Journal of Stem Cells Research Development & Therapy Category: Medical Type: Review Article
Stem Cells and Their Potential Applications in Dermatology
- Emma Bhattarai1*, Yaser Mansoor Almutawa1, Nishim Gautam1, Jingjun Zhao1
- 1 Department Of Dermatology And Venerology, Tongji Hospital, School Of Medicine, Tongji University, Shanghai 200092, China
*Corresponding Author:Emma Bhattarai
Department Of Dermatology And Venerology, Tongji Hospital, School Of Medicine, Tongji University, Shanghai 200092, China
Received Date: Jul 13, 2020 Accepted Date: Jul 22, 2020 Published Date: Jul 29, 2020
In recent years, huge advances have been made in the field of cell repair and regeneration, among which usage of Stem Cells (SCs) and its activators are at the foremost. Various studies have been conducted in the field of regenerative medicine using SCs in clinical applications. These studies have shown potential of SCs in the management of those disease where satisfactory outcome is still not available. Huge appeal in SCs is mainly due to their ability for self-renewal, capacity to differentiate into their tissue of origin and their potential to differentiate into completely new cell type. Experiments conducted with regards to dermatological problems have shown positive results in many cases. This review aims to summarize stem cells biology and types, and their potential use in many dermatological conditions. This article also summarizes about the stem cells present in the skin, their usage and identification.
Dermatology; Embryonic; Epidermal stem cells; Mesenchymal; Stem cells; Stem cell therapy
Stem cells technology and its potential usage is a novel idea in the field of in cellular repair and regeneration. Stem cells are basically precursor cells for all cell types. Basically for a cell to be stem cells, it must have capacity for self-renewal and the potency to differentiate into similar and new cell type . Self-renewal is the ability of SCs to undergo asymmetric mitotic division so as to retain same number of original undifferentiated cells and produce one progenitor cell which further divides to form required cell type. This ability of self-renewal should allow the stem cells to produce 40-60 doubling of population before the cell dies . Plasticity is another ability of stem cells which allows formation of a new cell type different to its original tissue type [3,4].
TYPES OF STEM CELLS
SCs are mainly categorized into embryonic and adult type. An example of embryonic stem cell is blastocyst . Embryonic SCs has the capability to divide into the three germ layers: ectoderm, mesoderm and endoderm; and thus it can differentiate into any cell type. Due to this ability, embryonic SCs can lead to teratoma formation and may cause graft rejection [5-7]. Adult stem cells are of hematopoietic and mesenchymal type. They can be obtained from bone marrow, umbilical cord, liver, skin, adipose tissues, etc. unlike embryonic SCs teratoma formation and graft rejection is rare with adult SCs .
A new concept of induced Pluripotent Stem Cells (iPSCs) has evolved where few genes (3-4) obtained from stem cells are transfected into the receiving cells thus allowing the receiving cells to develop similar characteristics like that of donor stem cells . This concept of converting the mesenchymal stem cells to iPSCs has given new ideas for treatment of incurable conditions as well as inherited skin diseases as iPSCs can act like embryonic stem cells i.e. it can give rise to any cell type and lineage, thus correcting genetic abnormality of the disease by homologous recombination. This concept can further revolutionize the future of stem cells and its use  (figure 1).
Figure 1: Stem cells classification.
Stem Cells in terms of cell differentiation fall under 4 types; Totipotent, pluripotent, unipotent and multipotent SCs where potency is the ability of a cell to differentiate into specialized cell types. Totipotent SCs have the ability to replicate into placental cells as well as any other type of cells, has the capacity to form an entire organism and are found exclusively in embryonic developmental stage. Pluripotent SCs can develop into any other cell type but placenta. They have the capacity to form tissues from all three germ layers. Unipotent SCs only has the ability to form single specific type of cell whereas Multipotent SCs can develop into different cell type but of similar tissue of origin  (Table 1).
