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Therapeutic Potential of Stem Cells in Follicle Regeneration.

1. Introduction

Hair loss is caused by a variety of factors: hereditary (trichodystrophy, androgenic alopecia), concomitant medical conditions, hormonal disorders (thyroid gland disorders, insulin resistance), autoimmune (patchy alopecia, systemic lupus erythematosus), nutritional disorders, environmental factors (medicines, UV radiation), psychological factors (stress, trichotillomania), and ageing. The damaging factors affect the hair cycle and decrease stem cell activity and hair follicle regeneration capability.

Alopecia is commonly regarded as a defect with apparently no significant health consequences. However, hair loss affects self-acceptance, which may result in depression and anxiety [1, 2]. It is not only an aesthetic issue. An early onset of androgenic alopecia is associated with an increased incidence of the metabolic syndrome and an increased risk of the cardiac ischaemic disease [3]. The ubiquity of alopecia provides an encouragement to seek new, more effective therapies aimed at hair follicle regeneration and neoregeneration.

1.1. Stem Cells in the Hair Follicle. Hair follicles have a niche for mature stem cells--hair follicular stem cells (HFSCs)--a so-called "bulge" in the attachment region of arrector pili muscles, which contain epithelial and melanocyte stem cells. Moreover, HFSCs are also situated within the outer root sheath (ORS), within the region of the proximal end of the isthmus--this area is also known as the "bulge" [4]. HFSCs take part in the regeneration of epidermal cells and the structure of hair follicles and sebaceous glands [5] (Figure 1).

Stem cells of the "bulge" can remain in their niche where they self-regenerate, but they can also move down to the hair matrix region, where they become progenitor cells which then form an internal hair follicle and the hair stem [6]. The "bulge" region is not uniform, with two compartments distinguishable in it: the lower part, close to the hair matrix, which generates the internal hair follicle cell line, and the upper part, which self-regenerates, but which does not directly participate in the regeneration of the hair follicle [7, 8]. Since the heterogeneity of the "bulge" also depends on its relationship with the basal membrane, two populations of CD34+ cells are distinguished. One of them, the so-called suprabasal SCs, contains lower levels of a6-intergin and has a lower proliferative potential [6, 9]. The "isthmus" region is, apart from the "bulge," another one which also contains stem cells participating in the formation of interfollicular epidermis and sebaceous glands [7, 10].

Another type of stem cells within the hair follicle is dermal papilla cells (DPCs), probably originating from dermal condensation, which is the initial stage of the hair follicle development [11, 12]. DPCs play an important role in induction and regulation of hair growth and the formation of new hair follicles [11,13,14]. Signals from DPCs activate stem cells in the "bulge" and germinal matrix cells in the late telogen/ early anagen phase [11, 15] by activating the Wnt/[beta]-catenin pathway [11,16]. Moreover, DPCs have potential for differentiation into lines of adipocytes and osteocytes [11, 17], and they can be transformed into pluripotential cells [11, 18].

Alopecia involves changes in two types of hair stem cells, both human hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) [19, 20]. They ensure conditions for proper hair regeneration [20]. In scarring alopecia (lupus erythematosus, lichen planus), inflammatory cell infiltration around the bulge results in an irreversible loss of HFSCs. Although the progenitor cells are damaged, HFSCs are preserved in patchy and androgenic alopecia. This is why this type of alopecia can be reversible [20].

Stem cells of the "bulge" are increasingly well characterised, especially in murine hair follicle, which facilitates their identification, although no universal marker has been found for them. One of them is cytokeratin 15 (CK15), which is why CK15+/integrin [alpha]6+ or CD34+/integrin [alpha]6+ cells have been identified as "bulge" cells [21]. Studies on murine hair follicles have also revealed expression of, inter alia, CK19 [8, 22] and numerous transcription factors, that is, Sox9, Lgr5, Gli1, Hopx, LHX2, Nfatc1, and Tcf3 [8, 25]. However, expression of certain markers depends on the hair cycle phase and on the precise location of the cells within the bulge [7, 8]. Lgr5, a receptor involved in the Wnt signaling pathway, has been identified as an actual marker of the hair follicle stem cells [25]. Stem cells of the upper and lower parts of the bulge in the telogen hair follicle affect the expression of CD34 and only of the lower part of Lgr5. Cells participating in the formation of a new anagen hair express Lgr5, but not CD34 [26]. Cells of the upper part of the "bulge" present a higher expression Nfatc1, which is associated with a state of rest [6]. Expression of Lgr6 [7, 10] and Lrig1 [7, 27] has been observed within the "isthmus." Meanwhile, progenitor cells of the germinal matrix are derived from stem cells of the bulge but, unlike them, exhibit a high level of P-cadherin [8, 28].

Human hair follicle stem cells are less known than murine HFSCs. It seems that certain markers are common to both human and mouse HFSCs, that is, CD34 [4, 23], K15 [4,19], K19 [4,29], and CD200 [4, 19,23]. The presence of other markers, i.e., Sox9 and LHX2, requires further studies [30]. Markers found only in human stem cell follicles belong to PHLDA1 [4, 24] and EpCAM/Ber-EP4, which is a useful marker of the telogen secondary hair germ [4, 28].

Dermal papilla cells present different markers, including those from hair follicle cells and dermal fibroblasts [11]. Alkaline phosphatase (ALP) is the most important for both human and murine HFs and is the most specific of the markers [11, 29, 30]; its high activity is a marker of DP cell differentiation [11, 31]. Moreover, expression of [alpha]-SMA [11, 17], laminin, and fibronectin [11] as well as CD133 [11, 32] has been observed in DPCs.

Marker expression changes in pathological states. Immunoreactivity of CK15 is decreased in people with patchy alopecia, and it is present in androgenic alopecia [21]. Hair follicles in the frontal parts of the scalp exhibit a deficit of CD34 in androgenic alopecia, and its expression is preserved in hair follicles of the occipital region [21]. Another marker CD200 of matrix cells is poorly expressed in patchy alopecia, which may be a sign of the disappearance of the immune privilege and can contribute to pathogenesis (reaction of autoreactive lymphocytes) [21, 33].

