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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. vol.45 no.3 Santiago  2012 

Biol Res 45: 215-222, 2012



Stem cells in embryonic skin development


Maria F. Forni, Marina Trombetta-Lima, Mari C. Sogayar*

NUCEL, University of São Paulo (USP), São Paulo (SP), Brazil Chemistry Institute, Biochemistry Dept., University of São Paulo, Brazil


The skin is a complex stratified organ which acts not only as a permeability barrier and defense against external agents, but also has essential thermoregulatory, sensory and metabolic functions. Due to its high versatility and activity, the skin undergoes continuous self-renewal to repair damaged tissue and replace old cells. Consequently, the skin is a reservoir for adult stem cells of different embryonic origins. Skin stem cell populations reside in the adult hair follicle, sebaceous gland, dermis and epidermis. However, the origin of most of the stem cell populations found in the adult epidermis is still unknown. Far more unknown is the embryonic origin of other stem cells that populate the other layers of this tissue. In this review we attempt to clarify the emergence, structure, markers and embryonic development of diverse populations of stem cells from the epidermis, dermis and related appendages such as the sebaceous gland and hair follicle.

Key words: Skin development, Embryonic skin, Epidermis, Dermis, Sebaceous Gland, Hair follicle.


The skin is the primary barrier which protects the body from dehydratation, mechanical trauma and microbial insults, consisting of an outer epidermis and appendages separated from the underlying dermis by a basement membrane (Koster and Roop, 2007).

As a complex organ, the skin is composed of several tissues and a variety of accessory structures. The primary function of human skin, as well as that of other terrestrial animals, is to prevent excessive loss of water through the body, serving as a permeability barrier. Moreover, the skin is the first organ of the body's defense mechanism against external agents, providing protection against mechanical, chemical, thermal, and sunlight injuries in addition to infection by microorganisms. It also displays thermoregulatory sensory and metabolic functions (Fuchs and Raghavan, 2002). To repair damaged tissue and replace old cells, the skin depends on stem cell populations residing in the adult hair follicle, sebaceous gland, dermis and epidermis for continuous self-renewal (Fuchs, 2007).

The skin may be divided into three layers. The outermost layer, called the epidermis, with thickness varying from 0.06 to 1 mm, is a squamous stratified epithelium composed mainly of keratinocytes, in addition to attachments which are inserted into the dermis such as follicles, sweat and sebaceous glands. The dermis (1-2 mm deep), separated from the epidermis by an epidermal basement membrane and consisting of the extracellular matrix, is a support system in which there are nails, blood and lymph vessels and nerve endings. The hypodermis (1-2 mm) is composed of adipose tissue which is molded to muscles and bones underlying the skin (Koster and Roop, 2007).

The mammalian skin is one of the best-studied epithelial systems containing stem cells to date, however, the origin of most of the stem cell populations found in the adult epidermis is still largely unknown (Benitah and Frye, 2012). Far more unknown is the embryonic origin of other stem cells which populate the other layers of this tissue. In this review we attempt to clarify the emergence, structure, markers and embryonic development of diverse populations of stem cells not only from the epidermis, which has been explored in several high quality reviews (Benitah and Frye, 2012; Driskell et al., 2011; Fuchs, 2007; Watt and Jensen, 2009), but also from the dermis and epidermis-related appendages such as sebaceous glands and hair follicles.


As a stratified epithelium, the interfollicular epidermis consists of several layers, each with its own characteristics. The cells from the basal layer display two main functions, adhesion of the epidermis to the underlying dermis through the basement membrane, and providing new cells to replace the ones shed from the cornified exterior of the tissue (Candi et al., 2005) (Dai and Segre, 2004). In order to accomplish these functions and maintain epidermal homeostasis, these cells must maintain a stringent balance between quiescence and proliferation (Simpson et al., 2011). The main structural proteins within the basal keratinocytes are keratins 5 and 14, which have long been known as hallmarks for cells displaying proliferative potential in this tissue (Fuchs and Green, 1980). After commitment to differentiation, certain basal keratinocytes (epidermal stem cells) migrate from the basal into the suprabasal layer, also known as the spinous layer. After reaching this layer, these cells progressively lose their proliferative potential and begin to synthesize a set of structural proteins and enzymes associated with the assembly of the cornified envelope, such as involucrin, envoplakin and periplakin (Candi et al., 2005). The specific and best known keratins present in this layer are keratins 1 and 10 (Fuchs and Green, 1980). In the next layer, the granular one, the keratohyalin granules, consisting of the filaggrin precursor profilaggrin, group keratin fillaments into tight bundles, inducing the collapse of the cell to a flattened shape (Candi et al., 2005). This protein is used as a scaffold in the next stratum, the cornified layer, for its full maturation through the deposit and cross-linking of proteins such as loricrin and periplakin, among several others, by enzymes of the transglutaminase family. After addition of a set of lipids, the final differentiated cells are known as corneocytes (Serre et al., 1991).