Embryonic stem cells, induced pluripotent stem cells
Hematopoietic stem cells, mesenchymal stem cells
Table 1: Classification of stem cells in terms of potency.
Adult stem cells can be of hematological and mesenchymal in origin. The mesenchymal stem cells are found in a niche of special surrounding needed for their control. Mesenchymal stem cells can be found in various organs and tissues of body where there is large cell turnover such as skin, liver, intestinal mucosa, periosteum, cornea, dental pulp, adipose tissue [8,12,13].
Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) originate from stroma and can be obtained from any tissues. According to The International Society for Cellular Therapy position statement there are three criteria to define MSC :
- Adherence to plastic
- Specific surface antigen (Ag) expression
- Multipotent differentiation potential
Mesenchymal Stem Cells (MSCs) are identified on basis of above three points.
- Adherence to plastic
Plasticity is a term that defines the ability of cells to differentiate into a completely new cell type than its original cells.
- Specific surface antigen (Ag) expression
Presence and absence of specific surface antigen expression helps in identification of mesenchymal stem cells. CD105, CD73, CD90 should be present on the cell surface while CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA class II must be lacking.
- Multipotent differentiation potential
The cells under standard in vitro differentiating conditions must have the capacity to differentiate into osteoblasts, adipocytes and chondroblasts .
Skin Stem Cells
In both epidermal and dermal layer of skin, stem cells are present in specific areas so named ‘niche’, where the microenvironment allows the stem cells to hold on to their defined properties without any modifications. This niche also defends stem cells from signals that leads to apoptosis causing them to be less likely for any oncogenic changes leading to cellular DNA damage .
Epidermal stem cells are found evenly distributed along basal layer of epidermis and bear a resemblance to somatic stem cells. Its main function is to repair and maintain the integrity of the tissues they reside on. Epidermal stem cell helps repair injuries as well as maintain skin homeostasis and helps in hair regeneration [15,16]. Identifying markers are p63, β1high/MCSP+(melanoma chondroitin sulfate proteoglycan+), CD71dim [17-19].
Melanocyte stem cells are found on the bulge region of outer root sheath of the hair follicle and functions in survival, growth, multiplication and differentiation of melanocyte cells [20,21]. The identifying cell markers for melanocyte stem cells are Dct, Pax3 and Sox10 [22,23].
Follicular stem cells are also found in the bulge region of hair follicles in the outer root sheath and helps in regeneration and repair of hair follicle including the outer, inner root sheath and the hair shaft . The identifying cell marker for follicular stem cells are K15, CD34, Lgr5, Sox9, Lhx2, NFATC1, NFIB, PHLDA1, CD200, K19 .
Sebaceous gland stem cells are found sebaceous gland and the infundibulum. The stem cells in sebaceous gland itself gives rise to and sustain the mature sebocytes. The stem cells in the bulge region goes towards gland region and helps maintain the gland [26,27]. The identifying cell marker is Blimp1 .
Mesenchymal stem cells are located in dermis and at the root of hair follicle. It helps in formation of some neural cell types as well as into other cells of mesenchymal derivatives [29,30]. The identifying cell marker are CD105, CD73, and CD90 and exclude expression of CD45, CD34, CD14 or CD11b, CD79a (Table 2).
Epidermal stem cells
Basal layer of epidermis
p63, β1high/MCSP+(melanoma chondroitin sulfate proteoglycan+), CD71dim
Melanocyte stem cells
Follicular bulge region and hair germ
Dct, Pax3, and Sox10
Follicular stem cells
Follicular bulge region
K15, CD34, Lgr5,Sox9, Lhx2, NFATC1, NFIB, PHLDA1, CD200, K19
Sebaceous gland stem cells
Sebaceous glands and infundibulum
Mesenchymal stem cells
CD105, CD73, and CD90 and negative for CD34,CD45, CD14 or CD11b, CD79a/CD19 & HLA-DR
Table 2: Skin stem cell type with identifying markers.