Stem cells in the bulge remain in the resting phase for most of their lives, but they can be activated depending on the hair cycle phase. Most of the concepts regarding the course and regulation of the hair cycle have been created during research on mouse models. During the hair cycle in mice, in the anagen phase, stem cells in the bulge are divided three times on average and stay within the niche, whereas cells of the germinal matrix divide intensely and differentiate, forming the growing hair stem. During the catagen phase, cells of the germinal matrix undergo apoptosis; stem cells of the bulge migrate out of it to the external hair follicle, and subsequently, at the end of the catagen phase, they form a new bulge around the hair stem and a new germinal matrix under the bulge. Stem cells in the bulge remain in the state of rest during the telogen phase, and between the telogen and anagen phases, they self-regenerate or migrate, creating a pool of germinal matrix cells which subsequently proliferate to form the hair matrix [6]. The precedence has been shown for the derivative cells in the bulge, the so-called "SC" progenitor cells of the germinal matrix, in the expression of genes that affect stem cell activation, and precedence in proliferation during the regeneration cycle, even before the cells of the bulge [8, 15, 34]. The translation of the mouse hair cycle into the human hair cycle has some limitations due to the different lengths of anagen [35, 36], asynchrony of the human cycle [35, 37], or a different reaction to the influence of hormonal factors [35, 38]. Currently, studies are conducted on human scalp skin xenografted into immunocompromised mice to establish the course of the hair cycle in vivo in humans [35].

The activity of stem cells in the bulge is controlled by the microenvironment that surrounds it, a so-called "niche." This includes daughter cells of stem cells of the bulge, which activate their self-regeneration during early and late anagen phases [39].

Stem cells are significantly affected by mesenchymal cells of the dermal papilla, which are in close contact with cells of the germinal matrix, separated only by the basal membrane [7]. They seem to be of key importance in the induction of hair growth and in signal transmission during its regeneration [8, 34]. Experiments have shown that hair regeneration is not possible after laser ablation because the hair follicle cycle stops at the telogen phase without progressing to the anagen phase [6, 7, 34, 40]. Injections of exosomes derived from DPCs to HFs have been found to accelerate the entry of anagen and catagen delay via the [beta]-catenin and Shh pathways [41]. HFSCs are also affected by fibroblasts in the reticular and papillary layers of the dermis as well as of the subcutaneous tissue [7].

Within the niche there are also melanocyte stem cells, which are responsible for the formation of mature melanocytes that impart the colour to a growing hair. The survival and growth of MSCs depend on signals transmitted by hair follicle epithelial cells, for example, the TGF-[beta] or the Wnt pathway [7, 39]. The extracellular matrix is another component of the microenvironment. It directly affects stem cells by the formation of the basal membrane, with which stem cells are in contact modulated, for example, by integrins [6, 8].

Stem cells of hair follicles are also affected by the macro-environment surrounding hair follicles, for example, adipose tissue. It seems to undergo similar changes to those of the hair follicle: the thickness of the adipose tissue increases during the anagen phase, and adipocytes proliferate intensively [8, 42]. Adipocytes secrete BMP2 during the late catagen phase and early telogen phase, which favours the resting states in the niche, whereas secretion of BMP2 is reduced at the end of the telogen phase, which supports the activation of HFSCs [8,42,43]. Communication between adipose tissue and the epithelium runs in both directions. Mutations blocking the hair cycle have been found to inhibit adipogenesis, which suggests that epithelium cells send signals activating the proliferation of adipocytes [6, 42].

Nerve ends affect stem cells situated at the upper part of the Gli1+ bulge by a signal of the Shh pathway [6, 44]. Therefore, denervation can reduce the effect of SCs in the "isthmus" on wound healing [6, 44]. However, it seems that nerves are not indispensable components of the niche, because denervation does not impair hair follicle regeneration, which may suggest that Gli+ cells receive Shh signal from other sources [7].

The hair follicle absorbs nutrients from the surrounding microvascular network, which is transformed during the hair cycle--angiogenesis is increased during the anagen phase [6, 45]. Cells of the bulge and of the matrix can probably stimulate angiogenesis [6]. Delayed induction of angiogenesis, which accompanies impaired angiogenesis, has been observed in mice [7,45]. It has been suggested that stem cells in general prefer a low-oxygen environment, where they secrete marker of hypoxia [6, 46]. The vascular network, especially that surrounding the "isthmus," containing venous vessels, can participate in maintaining the low-oxygen environment in the surrounding of the stem cell environment [6].

However, although the effect of the immune response has not been sufficiently elucidated, it is important that the role of maintaining the immune privilege of hair follicles, associated with decreased expression of MHC I molecules and with increased secretion of local immunosuppressors, should be maintained during the anagen phase [6, 47]. The loss of this privilege and an immune attack on cells of the matrix and the bulge are associated with alopecia [6, 48]. Dermal cells ydT are known to modulate posttraumatic regeneration of hair follicles by secreting FGF9 [7, 49]. Macrophages, in turn, increase the level of Wnt7b and Wnt10a ligands during the telogen phase after undergoing apoptosis, whereby activating HFSCs [6, 7, 50]. Macrophages play an important role in posttraumatic activation of HFSCs--arresting their recruitment into the wound delays hair growth, whereas transplantation of active macrophages is sufficient for induction of hair growth [6, 51]. Also important is the role of Treg, which presents a high level of Jag 1 from the Notch family, which affects the effective regeneration of HF [52] (Figure 2 and Table 1).

1.2. Stem Cell Use in Hair Follicle Regeneration. Hair follicles are immunologically privileged places, like the brain, eyes, and testicles, and they are under the influence of the neuroendocrine-immune network [32]. In physiological conditions, this is affected by

(1) low expression or absence of the main MHC I antigens,

(2) the presence of malfunctional Langerhans cells,

(3) local expression of immunosuppressive substances (TGF-[beta]1 and [alpha]-melanocytes MSH) [32, 48]. Owing to this, they can be easily used in transplantation.

