BJD
R E V I E W A RT I C L E
British Journal of Dermatology
Epidermal stem cells: practical perspectives and potential uses O. Abbas and M. Mahalingam* Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon *Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, U.S.A.
Summary Correspondence Meera Mahalingam. E-mail:
[email protected]
Accepted for publication 7 April 2009
Key words epidermal, melanocytic, stem cells
Conflicts of interest None declared. DOI 10.1111/j.1365-2133.2009.09250.x
Throughout adult life, the epidermis and the hair follicle undergo a perpetual cycle of growth, regression and rest. Stem cells in the epidermis not only ensure the maintenance of epidermal homeostasis and hair regeneration, but also contribute to repair of the epidermis after injury. These stem cells lie within specific niches in the hair follicle and the epidermis. The availability of monoclonal antibodies that can be used on formalin-fixed paraffin-embedded tissue has greatly facilitated the use of this methodology as an adjunct to uncovering stem cell niches. In this review, we attempt to provide an overview of the potential markers available to identify and study stem cells in an effort to providing a better understanding of the pathogenesis of skin diseases including disorders of hair loss and malignancies. The potential uses of these markers in prognosis and in expanding the therapeutic options in several disorders will also be addressed.
There are two broad categories of mammalian stem cells: stem cells that are capable of differentiating into all of the specialized embryonic tissues and stem cells that are found in different regenerative adult tissues and are of importance in the maintenance of normal tissue turnover and repair by replenishing specialized differentiated cells.1,2 In mammals, adult or tissue-specific stem cells have been identified in various tissues, including the haematopoietic system, central nervous system, corneal epithelium, thymic epithelium and neural crest, among others. Within these tissues, the stem cells are usually found in a specialized environment or niche that provides important signals to guide their function.2 All these tissue-specific stem cells are thought to share two main characteristics. Firstly, self-renewal or the ability to renew indefinitely, and, secondly, multipotency, or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.2 The former is believed to be maintained secondary to asymmetrical division of stem cells which gives rise to a stem cell that remains in the niche and to a lineagerestricted transient amplifying cell or progenitor cell which exits the niche and undergoes several limited rounds of proliferation before undergoing terminal differentiation.3 Compared with stem cells, the transient amplifying cells are more differentiated and committed unipotent cells that have, as a consequence, lost the ability to self-renew.1,3
Embryology of the skin There are many different types of cell residing in the skin and these originate from multiple different embryonic sources. In
mammals, the epidermis originates from neuroectodermal cells that remain at the surface of the embryo after gastrulation.4 The epidermis usually begins as a single undifferentiated progenitor cell layer which then gives rise to the interfollicular epidermis, the hair follicle and sebaceous glands.4 Dermal fibroblasts, vessels, arrector pili muscles, mature adipocytes in the subcutis and immune cells residing in the skin originate from mesoderm-derived cells while melanocytes and sensory nerve endings of the skin are derived from the neural crest.2,5 During adult life, the maintenance of these various cell types is the function of the different stem cells residing in the skin.