The main epidermal appendages in mammals are the sweat glands, sebaceous glands and hair follicles, discussed in more detail in other sections. The sweat gland will not be explored here, but has been explored in several reviews elsewhere (Lobitz and Dobson, 1961; Richert et al., 2000) Other cells such as melanocytes, Langerhans and Merkel cells are important components of the epidermis, but will not be discussed here due to space and scope limitation constraints.

2.1    Epidermal specification and differentiation — the role of interfollicular epidermal stem cells

Interfollicular epidermal stem cells rely on an underlying basement membrane enriched in extracellular matrix (ECM) proteins and growth factors. Basal cells attach to this structure through adhesion complexes such as the hemidesmosomes, which contain a core of α6β4 integrins and focal adhesions of α3β1 integrins. These proteins also play a role in growth control and migration (Fuchs, 2007). The α6 and β1 integrins have been used as markers of epidermal stem cells (Kaur and Li, 2000), similarly to p63, a p53 homologue which is expressed throughout the basal layer of the epidermis (Pellegrini et al., 2001) and has a putative function in maintaining these cells in a slow cycling state. These stem cells are responsible for a rapidly dividing progeny referred to as transit amplifying, which undergo a limited number of divisions before withdrawing from the cell cycle, committing to terminal differentiation and migrating towards the surface of the skin, generating dead, flattened, differentiated keratinocytes (Fuchs and Raghavan, 2002). The filagrin and involucrin intermediate filaments, expressed during this process, are specific markers of epidermal differentiation (Fuchs and Raghavan, 2002). These cells were described in the epidermal basal layer by Jones et al. in 1995 (Fuchs and Raghavan, 2002); several enrichment protocols are available in the literature for the isolation of epidermal stem cells, based on β1 integrin expression (Kaur and Li, 2000), α6 integrin and CD71 (Tani et al., 2000) or

Hoechst 33342 exclusion, combined with cell size (Dunnwald et al., 2001) (Reviewed in (Watt and Jensen, 2009)). The epidermis includes several other niches and populations of stem cells associated with the hair follicles, which are described in detail in another section.

2.2    Embryonic origins of the epidermis

In the mouse, after gastrulation a single cell layer of ectoderm is formed at embryonic day 9.5 (E9.5). Mesenchymal cells from the underlying layer begin to transmit signals that induce the stratification of the ectodermis, which will then generate the epidermis and also contribute to commitment of the several appendages present in this tissue (Koster and Roop, 2007; Millar et al., 1999). In response, the basal layer of the stratifying epidermis produces the basement membrane (Mikkola, 2007).

During the initial steps of stratification, which extend up to E12.5 to E15.5 in the mouse, proliferation is almost completely confined to the basal layer. During this period, a transient protective layer of tightly connected squamous endodermis-like cells (M'Boneko and Merker, 1988) called periderm covers the epidermis. The function of the periderm is still unclear, but it likely forms an early epidermal barrier to protect the developing skin from constant exposure to the amniotic fluid (Benitah and Frye, 2012). Once the stratification program is completed, the periderm is shed and the epidermis has fully stratified and differentiated (around E17.5) (M'Boneko and Merker, 1988). These events are summarized in Fig. 1.

  Figure 1: Timeline representing Epidermal Progenitor commitment steps during embryonic development

2.3     Signaling pathways of the developing epidermis

After gastrulation, emergence of the neuroectoderm is a key event, since it will allow the development of the nervous system and the skin epithelium. Neural induction is reinforced by a positive balance between fibroblast growth factors (FGFs) and inhibition of bone morphogenetic proteins (BMPs) (Gaspard and Vanderhaeghen, 2010). In the opposite direction, the epidermal fate is driven by the expression of BMPs, with additional Wnt signaling (Wilson and Hemmati-Brivanlou, 1995).