Multipotent stem cells can regenerate hair follicles with sebaceous glands in the skin. In the current state of knowledge, stem cells can be used to regenerate hair in several therapeutic strategies:

(1) Reversing the pathological mechanisms which contribute to hair loss (especially in androgenic alopecia)

(2) Regeneration of complete hair follicles from their parts (cells in the bulge can regenerate a whole hair)

(3) Neogenesis of hair follicles from a stem cell culture with isolated cells or tissue engineering [5, 53, 54]

1.3. Studies of Use of Autologous Stem Cell in Hair Follicle Regeneration. Hair transplant has become a conventional treatment technique in androgenic alopecia (micrografts, follicular unit transplantation (both FUT an FUE), and individual follicular group harvesting (IFGH)) [55]. Although an autologous transplant is regarded as the gold standard, its usability is limited, because of both a limited amount of material and a reduced viability of cells obtained in this way. Currently, methods are being developed which enhance the effectiveness of the use of autologous stem cells of the hair follicle.

Apart from cells of the "bulge," stem cells reside specifically in the HF mesenchyme and function to replenish the dermal papilla and connective tissue sheath. They are called self-renewing dermal stem cells (DSCs) [56, 57].When transplanted, DSCs integrate with mesenchymal cells and they act together with epithelial stem cells, participating in creating new hair follicles [56, 57]. In cultures, they form spherical, self-regenerating colonies. However, it is labour-consuming and ineffective. Therefore, methods have been developed for their simultaneous collection, isolation, and administration in vivo at acceptor sites with the use of the so-called stirred suspension bioreactors. They help to obtain cells of greater uniformity; increased cell density per volume; and control of the concentration of nutrients, metabolites, and growth factors [56, 58].

The findings of the study by Agabalyan et al. have confirmed that cells can retain their phenotype and an ability to form hair follicles even after five passages in bioreactors. Moreover, the productivity is five times higher compared to static cultures [56]. This has given rise to the possibility of using this method commercially in the treatment of alopecia.

Gentile et al. [5] demonstrated the application of an innovative Rigeneracons[R] bioreactor (certificate CE, class I) in order to provide autologous micrografts and their immediate use in clinical practice. They proved that cells isolated from the bulge region can improve the thickness of hair in patients affected by androgenic alopecia using a new method of isolating human mature stem cells obtained from a patient self-biopsy, without culturing. Enhanced hair thickness was achieved in 11 men (aged 38 to 61 years) with androgenic alopecia even at the stage of 3-5 in the Norwood-Hamilton scale. After the biopsy and removal of unwanted remnants of fatty tissue, a medical device Rigeneracons (certificate CE, class I) was used to obtain cell suspension. The percentage of mesenchymal stem cells CD44+ from the dermal papilla was approx. 5% + 0.7% and CD200+ from the bulge was approx. 2.6%+ 0.3%. After 23 weeks of therapy, after the last administration of stem cells, the average number of hairs and their thicknesses increased by 29% [+ or -] 5% compared to the baseline for the hair thickness in the treated area and by less than 1% of hair thickness increase in the placebo area [5].

Furthermore, Nilforoushzadeh et al. [59] evaluated the regeneration potential of cultured mature dermal papilla to induce the growth of a hair follicle injected to the skin of bare mice. Initially, dermal papilla cells in the culture were observed to multiply with expression of CD200, and these fusiform cells tended to form colonies after three to five days. Subsequently, after two weeks, they acquired a passaging capability and they formed an extracellular matrix after the third passaging. Histopathological examination in mice which received 1.2 x [10.sup.6] of cells of dermal papilla revealed structures that transformed into hair follicles at sites of injection in the dermis [59].

Ibrahim et al. used autologous bone marrow mononuclear cells (BMMC) (including stem cells) to treat refractory patchy alopecia and androgenic alopecia, and the therapeutic effects were compared to the group treated with autologous stem cells of hair follicles. Cells were administered in a single application (1 millilitre in a density of 100,000 cell/ml was injected, using a 26-gauge needle, intradermally at per centimetre square of the treated site), and a significant improvement was observed in all patient groups under treatment [21]. Interestingly, the effect of stem cells was similar despite the fact that they had been obtained from two different sources. The effect of intradermal injection of BMMC may result from the diversity of the cell mixture: progenitor, hematopoietic stem cells, various types of inflammatory cells, and mesenchymal stem cells. BMMC can stimulate hair growth as a consequence of the ability to differentiate into various cell types, the ability to secrete bioactive molecules which stimulate angiogenesis (VEGF) and anti-inflammatory molecules with an immunomodulatory and antiapoptotic effect [21].

1.4. Studies of the Use of Adipose-Derived Stem Cells. ADSCs (adipose-derived stem cells) seem an ideal cell population for use in regenerative medicine because of the absence of immunogenic properties, their ease of obtainment, multipotential character, ease of differentiating into various cell lines, and considerable potential for angiogenesis. ADSCs have been shown to originate from mural cells located in the perivascular niche, vascular smooth muscle cells and pericytes, both involved in the formation of normal vasculature and are responsive to VEGF [60]. Naturally, hair follicles surrounded by subcutaneous adipose cells and by dermis form an interfollicular dermal macroenvironment, which is important in maintaining the proper growth of bulge and follicle cells [11, 61, 62]. ADSCs are indispensable in the activation of epidermal stem cells, which they do by secreting growth factors. The vascular endothelial growth factor (VEGF) regulates hair growth and the size of the hair follicle size by stimulation of angiogenesis. The hepatocyte growth factor (HGF) is involved in the duration of the hair cycle phases. The platelet-derived growth factor induces and maintains the anagen phase, and the insulin-like growth factor I (IGF-I) controls the hair growth cycle and hair cell differentiation [11, 63-67]. Another direction of their action is the stimulation of angiogenesis and an improvement of the blood supply to dermal papilla cells. They also have immunomodulatory and immunosuppressive properties through the direct interaction between cells and secretion of prostaglandin E2 (PGE2), leukaemia-inhibiting factor (LIF), and kynurenine [11, 62].