Epidermal stem cells In mammals, the epidermis is a multilayered epithelium that is composed of hair follicles, sebaceous glands and interfollicular epidermis. The interfollicular epidermis, defined as the portion of the epidermis located between the orifices of hair follicles, regenerates throughout adult life in order to replace terminally differentiated cells that are continuously shed from the surface of the skin and also to renew the hair follicle.1 The regeneration of the epidermis and the hair follicle is sustained by many different types of epidermal stem cell, which also participate in the repair of the skin after injuries. In addition to their self-renewing capacity and multipotency, these cells are quiescent with a low tendency to divide, but upon injury are characterized by an extensive and sustained selfrenewal capacity.1 The bulge region of the hair follicle represents the best characterized epidermal stem cell population described to date, but there is evidence of other stem cell 2009 The Authors
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Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam 229
populations in the interfollicular epidermis and, potentially, the sebaceous gland.1,6,7
Identification of epidermal stem cells Several methods have been used to identify epidermal stem cells and to try to differentiate them from other types of cell residing in the epidermis including transient amplifying cells and terminally differentiated cells.1,6 The first method makes use of the slow-cycling nature of epidermal stem cells. Using this method all actively dividing cells within the epidermis are pulse-labelled with injections of a DNA precursor, such as tritiated thymidine or bromodeoxyuridine.8–10 This is then followed by a chase period (4–10 weeks) during which the label is lost from rapidly proliferating cells such as the transient amplifying cells as a consequence of proliferation-associated dilution, while the rarely dividing stem cells retain the label for prolonged periods and are therefore called label-retaining cells.8–10 Based on this method, label-retaining cells in mice were found to be present in the bulge region of the hair follicle, in the basal layer of the epidermis and even in select basal sebocytes.9,11 The second method makes use of the high proliferative capacity of epidermal stem cells.3 Using this method the proliferative potential of cultured cells is assessed by examining the clonogenicity of individual cells through serial passage or colony-forming efficacy.12,13 Based on this method, three types of epidermal cells with differing capacities to proliferate have been identified: cells with no proliferative capacity (terminally differentiated cells), cells with a limited proliferative capacity (transient amplifying cells) and cells with a clonogenic or high proliferative capacity (stem cells).12 Although these two methods help in the identification of epidermal stem cells, they do not allow for the easy isolation of living stem cells for further analysis.1 Several epidermal stem cell markers have been identified during the past few years through the use of a candidate approach or, more recently, by global gene expression profiling. However, reliable and specific stem cell markers for epidermal stem cells and their transient amplifying cell progeny are still lacking. In this paper, we review the current data available on stem cell markers of the different stem cell populations present in the epidermis with emphasis on the most reliable and specific, and to discuss their potential uses to uncover new stem cell populations and potential targets for gene therapy.
Hair follicle stem cells Development of the hair follicle occurs through a temporal series of epithelial–mesenchymal interactions which commence with the formation of the hair placode at sites of underlying dermal mesenchymal cell condensate that form the dermal papilla.14 The overlying hair placode proliferates and differentiates to form the hair follicle, a direct consequence of underlying dermal papilla cells.
The adult hair follicle consists of an upper portion that is permanent and a lower portion that constantly remodels during the hair cycle. The hair cycle consists of three phases: anagen (the growth phase in which the hair shaft, inner and outer root sheaths, and new hair matrix are generated), catagen (a phase of epithelial regression driven by apoptosis) and telogen (a phase of relative quiescence).9,15–17 Studies have shown that maintenance of the hair follicle cycle is largely dependent on different stem cell populations capable of giving rise to the different epithelial components of the hair follicle. The bulge region of the hair follicle, defined as the portion of the outer root sheath of the hair follicle at the insertion site of the arrector pili muscle, is currently the best characterized site of epidermal stem cell populations.