Another important cell signaling component in the formation of the epidermis is the Notch signaling pathway (Kolev et al., 2008). The process of lineage commitment between hair follicles and epidermal interfollicular lineages is regulated by Notch 1 and 2, as shown by experiments in which these genes were deleted (Yamamoto et al., 2003).


The hair follicle structure, located above the skin surface, may be divided into two different parts, a permanent upper part which does not visibly cycle and a lower part which is continuously being renovated with every hair cycle (Schlake, 2007). Once a hair follicle is produced it may undergo many of these cycles, continually generating, growing, and losing the hair shaft. In mammals the hair growth cycle includes three stages: anagen (follicle generation and hair production), catagen (follicle regression), and telogen (resting phase) (Philpott and Paus, 1998).

In the mouse, one of the most studied models for mammalian skin, there are four different types of hair. The guard hair has low abundance (2-10%); it is straight, very long and contains two columns of medulla cells. This is also the only type of hair with two sebaceous glands instead of one as the other types have (Jones et al., 1994). Awl and auchene hair together comprise around 28% of the hair follicles of the mouse, being characterized as significantly shorter than the guard hair, with two or more columns of medulla cells. Auchene differs from the awl hair by a single sharp bend. Zigzag hair (~70%), the fourth type, contains a single column of medulla cells, and owes its name to three to four sharp bends in alternating directions. These different types of hair are considerably interspersed across the entire body of the mouse (Panteleyev et al., 2001).

3.1     Embryonic origins of the hair follicle

Development of the hair follicle is intrinsically related to the stratification of the embryonic epidermis. This process occurs in three phases, which are known as hair placode formation, hair follicle organogenesis and cytodifferentiation, further subdivided into eight morphologically distinct stages (Schmidt-Ullrich and Paus, 2005; Stenn and Paus, 1999).

During the first stage, epidermal keratinocytes form clusters, which enlarge and elongate to generate hair placodes (E14). After this event, a cluster of specialized fibroblasts is formed just above the placode and the crosstalk of these two structures leads to increased proliferation of both (Michno et al., 2003). In the second stage, the enhanced proliferation leads to a downward growth of the epidermal component shaping the dermal papilla. The resulting structure, called the hair germ, is typically observed at E15.5. The keratinocytes continue to penetrate the forming dermis and envelop the dermal papilla, giving rise to the third-fifth stages, collectively known as the peg stage (E16.5-E17.5). The inner root sheath is then formed, triggering these cells to terminal differentiation, which generates the hair shaft (Stenn and Paus, 2001). Simultaneously, the outer root sheath starts to form a cylinder around the inner root sheath, and a bulbous peg structure is formed during stages 6-8 (E18.5).

The timelines described are for guard hairs, one of the most studied types of hair. Awl and Auchene hair follicles begin to form later on, at E15.5-E16, while zigzag hairs appear at E17 and do not reach the final process until postnatal life (Stenn and Paus, 1999). As illustrated in Fig. 2, the process of hair follicle formation is spatially and temporally controlled; the signals involved in this process are reviewed elsewhere (Andl et al., 2002; Benitah and Frye, 2012; Fuchs, 2007).

Figure 2: Embryonic developmental stages of the Hair Follicle.

3.2     Hair follicle-associated stem cell populations — markers, specification and differentiation

3.2.1    Bulge Stem Cells

One reservoir of stem cells is the permanent lower part of the hair follicle, called the bulge. Bulge stem cells were originally identified as slow cycling cells through pulses of BrDU experiments, in what became popularly known as label-retaining cells (Bickenbach and Mackenzie, 1984; Braun et al., 2003; Cotsarelis et al., 1990). More recently a large number of markers have been described for these cells, such as the high expression of α6 integrin (Li et al., 1998) and ABCG membrane transporter proteins (Tumbar et al., 2004), but all of these are shared with the interfollicular epidermal stem cells. One promising marker which appears to be specific for the bulge is the CD34 cell surface glycoprotein (Blanpain et al., 2004; Trempus et al., 2003). Lineage tracing analysis revealed the role of the bulge progeny: under normal homeostasis these stem cells contribute to all lineages of the hair follicle, with minimal contributions to the interfollicular epidermis and sebaceous glands (Kasper et al., 2011; Snippert et al., 2010). In more recent reports, the Lgr5 stem cell marker was considered to be a marker of bulge stem cells (Panteleyev et al., 2001) .