The paracrine activity of ADSCs is highly complex, and the factors secreted by stem cells have both a direct and an indirect effect on hair follicles. TB4 contributes to the activation of stem cells in a hair follicle, increasing their migration into the follicle and differentiation. SDF-1 acts through an increase in expression of EGR-1; it also increases the cell tropism towards the follicle and increases angiogenesis. The action of MCP-1 is less obvious; despite being an inflammatory factor, it has a proven tissue regenerative effect; also, a significant role of the microenvironment in the effect of paracrine factors in promoting the growth of the hair follicle has been emphasised [68]. Huang et al., in a study on rats, found that an addition of ADSCs to a culture of dermal papilla cells or core cells, the inner and outer sheath, enhances their viability [64]. A significant increase in the regenerative potential was recorded in a study by Huang et al., in which ADSCs were enriched with LL-37, which is an antibacterial peptide occurring naturally in wounds [64]. That study showed a significant increase in the local regenerative factors (endothelial growth factor, thymosin beta-4, monocyte chemoattractant protein-1, and stromal cell-derived factor-1). A significant promotion of the growth of hair follicles, in both in vitro and in vivo animal models, was observed [60, 69-71].

Physiologically, adipose tissue surrounding hair follicles plays an important role in extending the anagen phase. Adipocytes progenitor cells have been observed to multiply during the transition from the telogen to the anagen phase, around the hair follicle [61, 64]. The thickness of the subcutaneous layer increases significantly during the intense hair growth phase (anagen) compared to their amount in the resting phase (telogen) [11, 59]. ADSCs stimulate hair follicle cells through peroxisome proliferator-activated receptors, whose three isoforms have been found on their surface (PPAR[alpha], PPAR[gamma], and PPAR[delta]) [64]. Meanwhile, mature adipocytes have a negative effect on hair follicle cell proliferation and on proliferation of fibroblasts surrounding the hair follicle in simultaneous culture systems [11, 72].

Interestingly, a change in adipocyte cell line properties can cause skin and hair disorders. Lipid metabolism disorders can cause defects in the skin structure and functions. Over-expression of human apolipoprotein C1 (APOC1) with hyperlipidemia in transgenic mice causes hair growth disorders correlated with the level of expression of human APOC1 gene in the skin [11, 73].

Hypoxia, which is not toxic to mesenchymal cells, also increases the production of growth factors for ADSCs: vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and insulin-like growth factor II (IGF-II) [74, 75]. The effect of hypoxia on ADSCs was examined in a study conducted by Park et al. [74]. ADSCs passaged four times with C[O.sub.2] subsequently administered subcutaneously to mice to observe induction of the anagen phase and proliferation of human follicular cells of the dermal papilla and keratinocytes. Hypoxia resulted in increased secretion of insulin-like growth factor-binding protein-1 and protein-2 (IGFBP), macrophage colony stimulating factor (M-CSF), M-CSF receptor, PDGF receptor-[beta], and VEGF, whereas secretion of the epidermal growth factor was smaller [74].

Unfortunately, two-dimensional (2D) cultures of dermal papilla cells lose their hair formation capability in culture, which is why they require maintaining their spheroidal forms (3D) [76,77]. It is a challenge to develop methods that mimic in vivo conditions, which both maintain the 3D structure of cells and contain a special medium which imitates a natural niche rich in growth factors [56, 75].

Currently, there are no known tissue regeneration protocols applied for hair transplant with the use of ADSCs. Zanzoterra et al. [78] examined the capabilities of autologous cell suspension in the Rigenera system, which were obtained by mechanical fragmentation of subcutaneous and adipose tissue from the occipital area. The cell suspension was applied in the hair transplant area, thereby increasing the amount of growth factors. Microdamage has been observed to heal more quickly and to transplant hair to grow continuously even two months after the procedure, with the telogen phase shortened [78].

An ADSC-conditioned medium (ADSC-CM) was used in patients with alopecia (both male and female) in a study by Fukuoka and Suga [63]. A commercial product containing a protein solution with ADSCs was used (AAPE, Prostemics, Seoul, Korea) with various growth factors (hepatocyte growth factor, fibroblast growth factor I, granulocyte colony-stimulating factor, granulocyte macrophage-colony-stimulating factor, IL-6, VEGF, and TGF). The preparation (0.02 ml/[cm.sup.2] of the solution) was administered intradermally every 3 to 5 weeks (4-6 sessions), and hair growth was monitored with trichograms. A significant improvement in hair thickness was achieved in patients of both sexes [63].

Shin et al. [71] used ADSC and conditioned media of ADSCs (ADSC-CM) in a retrospective, observational study in 27 women with a female pattern hair loss (FPHL). The application of ADSC-CM showed efficacy in treating FPHL after 12 weeks of therapy with increased hair density and thickness without severe adverse reactions [71]. Won et al. [79] also showed that the application of ADSC-CM enhanced proliferation of cultured human dermal papilla cells (DPCs) by up to 130% [79].

Other studies have confirmed that enriching adipose tissue with a stromal vesicular fraction (SVF) supports adipocyte viability and yields better outcomes for a hair transplant procedure when they are present in grafts [62, 80]. Lipoaspirate obtained from abdominal fat (system Puregraft LLC, Solana Beach, CA, USA) was administered to the scalp at 1.0 ml/[cm.sup.2] in a Perez-Meza study. The amount of hair was found to increase by 23% after six months of the follow-up period [80].

1.5. Studies on Using Stem Cells from Wharton's Jelly

1.5.1. The Advantage of Stem Cells from Wharton's Jelly Compared to Other Mesenchymal Cells. Wharton's jelly has become a preferential source of stem cells due to its ready availability from a large pool of donors, noninvasive and painless acquisition, no risk to the donor, no ethical limitations, weak immunogenic potential, and high multipotential differentiation capability [81, 82]. Moreover, exposure to infectious agents occurs rarely, which guarantees safety to the donor [83].

