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Year : 2014  |  Volume : 1  |  Issue : 1  |  Page : 8-12

Stem cells in vitiligo: Current position and prospects

Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication26-Jun-2014

Correspondence Address:
Sunil Dogra
Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-5847.135430

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Skin is an easily accessible source of various sub population of stem cells including epidermal stem cells, hair follicle stem cells (HFSCs) and dermal mesenchymal stem cells. The outer root sheath (ORS) of the hair follicle is a rich source of a type of HFSCs called the melanocytes stem cells (MelSCs). These HFSCs have a vast, unexplored potential in the treatment of vitiligo as initial re-pigmentation often occurs around the hair follicles. Common therapeutic modalities such as tacrolimus, phototherapy and dermabrasion acts through MelSCs. Newer cellular techniques have explored the use of ORS hair follicle suspension in surgical treatment of vitiligo. Advancement in melanocyte and stem cell research has identified various cytokines, growth factors and regulators involved in proliferation and differentiation of melanoblasts, which can be used for autologous in situ melanocyte regeneration. In this review, we briefly discuss the current position and future prospects of stem cells in vitiligo.

Keywords: Follicular cell suspension, Hair follicle stem cells, Melanoblasts, Melanocyte stem cells, Stem cells, Vitiligo

How to cite this article:
Vinay K, Dogra S. Stem cells in vitiligo: Current position and prospects. Pigment Int 2014;1:8-12

How to cite this URL:
Vinay K, Dogra S. Stem cells in vitiligo: Current position and prospects. Pigment Int [serial online] 2014 [cited 2023 Feb 2];1:8-12. Available from: https://www.pigmentinternational.com/text.asp?2014/1/1/8/135430

  Introduction Top

Skin is a dynamic structure, which protects the body from many environmental assaults. It is continuously regenerated by specialized cells in the basal layer which replaces the dead cells. These specialized pluripotent stem cells have the capacity to self-renew and generate differentiated progeny. Stem cells are undifferentiated cells, capable of proliferation and regeneration following tissue injury. They form a self-maintaining population of cells producing a large number of differentiated functional progeny. [1] The various sub population of stem cells in the skin include, epidermal stem cells, hair follicle stem cells (HFSCs), stem cells in sebaceous and sweat gland and dermal mesenchymal stem cells (DMSCs). [2] The current interest in vitiligo research is directed towards the reservoirs of these stem cells, particularly the HFSCs, the regenerative properties of which are being increasingly exploited in the vitiligo management strategies. In this review, we briefly discuss the role of stem cells in vitiligo with particular emphasis on HFSCs.

  Hair Follicle Stem Cells Top

Hair follicle is a rich source of three different types of stem cells, all of which are important in hair growth. These include epithelial stem cells (ESCs), melanocytes stem cells (MelSCs) and neural crest stem cells (NCSCs) which are together known as HFSCs. [3] In addition, DMSCs are found in the peri-follicular connective tissue sheath and the dermal papilla. [4] HFSCs are multipotent stem cells that are located in the lower permanent bulge and sub-bulge area of the hair follicle. The ESCs normally contributes to the regeneration of the cycling portion of hair follicles during the anagen phase of the hair growth. ESCs also contribute to the regeneration of interfollicular epidermis after wounding and to the sebaceous gland population. [2]

Melanocytes stem cells are somatic stem cells of melanocytic lineage that function as the cellular source of the "hair pigmentary unit." The MelSCs directly adhere to ESCs, which form the niche cells for MelSCs and serve as a melanocyte reservoir for skin and hair pigmentation. [5] The MelSC population usually consists of small, oval-shaped cells with a high nuclear/cytoplasmic ratio. [6] They express the genes dopachrome tautomerase (DCT) and Pax3 and are identified by these markers. [7] These stem cells have the capability to supply the hair matrix with transient amplifying cells and differentiated progeny that eventually mature into melanin forming melanocytes. [5] MelSC also have the capacity to migrate and enter vacant niches in the epidermis as will be discussed further. [5]

Neural crest stem cells are label-retaining cells which are capable of self-renewal through asymmetric cell division in vitro. They express the neural crest-associated markers Twist, Slug, and Sox10 but do not express markers of more differentiated cell types. [3] Under specific differentiation conditions, NCSCs generates S100+ melanocytes, neurofilament+ neuron-like cells, smooth muscle actin+ smooth muscle cells, adipocytes, osteocytes, and chondrocytes. [8]