3.2.2   Skps - skin precursors

In 2001 Toma et al. described another multipotent precursor cell population in adult mammalian dermis, more specifically in the follicle dermal papillae (Toma et al., 2001). These cells -termed SKPs, for skin-derived precursors- were isolated and expanded from rodent and human skin and differentiated into both neural and mesodermal progeny, including cell types never found in skin, such as neurons. These cells expressed neuronal precursor markers such as Nestin and mesenchymal markers such as Vimentin, but not Fibronectin. Later on, the same group proposed that SKPs represent a multipotent neural-crest-like precursor which arises in embryonic mammalian tissues, and is maintained into adulthood (Fernandes et al., 2004). This may explain why SKPs are capable of differentiating into neurons (βÏ tubulin+) and glial cells such as oligodendrocytes (CNPase+) and astrocytes (GFAP+). In vivo, these cells were capable of generating myelinating Schwann cells, a fact of great impact in the spinal cord injury treatment area (Biernaskie et al., 2007).

3.3     The mouse hair follicle junctional zone cells

Recently it has been shown that cells of the junctional zone of the hair follicle, a region directly adjacent to the infundibulum and sebaceous gland, may contribute to the interfollicular and sebaceous lineages, presenting the Lrig1 protein as a specific marker (Jensen et al., 2009). Indeed, loss of Lrig1 leads to epidermal hyperplasia (Suzuki et al., 2002) in a mechanism most likely due to the lack of negative regulation by c-myc (Jensen et al., 2009). Therefore it appears that despite the fact that this population apparently does not contribute to the normal homeostasis of this tissue, these cells may act as stem cells in the case of injury.


The Dermal-Epidermal Junction (DEJ) is characterized by a basement membrane with components secreted by both basal keratinocytes and dermal fibroblasts. The DEJ acts not only by attaching the epidermis to the dermis, but also plays an important role in exchanging of signaling molecules between the two layers and allowing the transit of immune cells, and facilitates keratinocyte migration during wound-healing (Sorrell and Caplan, 2004). Almost imperceptible under regular staining, the DEJ undulating structure becomes clear with PAS or Giemsa staining. Its undulating feature is due to the presence of epithelial protuberances and dermal papillae (Prost-Squarcioni, 2006; Sorrell and Caplan, 2004).

DEJ has a complex and characteristic composition and may be subdivided into four regions by more detailed electron microscope analysis: (i) more superficially, the cell membrane of keratinocytes forming hemidesmosomes and melanocytes; followed by (ii) the lamina lucida, which is rich in pectin and laminin 5, 6 and 10; (iii) the osmiophilic lamina densa, composed mainly of type IV collagen and laminin 5 (electron dense); and more deeply (iv) the sub-basal lamina filamentous zone (Prost-Squarcioni et al., 2008; Sorrell and Caplan, 2004). Anchoring fibers are composed of collagen VII.

Located between the epidermis and hypodermis, the dermis is a connective tissue that acts supporting and protecting the epidermis. The dermal layer consists of fibroblasts, dendritic cells, macrophages/monocytes, neutrophils and lymphocytes, embedded in an extracellular matrix mainly composed of collagenous and elastic fibbers (Prost-Squarcioni, 2006; Prost-Squarcioni et al., 2008; Sorrell and Caplan, 2004). The width of the dermis varies according to its anatomic location, being thicker on the back of the palms and soles, for instance (Sorrell and Caplan, 2004). The dermal layers may be subdivided into the more superficial papillary dermis and the reticular dermis. Separating these two layers is the subpapillar vascular plexus, and at the lower limit of the reticular dermis, the cutaneum vascular plexus separates the dermis from the hypodermis (reviewed in (Sorrell and Caplan, 2004), (Kanitakis, 2002)). The limits between the papillary dermis and the epidermis show an undulating pattern due to the presence of dermal papillae which contain tactile corpuscles and vascular components (Kanitakis, 2002). The papillary and reticular dermis differ greatly in their extracellular matrix composition and structure. The papillary dermis contains collagen fibers, composed mainly of collagen type II and III in disorganized loose bundles, and thin elastic fibers composed of elastin stretching perpendicular to the DEJ (reviewed in Sorrell and Caplan, 2004). The reticular dermis displays more compact collagen fibers which tend to be parallel to the skin surface and thicker elastic fibers (Kanitakis, 2002). The ground substance, composed of glycosaminoglycans and proteoglycans, rich in hyaluronic acid, fills the space between cells and fibers (Kanitakis, 2002; Prost-Squarcioni, 2006).