Additionally, the decellularized Wharton's jelly matrix (DWJM) (fresh jelly was subjected to two cycles of osmotic shock, alternately with a hypertonic solution of NaCl, mannitol, Mg[Cl.sub.2], and KCl with the osmolarity of approx. 1.275 mOsm/l, and centrifuged at 5000 rpm at 4[degrees]C against a hypotonic solution of 0.005% Triton X-100) can provide a natural scaffolding for stem cells as a biocompatible matrix, which supports their viability, initiating aggregation of mesenchymal cells. DWJM contains TGF-[beta], collagen I, fibronectin, and tenascin, which may be responsible for condensation of added WJMSC in some areas of the DWJM. Hence, DWJM is a natural biocompatible 3D matrix which ensures adhesion, penetration, growth, and proliferation of cells--both in vitro and in vivo. To conclude, this paper presents DWJM as a new and natural 3D scaffolding which can be used in tissue engineering and regenerative medicine [84].

1.5.2. Neogenesis of Hair Follicles with Stem Cell Culture on Media and Grafting Them into the Skin: In Vitro Regeneration. In 2013, two researchers, demonstrated that it is possible to obtain cells with an expression of cytokeratin 19 and hair-like structures from WJMSC in in vitro conditions. Cytokeratin 19 (CK19) is a marker of bulge stem cells which determines the self-regeneration potential of modified skin [85, 86].

The Korean team of Yoo et al. [87-89] examined the effect of hWJSC on the acceleration of wound healing processes along with formation of hair follicles and other skin appendages. Enriched aggregates of hWJSC cells can form new hair follicles. The addition of growth factors to the culture medium is required: hepatocyte growth factor (HGF) stimulates growth of hair follicles in vivo and in vitro; basic fibroblast growth factor (bFGF) stimulates growth of dermal papilla cells in vivo; and vesicular endothelial growth factor (VEGF) stimulates growth of hair follicles and hair root in vivo. The hepatocyte growth factor (HGF) must be used at the stage of differentiation of the dermal papilla in culture, which is relatively expensive [87-89].

Moreover, Yoo et al. [88] compared effects of culturing bone marrow and umbilical cord stem cells to the spontaneous formation of dermal papilla-like tissues (DPLT). Isolated cells of the hair outer sheath were used for incubation: DPLT were recovered from 25T cell culturing plates and mixed with 1106 cells of hair sheath in 50 ml of physiological saline and injected into mice skin. The mice were examined after six weeks. Subsequently, the clinical effects of hair follicle formation in originally bare mice following their implantation in the skin were compared. No differences between the methods were observed [88].

Wu et al. (a Chinese study) [90] demonstrated the potential for differentiation of hMSC (from human embryos) to dermal papilla cells in cocultures of hMSC using dermal papilla cells previously obtained from patients. Expression of versican, Cd133, SCF (stem cell factor), ET-1 (endothelin-1), and bFGF (fibroblast growth factor) was observed during the process of differentiation [90].

1.5.3. Neogenesis of Hair Follicles from Isolated Cells (Stem Cells from Wharton's Jelly): In Vivo Regeneration. Intensive studies are being conducted on the commercial use of hWJSC in alopecia treatment at the University of Kansas Innovation and Collaboration, Kansas, USA (Dr. Omar Aljitawi) (no literature data) (Tables 2 and 3).

2. Conclusion

Maintaining a pool of stem cells is necessary for tissue homeostasis and damage repair. Their divisions are not frequent in mature organisms, and most of them are in a dormant state. Therefore, it is important to understand the mechanisms of their activation, which will allow for the use of multipotent cells in regenerative medicine [33]. Their use is additionally complicated by the fact that expression of receptors on different growth factors and the effect of the microenvironment may vary. Moreover, not all target points in stem cell therapy have been identified. It requires further studies aimed not only at the use of stem cells and their various fractions and compositions with adjuvants but also at broadening of knowledge on the physiology and cytophysiology of the hair follicle [35].

Conflicts of Interest

The authors declare that they have no conflicts of interest.


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Agnieszka Owczarczyk-Saczonek [ID], (1) Magdalena Krajewska-Wlodarczyk [ID], (2) Anna Kruszewska, (1) Lukasz Banasiak, (3) Waldemar Placek, (1) Wojciech Maksymowicz, (4) and Joanna Wojtkiewicz (5,6,7)

(1) Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland

(2) Department of Rheumatology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland111

(3) Department of Plastic, Reconstructive and Aesthetic Surgery, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland

(4) Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland

(5) Foundation for Nerve Cell Regeneration, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland

(6) Department of Pathophysiology, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland

(7) Laboratory for Regenerative Medicine, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland

Correspondence should be addressed to Agnieszka Owczarczyk-Saczonek;

Received 8 April 2018; Revised 24 June 2018; Accepted 22 July 2018; Published 5 August 2018

Academic Editor: Shibashish Giri

Caption: Figure 1: Hair follicle anatomy.

Caption: Figure 2: The markers of hair follicle: (a) in human, (b) in mouse.
Table 1: The markers of hair follicle and their role.

Author                 Signal            Researched object

Telerman et al.,       Blimp1            Transgenic mouse
2017 [91]

Kobielak et al.,       Bmpr1a            Transgenic mouse
 2007 [92]

Lei et al., 2014       DKK1              Transgenic mouse

Millar et al., 1999    Dvl2              Transgenic mouse

Lin et al., 2015       FGF1, FGF2,       Transgenic mouse
[95]                   FGF10

Kimura-Ueki et al.,    FGF18             Transgenic mouse
2012 [96]

Higgins et al.,        FGF5              DNA from families
2014 [97]                                with long eyelashes

Guo et al., 1993       FGF7              Transgenic mouse

Petiot et al., 2003    Fgfr2             Transgenic mouse

Ozturk et al., 2015    Gab1              Transgenic mouse

Milletal., 2003        Gli2              Transgenic mouse

Estrach et al.,        Jagged-1          Transgenic mouse
2006 [102]

Amalia Pasolli et      LHX2              Transgenic mouse
al., 2014 [103]

Ozturk et al., 2015    Mapk              Transgenic mouse

Du et al., 2018        miR-214           Human scalp skin
[104]                                    tissue; in vitro