  Stem Cells in Vitiligo Re-pigmentation Top

Evolutionarily, follicular and epidermal melanocytes are closely related with epidermal melanocytes evolving from the follicular ones. [9] Hair follicle melanocytes play an important role in re-pigmentation of vitiliginous lesion. Migration of the precursor melanocytes in the mid portion of the hair follicle, later found to be MelSCs have been implicated in the re-pigmentation obtained following both chemical and physical stimulus. [10],[11] Cui et al. observed that in vitiliginous lesions, there was the destruction of selectively DOPA-positive melanocytes, whereas the DOPA-negative MelSCs in the outer root sheath (ORS) of the hair follicle were spared. [12] This reservoir of nonfunctional melanocytes, MelSCs are present in the lesional epidermis of patients with vitiligo, even after disease of 25 years duration. [13] Similarly, this melanocyte reservoir was also found in ORS of the white hair in lesional skin. [14] These MelSCs were proposed to be responsible for re-pigmentation in vitiligo by dividing and migrating upward along the surface of the hair follicle to the nearby epidermis. Nishimura et al. in transgenic mouse experiments showed that HFSCs in the bulge region could migrate up into the epidermis to cause peri-follicular re-pigmentation which later spread in a concentric pattern causing diffuse re-pigmentation. [5] This however occurred only in the presence of steel factor (SLF, the ligand for kit receptor) expression in the epidermis. These observations suggested that SLF provided new routes connecting the follicular ORS and the epidermis, along which the melanoblasts can migrate to occupy vacant niches.

Pigmentation due to medical therapies

Tacrolimus is a common topical agent used in the treatment of vitiligo. Apart from its immunomodulatory action, it also has an effect on keratinocytes, melanocytes and melanoblasts. [15],[16] Lan et al. showed that cell cultures of immature melanoblasts when treated with tacrolimus, show activation of pigment cell maturation pathways, protein kinase A, protein kinase C, and p38 MAPK. [16] On further adding endothelin-3 (ET-3) to the cell culture, it resulted in migration of these melanoblasts. This differentiation-stimulating effect of tacrolimus on melanoblasts is clinically translated into peri-follicular re-pigmentation pattern commonly seen with its treatment. [17]

Pigmentation due to phototherapy

Re-pigmentation following phototherapy is usually seen in a peri-follicular manner, supporting the follicular origin of the epidermal melanocytes. However, until recently the exact molecular mechanism of the re-pigmentation following phototherapy was not known. Recently in their mouse experiments, Yamada et al. showed that MelSCs in bulge region of the hair follicle are responsible for epidermal pigmentation following ultraviolet (UV) radiation. [18] The authors found that UVB exposure induces MelSCs differentiation into melanoblasts by activation of the Wnt/β-catenin pathway. This was followed by their migration to the epidermis and differentiation into mature melanocytes. [18] Other stem cell population have also been shown to play a role in epidermal pigmentation following phototherapy. Dong et al. showed that narrow band UVB (NBUVB) radiation increases the expression of tyrosinase, tyrosinase-related protein-1 and DCT (markers of differentiation along melanocyte lineage) from NCSCs in hair follicles. [19] NBUVB irradiation causes the release of beta-fibroblast growth factor (β-FGF), ET-1 and alpha-melanocyte stimulating hormone from epidermal keratinocytes, which in turn has a proliferative, differentiating and migratory effect on melanocyte reservoir. [20] Thus following UVB irradiation, stem cells in the ORS of the hair follicle are reprogrammed towards melanocyte lineage. These transient amplifying cells (melanoblasts) under the influence of growth factors and cytokines released by epidermal keratinocytes proliferation and migrate towards epidermis. This is followed by differentiation of melanoblasts into mature functional melanocytes. In contrast to UVB, psoralen UVA mainly acts by its immunosuppressive effects. [21] It has no role in melanocyte proliferation, but promotes a favorable environment for melanocyte migration. [21]

Other than in the bulge and the sub-bulge area MelSCs have also been demonstrated in the interfollicular epidermis. [22] These cells may provide epidermal re-pigmentation in vitiligo, independently from the follicular reservoir. Epidermal re-pigmentation in palms and soles following phototherapy, which lack follicular reservoir of stem cells may be explained by the presence of interfollicular stem cell reservoir. [22]

Low level laser therapy has been shown to enhance the proliferation of mesenchymal and cardiac stem cells. [23] Helium-neon laser (632.8 nm) has a pro-differentiating effect on the immature melanoblasts. Irradiation with Helium-neon laser causes migration of the immature melanoblasts to the epidermis, followed by their functional development to produce melanin. [24]

Pigmentation due to dermabrasion

Staricco in 1961 showed that following dermabrasion of normally pigmented scalp, amelanotic melanocytes (probably MelSCs) in mid follicle proliferated, differentiated and migrated to colonize the basal layers of the epidermis. [25] Awad reported re-pigmentation in 8 out of 10 vitiligo patches treated with dermabrasion alone. [26] Skin biopsy specimens obtained 10 days after the dermabrasion showed spindle cells with dark longitudinal nuclei and slightly eosinophilic cytoplasm. These cells were interpreted as MelSCs migrating from the infundibulum and ORS of the hair follicle, though they stained negatively with C-KIT and MART-1.