4.1     Embryonic origins of the dermis

The dermis has multiple embryonic origins (Driskell et al.). Fibroblasts are differentiated based on their position along three anatomical divisions: anterior-posterior, proximal-distal and dermal-nondermal (Rinn et al., 2006). Head and facial fibroblasts derive from the neural crest, while dorsal and ventral trunk fibroblasts derive from somitic and lateral plate dermomyotomes, respectively (Driskell et al.; Rinn et al., 2008). It has been shown that primary adult fibroblasts retain several features of the embryonic pattern of expression of HOX genes, homeodomain transcription factors which act to specify position identity during development, homeostasis and regeneration (Rinn et al., 2008).

Cells derived from the Follicular Dermal Papilla (FDP) and the Dermal Sheath (DS) differ from other dermal fibroblasts by their in vitro biological properties; support for epidermal cell growth, aggregative behavior in culture depending on Versican (Feng et al.) and upregulation of specific biomarkers (alkaline phosphatase, alpha smooth muscle actin, epimorphin and protease-activated receptor-1 (reviewed in (Ohyama et al., 2010)). After formation of the hair follicle precursor, the placode (E14.5), an aggregate of mesenchymal cells, the dermal condensate, is recruited below the placode at the base of the follicle (Driskell et al.; Ohyama et al.). Signaling between the condensate and the placode leads to the downward growth of the follicle into the dermis and encapsulation of the dermal condensate by epithelial cells, forming the mature FDP (Driskell et al.; Millar, 2002). The FDP cell number does not increase during follicular downward growth; its size is correlated with the hair fiber dimensions (Ohyama et al.). The mature FDP induces the surrounding epithelial matrix cells to proliferate, migrate and differentiate (Driskell et al.; Millar, 2002; Schneider et al., 2009).

4.2     Dermis - niche and signaling pathways

Platelet-derived growth factor A (PDGF-A) is expressed in developing hair follicle epithelium, and its receptor (PDGF-Ra) is expressed in the dermal condensate. Knockout mice for PDGF-A develop thinner dermis, misshapen hair follicles, smaller dermal papillae, abnormal dermal sheaths, thinner hair and reduced cell proliferation in the dermis and dermal sheaths compared to wild type mice, suggesting that PDGF-A plays a role in FDP, dermal sheath and dermal fibroblast establishment (Karlsson et al., 1999). Wnt signaling has a key role in recruitment of the dermal condensate, which is unable to develop in the absence of epithelial β-catenin, a downstream effector of the WNT signaling pathway (Schneider et al., 2009; Zhang et al., 2009). Sonic hedgehog (Shh) knockout mouse embryos show disrupted formation of the FDP (Karlsson et al., 1999). Shh signaling controls the expression of a subset of FDP-specific signature genes, being critical for subsequent signaling modulating proliferation and further downward growth of the follicular epithelium, in addition to development of the FDP (Schneider et al., 2009; Woo et al.). Wnt5a is expressed in the developing dermal condensate in wild type but not in Shh-null mice embryos, indicating that Wnt5a is a target of Shh in hair follicle morphogenesis (Reddy et al., 2001). Shh-null skin analysis showed that Shh is not a component of the first epithelial signal (Schneider et al., 2009). Dermal Smoothened (smo) loss of function results in loss of the dermal condensate and overexpression of Shh-dependent Noggin. This phenotype is partially rescued by the knockdown of noggin in the hair follicle by increasing the expression of epithelial shh (Woo et al.).