Horsley et al.,        Nfatc1            Transgenic mouse
2008 [105]

Krieger et al.,        NF-kB             Transgenic mouse
2018 [106]

Demehri and Kopan,     Notch             Transgenic mouse
2009 [107]

Lin etal., 2011        Pofut1            Transgenic mouse

Oro and Higgins,       Ptch              Transgenic mouse
2003 [109]

Hoi etal., 2010        Runx1             Transgenic mouse

St- Jacques et al.,    Shh               Transgenic mouse
1998 [111]

Kadajaetal., 2014      Sox9              Transgenic mouse

Foitzik et al.,        TGF-[beta]1       Transgenic mouse
2000 [113]

Foitzik et al.,        TGF-[beta]2       Transgenic mouse
1999 [114]

Oshimori and Fuchs,    TGF-[beta]RII     Transgenic mouse
2012 [115]

Qiu et al., 2017       TPA               Transgenic mouse

Lei et al., 2014       Wnt10b            Transgenic mouse

Millar et al., 1999    Wnt3              Transgenic mouse

Donget al., 2017       Wnt7a             Transgenic mouse

Kandyba and            Wnt7b             Transgenic mouse
Kobielak, 2013

Enshell-Seijffers      [beta]-Catenin    Transgenic mouse
et al., 2010 [119]

Author                 Conclusions

Telerman et al.,       Ablation delayed HF morphogenesis, and growth
2017 [91]              and prevented new HF formation after
                       wounding; role in promoting the dermal
                       papilla inductive signaling cascade that
                       initiates HF growth

                       Ablation leads quiescent SCs to activate and
Kobielak et al.,       to proliferate, causing an expansion of the
 2007 [92]             niche and loss of slow-cycling cells; HFSCs
                       are unable to terminally differentiate into

                       DKK reduce hair follicle enlargement and
Lei et al., 2014       decrease proliferation; injection of DKK1
[93]                   during early anagen significantly reduced
                       the width of prospective hairs

Millar et al., 1999    Overexpression in the outer root sheath
[94]                   causes the short-hair phenotype

                       Topical application of FGFs induced an
Lin et al., 2015       earlier anagen phase and prolonged the mature
[95]                   anagen phase; FGFs promoted hair growth by
                       inducing the anagen phase in telogenic mice

Kimura-Ueki et al.,    Ablation causes telogen to become very short,
2012 [96]              giving rise to a strikingly rapid succession
                       of hair cycles

Higgins et al.,        FGF5 is associated with long-hair phenotype
2014 [97]

Guo et al., 1993       Overexpression causes marked suppression of
[98]                   hair follicle morphogenesis

Petiot et al., 2003    Lack of Fgfr2 leads to a decreased number of
[99]                   HFs, and follicles were developmentally

Ozturk et al., 2015    Lack of Gab1 caused HF not to enter
[100]                  catagen; instead HFSCs lose quiescence

                       Lack of Gli2 causes arrest in HF development
Milletal., 2003        with reduced cell proliferation and Shh-
[101]                  responsive gene expression, but normal
                       epidermal differentiation

                       Deletion of Jagged-1 results in inhibition of
Estrach et al.,        the hair growth cycle and conversion of hair
2006 [102]             follicles into cysts of cells undergoing
                       interfollicular epidermal differentiation

                       Ablation of LHX2 results in cellular
                       disorganization and HFSC polarization within
Amalia Pasolli et      the niche. LHX2 loss leads to a failure to
al., 2014 [103]        maintain HFSC quiescence and hair anchoring
                       and progressive transformation of the niche
                       into a sebaceous gland

Ozturk et al., 2015    Activation of Mapk signaling can restore
[100]                  quiescence of the SCs

                       Downregulation of miR-214 promotes the
Du et al., 2018        proliferation and differentiation of HFSCs;
[104]                  overexpression of miR-214 led to decreased
                       expression of EZH2, [beta]-catenin, and TCF4

                       Ablation causes stem cells to be activated
Horsley et al.,        prematurely, resulting in precocious
2008 [105]             follicular growth

                       Role in HF stem/progenitor cell activation
Krieger et al.,        during anagen induction, involvement in hair
2018 [106]             fiber morphogenesis during HF cycling

                       Absence of Notch signaling leads bulge stem
                       cell descendents to retain their capacity to
Demehri and Kopan,     execute the follicular differentiation
2009 [107]             program but failing to maintain it owing to
                       their genetic deficiency

                       Disruption of Pofut1 in HF resulted in
                       aberrant telogen morphology, a decrease of
Lin etal., 2011        bulge SC markers; HF displayed a delay in
[108]                  anagen reentry and dysregulation of
                       proliferation and apoptosis during the hair
                       cycle transition

Oro and Higgins,       Reduced Ptch is associated with tumor
2003 [109]             formation during anagen

Hoi etal., 2010        Role in promoting anagen onset and
[110]                  HFSC proliferation

                       Shh signaling is not required for initiating
St- Jacques et al.,    hair follicle development; however, it is
1998 [111]             essential for controlling ingrowth and
                       morphogenesis of the hair follicle
                       Sox9-deficient bulge HFSCs begin to
                       differentiate into epidermal cells; as

Kadajaetal., 2014      HFSC numbers dwindle, outer root sheath
[112]                  production is not sustained, and HF
                       down-growth arrests prematurely

Foitzik et al.,        Injection ofTGF-beta1 induced
2000 [113]             premature catagen development

                       Ablation causes delay of hair follicle
Foitzik et al.,        morphogenesis, with a 50% reduced
1999 [114]             number of hair follicles

                       TGF-[beta]2 signaling antagonizes BMP
Oshimori and Fuchs,    signaling in HFSCs with increased
2012 [115]             telogen length

                       Refractory telogen hair follicles
                       entered anagen prematurely after
Qiu et al., 2017       TPA treatment, with the enhanced
[116]                  proliferation of CD34-positive hair
                       follicle stem cells

                       Prolonged overexpression increased
Lei et al., 2014       the size of regenerated hair follicles
[93]                   and increased expression of CD34
                       in the bulge

                       Overexpression causes a short-hair
Millar et al., 1999    phenotype and cyclical balding resulting
[94]                   from hair shaft structural defects

                       Cultured human umbilical cord-MSCs
                       (UC-MSCs) overexpressing Wnt7a
Donget al., 2017       can accelerate wound repair and induce
[117]                  hair regeneration via cellular communication
                       in the wound microenvironment

                       Underexpression causes shorter anagen,
Kandyba and            premature catagen onset with overall shorter
Kobielak, 2013         hair production, and diminished
[118]                  HF differentiation marker expression

                       Inactivation in DP of HF results in reduced
Enshell-Seijffers      proliferation of the progenitors and their
et al., 2010 [119]     immediate progeny that generate the HS
                       and premature catagen

HF: hair follicle; HS: hair shaft; DP: dermal papilla; SC: stem cell.