Extracted hair follicle outer root sheath cell suspension

It is a novel technique of cellular graft surgery for patients of stable vitiligo. The technique of follicular cell suspension (FCS) is based on the findings that, hair follicle is an important reservoir of melanocytes and their precursor cell, MelSCs. In follicular melanin unit, there is a high concentration of melanocytes; one for every five keratinocytes in the hair bulb. [27] These melanocytes also have higher synthetic capacity, are larger, more dendritic, and produce larger melanosomes. [28] MelSC has been recognized in the hair follicle but not in the epidermis. All these properties make hair a more attractive source of melanocytes than the epidermis for cell based therapies in vitiligo. [29]

Vanscheidt and Hunziker [30] in a small case series, have used single cell suspension of "plucked" hair follicles in the treatment of vitiligo. They found almost complete (>90%) re-pigmentation in three of five patients with vitiligo, around 50% re-pigmentation in one patient and <10% re-pigmentation in one patient. However, the cell yield is less in case of plucked hair follicles. Cell suspension prepared from hair follicles obtained by follicular unit extraction (FUE) method contains more CD200+ cells (a marker for HFSCs) when compared to plucked hair. [31] As a refinement of this technique Mohanty et al. performed FCS in 14 patients of vitiligo using FUE method and achieved >75% pigmentation in nine patients. [32] Singh et al. compared the treatment outcome in patients of stable vitiligo treated with FCS and epidermal cell suspension (ECS) method. [33] The authors found no statistically significant difference in the treatment outcome between both groups. Vinay et al. in their study found a strong correlation between re-pigmentation at 24 weeks and the number of melanocytes and HFSC transplanted in patients of stable vitiligo undergoing FCS. [34] Further, number of HFSC transplanted significantly predicted the probability of achieving re-pigmentation of >75%. [34]

Theoretically one would expect more re-pigmentation with FCS, due to the presence of MelSCs, better melanocyte-keratinocyte ratio and morphological properties of melanocytes in the hair follicle, in comparison to ECS. But in the study by Singh et al. the outcome of FCS was numerically inferior to the response seen with ECS. It is proposed that the presence of keratinocytes in the suspension supplies essential growth factors for melanocyte growth. [35] Melanocytic homeostasis is modulated via a complex network of autocrine and paracrine factors. Melanocyte proliferation, melanogenesis, migration, dendricity, and differentiation are influenced by keratinocytes and fibroblasts, as well as the melanocyte-derived growth factors and cytokines. [36] So, better pigmentation rate may be obtained by adding keratinocyte growth factors to FCS. This needs to be assessed in future studies.

  Future Applications of Stem Cells in Vitiligo Therapy Top

In the era of cell based therapies, the future may involve culturing melanocytes to treat a variety of pigment disorders, such as albinism and vitiligo. Surgical treatment involving cell culture offers a potential solution for treating extensive lesions. Cultivation of melanocytes in vitro can increase the cell number dramatically and cells from a small piece of normal skin can be used to treat large depigmented areas. Melanocyte culture can be achieved either by autologous cultured melanocyte transplantation or from reprogramming embryonic, induced pluripotent or mesenchymal stem cells to melanocytes. [7],[37],[38] Pure yield of differentiated melanocytes can also be obtained by differentiation and amplification of pluripotent cells of ORS of the hair follicle. [39] Certain growth factors like tetradecanoylphorbol acetate used in melanocyte culture are tumor promoters with risk of mutagenicity. However, improved culture methods have made the procedure relatively safe by using alternative growth promoters like β-FGF. [40]

Mesenchymal stem cells inhibit T-cell proliferation and induce T-cell apoptosis. [41] Studies have shown that DMSCs modulate the infiltration of peri-lesional CD8+ T-cells. [42] They inhibit CD8+ T-cell proliferation, induce their apoptosis and regulate their cytokines/chemokines production. Thus DMSCs might be used as auxiliary agent to improve transplantation efficacy in patients undergoing noncultured/cultured autologous melanocyte transplantation.

Autologous in situ melanocyte regeneration is another future strategy for epidermal re-pigmentation, wherein specific melanocyte inducers applied on the skin surface can stimulate skin stem cells to differentiate into melanocytes, which would compensate for the melanocyte loss and restore pigment production. [18],[43]

  Conclusion Top

Stem cell research has a vast, unexplored potential in the treatment of vitiligo patients. Differentiation and amplification of pluripotent cells of ORS of the hair follicle can provide an unlimited supply of melanocytes for cell based treatment. Development in melanocyte and stem cell research has identified various cytokines, growth factors and regulators involved in proliferation migration and differentiation of melanoblasts to mature melanocytes. These growth factors can be explored in the future for in situ melanocyte regeneration. Advancement in molecular biology has made the future prospect of vitiligo treatment bright and hopeful.

  References Top

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