Markers of hair follicle stem cell populations Bulge keratinocyte stem cells, in addition to being quiescent, have been shown to have all of the characteristics of stem cells.1,17 Although previous studies indicate that bulge stem cells give rise to all components of the epidermis, there is more recent evidence to indicate that in normal states, they do not contribute to the reconstitution of the interfollicular epidermis.17,18 Injury to the epidermis results in migration of the bulge cells to the epidermis where they then contribute to wound repair.18,19 Identification of this stem cell population in both mice and human hair follicles has been made possible by the use of markers with differing specificities (Table 1, Figs 1, 2). Integrins Integrins are adhesion molecules that mediate keratinocyte adhesion to the underlying basement membrane and also play a role in controlling epidermal differentiation and morphogenesis.1,13,20–24 Expression of a6-integrin was consistently found in the outermost layer of the outer root sheath of the hair follicle with no specific delineation of the bulge.24 Other areas showing increased expression included the basement membrane of the entire follicle and the dermal papilla.1,22–24 Expression of b1-integrin expression, on the other hand, appears to be confined to the bulge region of the hair follicle, in select studies, although others have indicated that it displays a similar, albeit less specific, expression to that of a6-integrin with upregulation in the outermost layer of the outer root sheath, basement membrane of the hair follicles and the dermal papilla.13,20–24 Based on these expression patterns, the utility of integrins as stem cell markers, for now at least, appears limited. Keratins Keratinocytes are characterized by the differential expression of keratin intermediate filaments. In the epidermis, keratinocytes in the basal cell layer express keratins 5 and 14, while keratins 1 and 10 are expressed by cells in the suprabasal
2009 The Authors Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp228–236
230 Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam Table 1 Spectrum of markers available to identify bulge keratinocyte stem cells Murine studies
Human studies 11
a6-Integrin
ORS mostly bulge IFE and SG
b1-Integrin
CK15
Most of ORS11 Bulb11 IFE and SG11 Bulge11
CK19
Bulge30
p63
–
CD34
Bulge region34
CD200
–
Tenascin-C
–
Lhx2
Postnatal bulge compartment41
MTS24
Upregulated in an area between SGs and the HF bulge42
Bmi-1
–
Comments 21,24
ORS of bulge and of all HF BM of the whole HF24 DP24 ORS of bulge and of all HF21,24 BM of the whole HF24 DP24 Bulge24,25,27 Part or all of ORS24,27 Basal layer of the epidermis24 Eccrine glands24,27 Bulge24,30 Most of ORS of entire HF24 Basal layer of the epidermis30 Basal and suprabasal epidermal cells32,34 ORS and hair matrix of HF34 Low or absent in human bulge17,24 ORS lower to the bulge24,27 Increased in bulge cells24,26 ORS of isthmus, DP, sweat glands and companion layer24 Homogeneous expression along the CTS of HF, with upregulated expression in the bulge mesenchyme24 Companion layer24 ORS distant (both proximal and distal) from the bulge24 –
HF bulge43 Basal and suprabasal cells43 ORS of HFs43 Sebaceous and sweat glands
Nonspecific24
Nonspecific24
In mice, colocalize with LRCs11
CK-positive cells also expressed b1-integrin30 Homologue of the p53 tumour suppressor gene34 May be a marker of TAC1,34 Most specific marker of HF bulge in mice34 Best marker of the human bulge keratinocyte SCs26 CD200 may suppress immune responses37–39 May be an important functional component of SC niches40 In mice, may play a role in the maintenance of the undifferentiated state of HF progenitor cells41 These cells did not express CD34 or CK1543 In mice, identifies epithelial progenitor cells in thymus43 Maintains SCs by downregulating p16ink4a43 Not specific
ORS, outer root sheath; IFE, interfollicular epithelium; SG, sebaceous gland; HF, hair follicle; BM, basement membrane; DP, dermal papillae; LRC, label-retaining cells; TAC, transient amplifying cell; CK, cytokeratin; SC, stem cells; CTS, connective tissue sheath.
Fig 1. Most consistent immunoreactivity of the human hair follicle and interfollicular epidermis for the stem cell markers a6b1, CK15, CK19, CD200, CD34, nestin and MITF. ORS, outer root sheath.
Fig 2. Most consistent immunoreactivity of the murine hair follicle and interfollicular epidermis for stem cell markers a6b1, CK15, CK19, CD34, nestin, MTS24 and Blimp1. ORS, outer root sheath. 2009 The Authors
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Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam 231
layer.17,24 In addition to the above, the hair follicle expresses keratins 6, 16 and 17.17,24 Initial observations of the presence of cytokeratin (CK)-15 positive cells in the bulge region of the murine and human hair follicle indicate that CK15 might be targeting a population of stem cells restricted to the bulge region.11,25 However, other studies have shown that CK15 expression is also seen in the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis and the eccrine glands.24,26,27 Based on CK15 expression in the mitotically active basal cell layers of the hair follicle, it is believed that CK15 may play a pivotal role in early keratinocyte differentiation and one that pre-dates the fate of a cell becoming epidermal or hair-like.28 Other keratins believed to be restricted to the bulge region include CK19 although more recent studies indicate that CK19-positive cells may also be seen in the outermost layer of the outer root sheath proximal and distal to the bulge.24,29,30 In vivo and in vitro studies have shown that CK19 may be important in the commitment of stem cells to an epidermal cell fate and differentiation.24,31 Transcription factors Structurally related proteins belonging to the family of transcription factors include p53, p63, considered to be a homologue of