Table 2: Researches on the use of stem cells in the regeneration
of hair follicles.

Authors                Research object        Indication

                       Usage of hair follicle stem cell

Agabalyan et al.,      Sprague Dawley rats/   Nude mice
2016 [56]              nude mice              genetically mutated

Nilforoushzadeh et     Human/mice             Nude mice
al., 2016 [59]                                genetically mutated

Elmaadawi et al.,      Human                  Alopecia areata and
2018 [21]                                     androgenetic

Gentile et al.,        Human                  Androgenetic
2017 [5]                                      alopecia

Kalabusheva et al.,    Human                  In vitro study
2017 [120]

Hoffman et al.,        Human/mice             In vitro study
2018 [121]

                       Usage of adipose-derived stem cells

Park et al., 2010      Human/mice             C (3)H/NeH nude
[74]                                          mice

Zanzoterra et al.,     Human                  Androgenic alopecia
2014 [78]

Sabapathy et al.,      Rats                   In vitro study
2016 [82]

Yang et al., 2016      Human/mice             C57BL/6 nude mice

Anderi et al., 2018    Human                  Alopecia areata

                       Usage of Wharton's jelly and embryo stem cells

Yoo et al., 2010       Human                  In vitro study

Yoo et al., 2010       Human/mice             Athymic nude mice
[89]                                          genetically mutated

Wu et al., 2012        Human embryo           Nude mice
[90]                   MSCs/mice              genetically mutated

Authors                Methods of obtaining   Results

Agabalyan et al.,      Bioreactors and        Inducing de novo HF
2016 [56]              static cell cultures   formation,
                       with bFGF, PGF         reconstituting the
                                              DP and connective
                                              tissue sheath

                       Human scalp biopsy,    Evidence of hair
Nilforoushzadeh et     isolation of only      growth in mice
al., 2016 [59]         papilla cells which    received epithelial
                       were cultured and      and DP cells
                       injected into nude

Elmaadawi et al.,      Autologous bone        Good clinical
2018 [21]              marrow-derived         improvement in both
                       mononuclear cells      diseases
                       compared to
                       follicular stems
                       cells (skin punch
                       biopsy from
                       unaffected areas)

Gentile et al.,        Biopsies were          A 29% [+ or -] 5%
2017 [5]               collected and          increase in hair
                       disaggregated by       density for the
                       Rigeneracons without   treated area and
                       culture condition,     less than 1% in hair
                       then injected to the   density for the
                       frontal scalp          placebo area

                                              Aggrecan, biglycan,
                       Human DP cells and     fibronectin, and
Kalabusheva et al.,    skin epidermal         hyaluronic acid
2017 [120]             keratinocytes in a     significantly
                       hanging drop culture   stimulated cell
                       to develop an          proliferation in a
                       artificial HF germ     DP cell monolayer
                                              culture without any
                                              effect on DP cell

Hoffman et al.,        Hair follicle-         Intensive hair
2018 [121]             associated-            growth was observed
                       pluripotent stem       in the pieces of
                       cells from human       shaved mouse skin
                       scalp skin and         histocultured on
                       transgenic mice with   Gelfoam
                       nestin-driven GFP

Park et al., 2010      ADSCs in a             ADSCs in a
[74]                   conditioned medium     conditioned medium
                       injected               increased the
                       subcutaneously         proliferation of
                       induced the anagen     human DP and human
                       phase from telogen     epithelial
                       and increased hair     keratinocytes; the
                       regeneration in nude   effect of hypoxia on
                       mice                   ADSC function
                                              increased hair

Zanzoterra et al.,     Injection of ADSCs     After 2 weeks, the
2014 [78]              and growth factors     healing of
                                              microwounds was
                                              complete and HF
                                              continued growing

Sabapathy et al.,      ADSCs isolated from    A core-shell
2016 [82]              rats were cocultured   structure, outer
                       with DP spheres        ASCs shell, and an
                                              inner DP core
                                              exhibited superior
                                              potential to HF
                                              formation compared
                                              to a mixed sphere of
                                              ADSCs with DP cells

Yang et al., 2016      Cocultured human       The conditioned
[69]                   ADSCs with LL-37 was   medium of ADSCs
                       topically applied      preactivated with
                       daily on the mouse     LL-37 strongly
                       skin                   promoted hair growth
                                              in vivo

Anderi et al., 2018    Lipoaspiration,        Increased hair
[122]                  autologous ADSCs       growth and decreased
                       were injected into     pull test, 3 and 6
                       the scalp of the       months after ADSCs
                       patient (4-4.7 x
                       [10.sup.6] cells)

Yoo et al., 2010       Cultivated umbilical   Formation of
[88]                   stem cells with EGF,   aggregates similar
                       HGF, and NGF           to native DP in
                                              special media and
                                              reconstructed dermal
                                              papilla-like tissues

Yoo et al., 2010       Isolated and           Effect of inducing
[89]                   cultivated stem        new HF in mice
                       cells from bone        within 45 days
                       marrow and umbilical
                       cord, after
                       obtaining a DP-
                       forming medium,
                       injected in skin of
                       nude mice

Wu et al., 2012        Three cultures: DP     In fibroblast
[90]                   cells cocultured       injection to mice,
                       with hMSCs; DP cells   no HF was found
                       cocultured with
                       fibroblasts; hMSCs
                       cultured single,
                       next injected into
                       skin of mice

