferating cells have been shown to be more susceptible to tumor initiation, and we have recently demonstrated that cells in the bulge undergo transient proliferation during early anagen. Therefore, we theorized that mouse skin should be particularly susceptible to carcinogen application during early anagen phase. In this paper, we show that early anagen Swiss and Sencar mouse skin is indeed particularly susceptible to one- and two-stage chemical carcinogenesis, resulting in tumor yields one to five times those obtained with telogen-timed carcinogen application. Our findings implicate a possible involvement of the bulge cells as precursors to some of the skin cancers, and support the concept that these are stem cells. These observations also raise important questions about the cellular origins and biologic behavior of chemically induced murine skin tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2007

Hair follicle bulge: a fascinating reservoir of epithelial stem cells.

Hair follicles reconstitute themselves though the hair cycle, suggesting the presence of intrinsic stem cells. In contrast to the previous belief that stem cells reside in the bulbar region of hair follicles, stem cells were detected in the bulge area, a contiguous part of outer root sheath, that provides the insertion point for arrector pili muscle and marks the bottom of the permanent portion of hair follicles. The bulge cells are morphologically undifferentiated and slow-cycling under the normal conditions. Later, studies successively demonstrated that bulge cells possess stem cell properties such as high proliferative capacity and multipotency to regenerate not only hair follicles but also sebaceous glands and epidermis. Our knowledge of the bulge cell biology is rapidly increasing because of the identification of novel cell surface markers, the ability to isolate living bulge cells, and microarray analysis of multiple gene expression. Importantly, novel cell surface markers were identified on human bulge cells using precise laser capture microdissection and microarray analyses. Use of these markers enabled the successful enrichment of living human bulge cells, raising the possibility of future treatments of hair disorders using stem cells. Additional clinical relevance of bulge cell biology includes the importance of bulge cells as a gene therapy target and their possible roles in tumorigenesis.

Animals↗
PubMed1996

The primary target cells of the high-risk cottontail rabbit papillomavirus colocalize with hair follicle stem cells.

Papillomaviruses are small DNA tumor viruses with a life cycle inseparably linked to the differentiation of the pluristratified epithelium. The infection of epithelial layers of the skin may remain latent or may result in the development of benign tumors. A certain number of distinct papillomavirus types, however, cause lesions which have a high risk of progression into carcinomas, and extensive efforts have been made to understand this process. comparatively little is known about the initial events during the establishment of a persistent infection and papilloma development. Although it is generally accepted that the growth of a papilloma requires the infection of cells in the basal layer of the epithelium, it remains unknown which cells perform this task. We have analyzed by in situ hybridization biopsy samples taken at various time points after infection of domestic rabbits with cottontail rabbit papillomavirus. The positive cells detected at a low frequency in biopsy samples taken after 11 days predominantly expressed high levels of E6 and E7 mRNA and were localized in the outer epithelial root sheath and in the bulbs of hair follicles. A clonal analysis of keratinocytes isolated from different subfragments of individual rabbit hair follicles demonstrated a clear colocalization of cottontail rabbit papillomavirus mRNA-positive cells with clonogenic cells in hair follicles. These data suggest that the cells competent to establish papillomatous growth represent a subpopulation of keratinocytes in hair follicles with properties expected of epithelial stem cells.

3T3 Cells↗