the p53 tumour suppressor gene, and p73.32–34 Although early in vitro studies identified p63 as a stem cell marker, more recent in vivo studies indicate that p63 expression is not restricted to epidermal stem cells, but involves basal and suprabasal epidermal cells as well as the outer root sheath and hair matrix of hair follicles. Given this pattern of expression, it is believed to be a marker of transient amplifying cells rather than stem cells.32–34 Haematopoietic progenitor cells Expression of CD34, a marker purportedly specific for haematopoietic progenitor cells, has also been shown in the bulge region of murine hair follicles.35 Currently, CD34 is believed to be the best marker to delineate stem cells in the bulge region in murine models.35 Contrasting sharply with this, one study demonstrated the absence of CD34 expression in the human bulge.17 More recent evidence indicates that CD34 is expressed in the outermost layers of the outer root sheath, below the bulge region, of the human hair follicle.24,27,36 Of particular interest, these CD34-positive cells were CK15negative indicating that they may represent transient amplifying cells or progeny of bulge stem cells.27,36 Other markers More recently, using laser capture microdissection and microarray analysis for global gene expression profiles, CD200positive cells have been isolated from label-retaining human bulge cells.26 Evidence from murine studies indicates that CD200, through its interaction with immunologically active cells expressing the CD200 receptor, may play a role in the
suppression of immune responses that help protect keratinocytes in the hair follicle from destruction by inflammation.37–39 Other human epithelial structures that showed upregulated expression of CD200 included the outermost layer of the outer root sheath of the isthmus, the dermal papilla including its blood vessels, the sweat glands and the companion layer of the human hair follicle.24,26 In contrast to the preferential expression of CD200 in the human bulge stem cells,26 murine studies have shown that CD200 is expressed only in the outer root sheath of hair follicles.37 Tenascin-C, a key extracellular matrix protein, is thought to be an important functional component of stem cell niches.40 Favouring this, a recent study documented homogeneous expression of tenascin-C along the connective tissue sheath of human scalp hair follicles (this is comparable to the basement membrane, so is not part of the epithelium) and upregulated expression in the bulge mesenchyme.24 Although Lhx2 (Lim-homeodomain transcription factor) may play a role in the maintenance of the growth and undifferentiated nature of murine hair follicle progenitor cells,41 a recent study on human anagen hair follicles showed that Lhx2 is not a useful marker of stem cells in the human bulge as its expression appeared to be most prominent in the companion layer (the layer between the outer root sheath and the inner root sheath), with reduced expression in the outer root sheath distant from the bulge region.24 More recently, MTS24, a cell surface marker labelling a membrane-bound antigen present in the early stages of hair follicle development in adult mice has identified a new reservoir of hair follicle keratinocytes between sebaceous glands and the bulge region with a proliferative capacity and gene expression profile indicating that they may be identifying progenitor or stem cells. Of interest, these cells do not express the stem cell markers CD34 or CK15.42 Another marker tested for its role as a stem cell marker is Bmi-1 (B-cell-specific Moloney murine leukaemia virus integration site 1), which normally plays a role in the maintenance of stem cells by downregulating p16ink4a, a tumour suppressor gene.43 However, its variable expression in basal and suprabasal keratinocytes, outer root sheath of hair follicles, sebaceous glands and sweat glands indicates that is not restricted to the bulge region and may therefore not be of any utility as a specific epidermal stem cell marker.43
Bulge melanocyte stem cells In each hair cycle, at the transition from the anagen to catagen phase, melanocytes in the hair bulb matrix undergo apoptosis with their reconstitution occurring at the beginning of the next anagen phase.1 Evidence from murine and human studies indicates that this reconstitution process is made possible by a population of follicular bulge stem cells committed to melanocyte differentiation.1 These melanocyte stem cells are usually quiescent but become activated and proliferate at the onset of the anagen phase leading to the repopulation of the hair follicle matrix with melanocytes that generate melanin leading to
2009 The Authors Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp228–236
232 Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam Table 2 Spectrum of markers available to identify bulge melanocyte stem cells
Pax3 MITF Dct (TRP-2)
Murine studies
Human studies
Comments
Highlight cells in the bulge region47,48,50 Highlight cells in the bulge region48,50 Highlight cells in the bulge region44,50
Highlight cells in the bulge region47,48 Highlight cells in the bulge region45,48 –
Melanocyte SC maintenance and differentiation47 Controls MITF expression50 Regulate balance between SC maintenance and differentiation45,48,50 Early marker to be discovered for this SC population44,50
MITF, melanocyte master transcriptional regulator; SC, stem cells.