Laminin-511 mutants show developmental defects by E16.5, with decreased length and structure of primary cilia in vitro and in vivo. Inhibition of the laminin-511 receptor β1 integrin disrupted FDP primary cilia formation and hair development. Laminin-511 triggers noggin expression through a mechanism that is dependent both on Shh and PDGF (Gao et al., 2008), showing the importance of laminin-511 for FDP maintenance.

The peribulbar DS, which covers the outside of the hair follicle, contains mesenchymal cells that contribute to the maintenance and regeneration of the FDP (Jahoda and Reynolds, 2001; Driskell et al., 2011). Upon amputation of the lower vibrissae follicle or surgical removal of the FDP alone in adult mice a new FDP was formed, suggesting that DS cells contribute to reconstitution of the new FDP (reviewed in (Ohyama et al., 2010)).

4.3     Specification and differentiation of the dermal papillae and its role in hair follicle development

The FDP gene expression pattern is heterogeneous and depends on the hair follicle type. It has been shown that Sox2 is expressed in all dermal papillae at E16.5, but from 18.5E onwards its expression is confined to the FDP of guard/awl/ auchene follicles, whereas CD133 is expressed in FDP associated with all hair follicle types (Driskell et al., 2009). Sox2 distinct subpopulations express different sets of genes in addition to the FDP gene signature (Driskell et al., 2009; Driskell et al.). FDP cells are not believed to divide, but during anagen the number of dermal cells in the dermal papillae increases, probably due to migration of cells from the DS (Chi et al.). Inhibition of β-catenin signaling in FDP cells resulted in reduced proliferation of epithelial cells inducing catagen and preventing anagen induction, possibly through inhibition of the FGF pathway (Driskell et al., 2011; Enshell-Seijffers et al., 2010). During anagen, FDP induces downward growth of the stem cells in the secondary hair germ. A quantitative analysis using the rodent vibrissa model indicated that the hair inductivity capacity of FDP cells is altered between early anagen and mid-anagen, being higher in the former, a phenomenon probably linked to the proliferative activity (Iida et al., 2007). Specific FDP markers which are upregulated during anagen in the adult mouse skin are the Corin serine protease and Sox-2 (Driskell et al., 2011), highlighting the crucial role of FDP signaling for hair follicle development. The FDP is also a reservoir of multipotent stem cells (Biernaskie et al., 2009; Hoogduijn et al., 2006; Lorenz et al., 2008; Wong et al.). At least three different subpopulations of progenitor cells may be identified: (i) Sox-2 positive cells, which are associated with Wnt, BMP, and FGF signaling; (ii) Sox-2 negative cells, associated with Shh, Insulin Growth Factor (IGF), Notch, and Integrin pathways; and (iii) skin-derived precursors (SKPs), which may differentiate into adipocytes, smooth myocytes and neurons in vitro; they are believed to originate from Sox-2 positive cells, and in part from the neural crest (Biernaskie et al., 2009; Lorenz et al., 2008; Wong et al.). The fact that cells isolated from different anatomical locations (including the back skin derived from the dermomyotome) display multipotent stem cell characteristics suggests that the hair follicle environment, rather than the embryonic origin, induces the generation of cells with the characteristics of neural crest derivatives (Driskell et al., 2011). A comparative analysis between the mesenchymal stem cells (MSCs) isolated from FDP and DS and those isolated from bone marrow showed that these MCs have similar morphology and population doubling time and express the same cell surface biomarkers (Hoogduijn et al., 2006). Also, both cell populations had the capacity to differentiate into the same mesenchymal lineages (osteoblasts, adipocytes, chondrocytes and myocytes) at similar rates and extent of differentiation (Hoogduijn et al., 2006). Progenitor cells derived from the FDP have also been explored as a source for generation of iPS cells (Tsai et al., 2010; Tsai et al., 2011). As a non-invasive source of progenitor cells, the dermal papilla and dermal sheath are viable and promising candidates for use in the clinic.


Sebaceous glands are important in the maintenance of the hair, since absence of these glands was associated with scarring alopecia and doxorubicin-induced hair loss (Al-Zaid et al., 2011; Selleri et al., 2006). The sebaceous glands are composed mainly of sebocytes, which are highly specialized epithelial cells that release their sebum content through a process that culminates in the rupture of the cell membrane and cellular extravasation known as holocrine secretion (Frances and Niemann, 2012).