Authors                Comments

Agabalyan et al.,      Compared with static
2016 [56]              culture, stirred
                       bioreactors were
                       reduced, but they
                       can generate larger
                       numbers of
                       autologous DSCs,
                       maintaining their

                       The combination of
Nilforoushzadeh et     human cultured DP
al., 2016 [59]         and epithelial cells
                       could induce HF in
                       nude mice

Elmaadawi et al.,      Nonstatistically
2018 [21]              significant
                       difference between
                       the source of cells

Gentile et al.,
2017 [5]               No culture required,
                       quick time of
                       surgery (about 60

                       Most of the ECM
                       compounds prevented
Kalabusheva et al.,    the formation of
2017 [120]             cell aggregates
                       while hyaluronic
                       acid promoted the
                       formation of larger

Hoffman et al.,        Model for
2018 [121]             chemotherapy-
                       induced alopecia
                       (observing a
                       doxorubicin effect)

Park et al., 2010      The secretion of
[74]                   IGFBP, M-CSF
                       receptor, PGF, and
                       VEGF was
                       increased by
                       hypoxia, while the
                       secretion of EGF
                       production was

Zanzoterra et al.,     Rigenera system for
2014 [78]              the automated
                       disaggregation of
                       cell population

Sabapathy et al.,      PPAR[alpha] signal
2016 [82]              in ADSCs can induce
                       the hair formation

Yang et al., 2016      LL-37 treatment
[69]                   significantly
                       increased EGR-1

Anderi et al., 2018    Significant
[122]                  variation was
                       observed between men
                       and women only for
                       hair diameter, no
                       differences with age

Yoo et al., 2010       HGF is necessary in
[88]                   the differentiation

Yoo et al., 2010

Wu et al., 2012        The expression in
[90]                   vivo of HLA-I was
                       confined to DP of
                       the newly grown
                       hair, and the
                       survival time of
                       hMSCs in mice is 1

ADSCs: adipose-derived stem cells; DP: dermal papilla; DSCs: dermal
stem cells; EGF: epidermal growth factor; bFGF: basic fibroblast
growth factor; HF: hair follicle; HGF: hepatocyte growth factor;
HFA-F human leucocyte antigen class I; hMSCs: human mesenchymal
stem cells; IGFBP: insulin-like growth factor-binding protein;
M-CSF: macrophage colony-stimulating factor; NGF: nerve growth
factor; PGF: platelet- derived growth factor; VEGF: vascular
endothelial growth factor.

Table 3: Current studies of stem cell use registered on [122].

Number    Study                         Kind of stem cells

1         "Stem Cell Educator           Cord blood-derived
          Therapy in Alopecia Areata"   multipotent stem
                                        cells (CB-SCs)

2         "The Effect of Allogeneic     Allogeneic human ADSC
          Human Adipose Derived Stem    component extract
          Cell Component Extract on
          Androgenic Alopecia"

3         "Adipose Tissue Derived       Autologous MSC and
          Stem Cell Based Hair          human platelet-rich
          Restoration Therapy for       plasma
          Androgenetic Alopecia"

4         "Biocellular-Cellular         High-density platelet-rich
          Regenerative Treatment        plasma and adipose-derived
          Scaring Alopecia and          tissue stromal vascular
          Alopecia Areata"              fraction (AD-tSVF)

5         "AGA Biocellular Stem/        Adipose-derived tissue
          Stromal Hair Regenerative     stromal vascular fraction
          Study"                        (AD-tSVF) and high-density
                                        platelet-rich plasma

6         "Point-of-Care Adipose-       Stromal vascular fraction
                                        (SVF) cells

Number    Method                                Conditions

1         A closed loop system that             Alopecia areata
          circulates a patient's blood
          through a blood cell separator,
          briefly cocultures the patient's
          lymphocytes with adherent
          CB-SCs in vitro, and returns
          the educated lymphocytes
          (but not the CB-SCs) to the
          patient's circulation

2         Applying 1.2 g of allogeneic          Androgenic
          human adipose-derived stem            alopecia
          cell component extract on their
          scalp for 16 weeks

3         MSCs derived from adipose             Androgenic
          tissue with human platelet-           alopecia
          rich plasma will be applied

4         Use of high-density platelet-rich     Alopecia areata,
          plasma concentrates and cell-         scarring
          enriched emulsified adipose-          alopecia
          derived tissue stromal vascular
          fraction (AD-tSVF) via
          intravenous infusion

5         Biocellular mixture of                Androgenetic
          emulsified AD-tSVF and high-          alopecia, female
          density platelet-rich plasma          pattern hair
          concentrate (HD-PRP) as               loss
          compared with adipose-
          derived cell-enriched SVF
          and HD-PRP using
          Healeon Centricyte 1000
          system and intradermal

6         A single injection into the           Androgenic
          scalp of autologous adipose-          alopecia
          derived SVF cells

Number    Status       Trial institution/sponsor   NCT number and
                       and country                 duration period

1         UKN          The First Hospital of       NCT01673789
                       Hebei Medical University    2012-2013
                       Shijiazhuang, Hebei,

2         Completed    Pusan National              NCT02594046
                       University                  2015-2017
                       Hospital, South

3         Not yet      King Edward Medical         NCT02865421
          recruiting   University, Pakistan

4         Recruiting   Regeneris Medical,          NCT03078686
                       Global Alliance for         2017-2019
                       Regenerative Medicine,
                       Healeon Medical Inc.,

5         Recruiting   Healeon Medical Inc.,       NCT02849470
                       Ministry of Health,         2016-2018
                       Honduras Irvine,
                       California, USA

6         Recruiting   University of Florida       NCT02729415
                       Gainesville, Florida,       2016-2017
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Author:Owczarczyk-Saczonek, Agnieszka; Krajewska-Wlodarczyk, Magdalena; Kruszewska, Anna; Banasiak, Lukasz;
Publication:Stem Cells International
Date:Jan 1, 2018
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