pigmentation of the hair shaft.44 In addition, the defective self-maintenance of these melanocytes stem cells, which is thought to be part of physiological ageing, may be the underlying cause of hair greying.45 The melanocyte stem cell markers include Pax3 and MITF, also known as melanocyte master transcriptional regulator (Table 2).46–49 The former, Pax3, has been shown to maintain the undifferentiated state of stem cells while simultaneously functioning in initiation of the melanogenic cascade.46,47,49 More recently, MITF, which may play a role in stem cell maintenance within the bulge through an antiapoptotic effect mediated by induction of Bcl-2 expression, has been shown to be highly expressed in the human bulge and is believed to serve as a potential marker of this stem cell population.47,48
Bulge neural crest-derived stem cells Recently, a new population of stem cells, neural crest-derived stem cells, has been identified within the murine hair follicle bulge.50–53 These stem cells, with markers that differentiate them from other stem cells in the bulge, apparently have the ability to differentiate in vitro to keratinocytes, neurons, melanocytes, glial cells, smooth muscle cells and adipocytes.50–53 One of the markers which helped in the identification of this stem cell population is nestin, an intermediate filament protein expressed in the neuroepithelial stem cell cytoplasm and known to be a marker for neural stem cells (Table 3). Although these nestin-positive cells do not contribute to the keratinocyte compartment in homeostatic conditions, they have been shown to enhance blood vessel formation during hair follicle growth.50 Of interest, in the murine bulge region, nestin-positive cells were also CD34-positive but CK15negative.50–53 Previous studies indicating an absence of a
similar population of cells in the human hair follicle epithelium have been contradicted by more recent studies showing a population of nestin-positive cells residing in the upper two-thirds of the hair follicle, hair follicle connective tissue sheath, dermal papilla, sweat gland epithelium and in the inner aspect of the outer root sheath below the bulge.24,27,53–56
Sebaceous gland progenitor cells Being a hair follicle appendage located above the bulge and below the hair shaft orifice, sebaceous glands function in the generation of terminally differentiated sebocytes.57 While development of sebaceous glands starts with the formation of progenitor cells towards the end of embryogenesis, maturation of the sebaceous gland occurs only after birth.57 Shortly thereafter, they go into a resting phase to become activated again at puberty. Although there is evidence to indicate that, when the skin is wounded, bulge sebaceous glands contribute to all components of the epidermis including sebaceous glands, recent studies have shown that, under homeostatic conditions, bulge cells do not contribute to the formation of the sebaceous glands.17 Thus, sebaceous gland homeostasis necessitates the presence of a progenitor population of cells that gives rise to a continual flux of proliferating, differentiating and disintegrating sebocytes. In fact, recent murine studies identified a resident basal sebocyte population with characteristics of progenitor cells suggesting that the sebaceous glands are capable of self-maintainance.58 The recent identification of Blimp1 (B lymphocyte-induced maturation protein 1) has helped characterize the progenitor cell population in the sebaceous glands of mice. Normally, Blimp1 represses c-myc, which plays an important role in sebaceous gland differentiation, thus inhibiting proliferation
Table 3 Spectrum of markers available to identify bulge neural crest-derived stem cells Murine studies Nestin
Human studies
Highlight cells in the bulge region50–53
Comments 24,27
Inner aspect of the ORS below the bulge Also, upper 2 ⁄ 3 of HF, HF CTS, DP and sweat gland epithelium
In mice, these cells were also CD34-positive but CK15-negative52 In mice, these cells can form keratinocytes, neurons, melanocytes, glia, muscle cells and adipocytes
HF, hair follicle; ORS, outer root sheath; CTS, connective tissue sheath; DP, dermal papillae; CK, cytokeratin.
2009 The Authors Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp228–236
Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam 233 Table 4 Spectrum of markers available to identify sebaceous gland progenitor cells
Blimp1
CK15
Murine studies
Human studies
Comments
Basal sebocytes with characteristics of progenitor cells58 Few basal sebocytes11
–
These cells can give rise to HF under effect of b-catenin59
Basal sebocytes of both sebaceous gland and duct7
Sebaceous tumours were also positive for CK157
HF, hair follicle; CK, cytokeratin.
and differentiation of sebocytes.58 That these Blimp1-positive progenitor cells have stem cell potential is based on studies indicating that under the effect of b-catenin, a hair follicle inductive signal, they give rise to the hair follicle.59 More recently, CK15 has been shown to highlight basal cells in the sebaceous gland and duct.7 Whether or not these cells represent the same population of cells identified by Blimp1 remains to be elucidated by further studies (Table 4).