The majority of sebaceous glands are an integral part of a pilosebaceous unit, although this structure can appear as an independent structure in mutant mice lacking hair follicles (Mecklenburg et al., 2001; Nakamura et al., 2001; Schneider and Paus, 2010).

5.1    Embryonic origins of the of the sebaceous gland

The Sebaceous Gland (SG), of ectodermal origin, develops late in embryogenesis in the upper portion of the HF, from the same lineage as that of keratinocytes. During the differentiation process Sox9 and Lrig1 are initially co-expressed by epidermal progenitor cells, but SG is driven by the asymmetric cell fate decision of Lrig1- positive stem cells but not of MTS24/Plet1-positive precursor cells (Frances and Niemann, 2012). Nevertheless, Sox-9 ablation in the embryo led to failed SG formation, even though Sox-9 is not expressed in the SG lineage or in its resident precursors (Nowak et al., 2008), indicating a more complex role for Sox-9 in SG morphogenesis. During homeostasis of adult mouse skin, Lrig1-positive cells contribute to the infundibulum and the sebaceous glands (Jensen et al., 2009), as illustrated in Fig. 3.

Figure 3: Steam cell involvment during Sebaceous Gland embryonic development.

5.2    Sebaceous gland stem cell -- niche and signaling pathways

Blimp1, a transcriptional repressor, was shown to be a marker of the early stage SG-residing progenitor cell linage. Loss of Blimp1 leads to elevated c-myc expression, augmented cell proliferation and SG hyperplasia, resulting in enhanced bulge stem cell activity (Horsley et al., 2006), suggesting that Blimp1 is important for maintenance of SG progenitor cells. In addition, SG fails to develop in gamma-secretase null mice, in a mechanism dependent on Notch proteolysis (Pan et al., 2004). Inhibition of the Shh pathway selectively suppresses sebocyte development, whereas its activation leads to an increase in the size and number of SG (Allen et al., 2003). Knockout mice for CD109, a glycosylphosphatidylinositol glycoprotein which negatively regulates TGF-| signaling, also display SB hyperplasia (Mii et al.). Activation of the Protein Kinase C system by phorbol 12-myristate 13-acetate (PMA) in immortalized sebocytes stimulated lipid synthesis (a marker of sebocyte differentiation) with translocation and downregulation of the cPKCa and nPKCô isoforms (Geczy et al.). On the other hand, Wnt pathway inhibition appears to be crucial for SG development, since Smad7 transgenic induction perturbed hair follicle morphogenesis and differentiation and accelerated SG morphogenesis (Han et al., 2006). Smad7 binds to | -catenin, inducing its degradation and thereby inhibiting the Wnt/ | -catenin signaling pathway (Han et al., 2006). The Wnt pathway is also overexpressed in sebaceous gland carcinoma (Erovic et al.). Taken together, these findings show that SG development and maintenance involves a unique gene signature that interplays with the HF and FDP signaling pathways.


The skin constitutes a reservoir for adult stem cells of different embryonic origins. Skin stem cell populations reside in the adult hair follicle, sebaceous gland, dermis and epidermis; however, the origin of most of these stem cell populations is still unknown. In this review we attempted to clarify the emergence, structure, markers and embryonic development of diverse populations of stem cells from the epidermis, dermis and related appendages such as the sebaceous gland and hair follicles. Further studies on skin stem cell specification and commitment are crucial for development of the knowledge of the dynamics of this tissue and for effective cell therapy protocols.



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Abbreviations: 5-bromo-2'-deoxyuridine(BrDU) - 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase) - Dermal-Epidermal Junction (DEJ) - Glial Fibrillary Acid protein (GFAP) - Follicular Dermal Papilla (FDP) - Dermal Sheath (DS) - Platelet-derived growth factor A (PDGF-A) - Sonic hedgehog (Shh) - Sebaceous Gland (SG)

Received: August 28, 2012. Accepted: September 14, 2012

* Corresponding author: Professor Mari Cleide Sogayar ( Chemistry Institute - University of São Paulo. Av. Prof. Lineu Prestes, 748, B9S, Room 964. ZIP code: 05508000. São Paulo/SP, Brazil

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