Stem cells in the interfollicular epidermis The only mitotically active layer in the interfollicular epidermis, a layer of stratified squamous epithelium, is the basal layer.57 The outermost layer consists of cells that are continuously shed from the surface and, given recent evidence indicating that bulge stem cells do not contribute to the regeneration of interfollicular epidermis under normal homeostatic conditions, it seems plausible that the interfollicular epidermis has its own stem cell population.18,19 Labelling studies on murine DNA have demonstrated that the interfollicular epidermis is dependent on multiple, functionally independent, hexagonal units, called the epidermal proliferative units.60–62 These epidermal proliferative units ensure lifelong cell production to compensate for the continual loss of cells from the surface of the skin.60–62 Each epidermal proliferative unit consists of a single centrally located stem cell, its immediate transient amplifying cell progeny adjacent, with more differentiated keratinocytes lying directly above and mature, albeit enucleated, squames at the surface.60–62 However,
studies on other animal models indicate a different organization in specific anatomical sites such as the palms and soles.63 These include the localization of label-retaining cells, representing stem cells, in the deep rete ridges of the monkey palmar epidermis.63 In humans, the task of identifying stem cells in the interfollicular epidermis has been more difficult owing to the inability to use label-retaining studies (there are ethical and technical limitations as the label may be harmful). Initial human studies on neonatal foreskin and breast skin tissue have suggested the presence of a population with stem cell properties in the shallow rete ridges.64,65 More recently, a population with the molecular signature of stem cells and transient amplifying cells has been shown to reside at the tips of deep rete ridges in the adult breast, palms and soles, sites relatively protected from external injury.20,66,67 Markers of potential utility in the identification of these cells include a6-intgrin, b1-integrin and CK15, CK10, CD71, and desmosomal proteins (Table 5).66–68 A recent study on human neonatal foreskin demonstrated that although CD200 is useful in the identification of bulge keratinocyte stem cells,26 its use in the identification of interfollicular epidermal stem cells appears limited.69
Potential clinical uses of stem cell markers In addition to uncovering multiple stem cell populations in the epidermis with differing potentials for proliferation and differentiation, stem cell markers have led to advances in epidermal stem cell research by providing insights into
Table 5 Spectrum of markers available to identify interfollicular epidermis stem cells Murine studies b1-Integrin
CK19
Upregulated in basal IFE keratinocytes11 Upregulated in basal IFE keratinocytes11 Upregulated in basal IFE keratinocytes11 Bulge30
CD200
–
a6-Integrin CK15
Human studies
Comments 64,65
Shallow rete ridges Tips of the deep rete ridges66–68 Upregulated in few basal IFE keratinocytes66,67
These cells had low to negative levels of CK10 and desmosomal proteins68 These cells had low CD71 expression20,66,67
Upregulated in few basal IFE keratinocytes at tips of rete ridges20,27 Deep rete ridges of glabrous skin27 Bulge and most of ORS24,30 Few basal keratinocytes were positive68
These cells were also a6 positive, CK10 negative20 CK-positive cells also expressed b130 These cells did not have the properties of SCs68
IFE, interfollicular epithelium; CK, cytokeratin; ORS, outer root sheath; SC, stem cells.
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234 Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam
understanding stem cell biology and behaviour. Their use has also proven to be of importance in shedding light on the aetiopathogenesis of genetic, neoplastic and inflammatory dermatoses, as well as in the prognosis and expansion of therapeutic options of these disorders.
or Bowen disease.74 Nestin and CD133 show significantly higher expression in melanomas compared with benign naevi, and in metastatic compared with primary melanomas.77 Thus, progression from benign to malignant to metastatic disease appears to be mediated by pathways that restore the stem cell features and characteristics.
Shedding light on aetiopathogenesis Recent reports confirm involvement of the hair follicle bulge region in scarring alopecias.27,70,71 Briefly, Mobini et al.70 hypothesized that the pathogenesis of lichen planopilaris involves cytotoxic-mediated destruction of bulge stem cells by an inflammatory infiltrate composed predominantly of CD8-positive T lymphocytes. Pozdnyakova and Mahalingam71 confirmed involvement of the bulge region in primary scarring alopecias by demonstrating the absence of bulge CK15-positive stem cells during early active stages of a heterogeneous group of scarring alopecias characterized by moderate to heavy inflammation. This effect on the bulge stem cells in scarring alopecias is further supported by studies showing that CD200, a recently identified marker for human bulge cells, plays an important role in the regulation of immune response.37,39 CD200 is a transmembrane protein which through its interaction with CD200 receptors on immune cells provides inhibitory immunoregulatory signals.37,39 Based on this, upregulated expression of CD200 within the human bulge region is thought to provide a degree of immune privilege to stem cells. Cancers contain cells with variable differentiation lineages among which there seems to be a small population of cancer stem cells that are needed to maintain the tumour mass.72 As cancer stem cells share characteristics of self-renewal, increased proliferative capacity and multipotency with normal stem cells, it has been hypothesized that cancer stem cells originate from mutated normal stem cells.72 Supporting this is evidence demonstrating stem cell populations in cutaneous neoplasms, such as increased CK19 expression in squamous cell carcinoma, CK15 expression in hair follicle and sebaceous gland carcinomas and nestin and CD34 expression in melanoma.7,73–77 The use of MITF has helped in the delineation of the migratory pathway of stem cells of melanocytic lineage with evidence indicating that melanocytes demonstrate progression from an intradermal to an intraepidermal to an intrafollicular localization.48 This may be of significance in understanding the pathogenesis of intradermal melanocytic proliferation or genodermatoses such as Waardenburg syndrome, in which incomplete migration and persistence of melanocytes in the dermis occurs.48 Prognostic implications Expression of stem cells in cutaneous malignancies is not only increased, but may have prognostic implications.73 Significantly higher CK19 expression has recently been demonstrated in squamous cell carcinoma compared with actinic keratosis
Expanding therapeutic options By the identification and isolation of different stem cell populations, stem cell markers may provide a bank of stem cells of potential utility in cutaneous regenerative medicine. For example, bulge keratinocyte stem cells can theoretically be used to produce bioengineered hair follicles to treat alopecia. Although an in vivo method to reconstitute human hair follicles has not, to date, been done,78 de novo hair follicle generation using in vivo hair follicle reconstitution assays has indeed been established in mice.79 Another example is the use of the murine bulge neural crest stem cells in the regeneration of nerves.52 Through the use of new and more specific markers, it may be possible in the future to identify a similar stem cell population in humans that will serve in the regeneration of nerves in humans. The exhaustion or incomplete maintenance of melanocyte stem cells is believed to be the cause of loss of hair shaft pigmentation and grey hairs.45 Using specific markers, better isolation and study of this population of stem cells may provide clues that are of help in the prevention of hair greying. Using specific stem cell markers may also uncover stem cell populations that could serve as targets for gene therapy. Gene delivery to specific stem cell populations in the skin may in the future serve as a therapeutic modality for the correction of several congenital disorders including hair diseases such as ectodermal dysplasias, monilethrix, Netherton syndrome and Menkes disease, as well as other genodermatoses such as hereditary epidermolysis bullosa.80,81 In addition, the identification and characterization of cancer stem cells within different cutaneous malignancies may uncover key molecules as putative targets in therapies aimed at inhibiting tumour growth.72,73 Finally, the potential of CD200 expression within the human bulge in providing immune privilege to bulge stem cells may have important therapeutic implications in scarring alopecias as inducing overexpression of CD200 in the bulge area might be protective and therapeutic.37,39
Conclusions Overall, some markers appear to be better than others in reliably identifying stem cells, an issue further compounded by the potential presence of more that one stem cell population in the skin. The use of stem cell markers is also proving to be an important tool in better understanding the aetiopathogenesis of many dermatological disorders as well as in providing prognostic information and more revolutionary therapeutic options. 2009 The Authors
Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp228–236
Potential uses of epidermal stem cells, O. Abbas and M. Mahalingam 235
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2009 The Authors Journal Compilation 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp228–236