POTENTIAL USES OF STEM CELL THERAPY IN DERMATOLOGICAL CONDITIONS
Cutaneous wound healing
The normal wound healing of human skin in not perfect even in best circumstances with the delayed healing, scar formation being a persistent eventuality. In the scenario of long term delayed wound healing, scarring mesenchymal stem cells have shown excellent promise. Migration, angiogenesis, epithelialization, and granulation tissue formation is encouraged by MSCs which expedites wound healing and further promotes regenerative wound healing leading to decrease scarring . In both acute and chronic wounds, MSCs can be administered directly to the wounds by injecting, or even spraying (e.g., autologous MSCs using fibrin spray, lead to direct delivery of stem cells in acute and chronic wounds in mice and humans ) leading to acceleration of wound healing, angiogenesis, releasing of paracrine signalling molecules as well as enhanced reepithelialisation. Similarly, Studies have shown that hair follicle stem cells contributes to wound healing [33,34]. Stem cells from hair follicles and interfollicular epidermis move towards the wound area in response to injury. In a study by Ito et al.,  fate-mapping experiments have shown that, k15 positive hair follicle stem cells help in re-epithelialization of full-thickness wounds. After the injury to epidermis, the follicular epithelial cells migrate rapidly towards the center of wound in a radial pattern thereby forming transient cells which oversees acute wound repair.
Vitiligo, a disorder caused by loss of melanocytes leads to formation of colourless patchy skin. Presence of melanocytes from the hair follicle unit, border of lesion and from unaffected melanocytes within the depigmented areas decides regimentation in vitiligo . Tacrolimus, phototherapy and dermabrasion are commonly used therapy for vitiligo which does provide result in some patients. Progress in stem cells therapy has brought new hope in field of vitiligo management. In a study by Zhu et al., , the expression of PTEN (phosphatase and tensin homolog) in human vitiligo was found to be elevated with due inhibition of the AKT growth signalling pathway. This finding actually shows that PTEN has an important role in melanocytic growth and survival. In same study Zhu et al., found that MSCs can regulate the expression of PTEN protein in Melanocytes and can further decrease impairments due to overexpression of PTEN and H2O2 induced oxidative stress. Similarly, dermal MSCs can help in vitiligo by improving melanocyte transplantation efficacy as dermal MSCs inhibits CD8+ T cell proliferation, induce apoptosis of T cells and further regulate the cytokine and chemokines production .
Hair loss from single area or multiple areas forming bald patches is seen in alopecia. Autologous hair transplantation is considered gold standard but its use is limited due to limited amount of material as well as decreased viability of the material. In study by Nilforoushzadeh et al.,  induction of new hair growth was seen after Injecting a combination of human cultured dermal papillary cells and hair epithelial cells with CD200+ and k15 identifying markers in nude mice. This does give emphasis on the subject that stem cell therapy does indeed lead to hair growth in alopecia patient. Recently a new method for hair regrowth in androgenic alopecia was suggested by Gentile et al.,  which used a mixture of centrifuged hair follicle stem cells and dermal MSCs. The study showed hair growth and increased hair density in the sites where the mixture was injected. This study suggests that injection of HFSCs has good prognostic value on male pattern androgenic alopecia.
Stem cell therapy has thus come forward for alopecia as it helps to regenerate hair by altering pathological reasons of hair loss, helps to regenerate complete hair follicles and helps form new hair follicles.
Melanoma in past was thought to be due to cancer cells arising from melanocyte cells but these days it has been studies that it may also occur due to cellular changes in melanocytes, melanocytic stem cells or both [41,42]. Studies have shown MSCs can reach both the primary and metastatic tumor site with help of various chemokines and cytokinesemitted from the tumor [43,44]. Pessina et al.,  demonstrated that MSCs, when loaded in vitro with an anti-cancer drug (e.g. Paclitaxel(Dr-MCsPTX)) becomes drug releasing mesenchymal cells which inhibits the growth of cancer cells strongly. MSCs in melanoma act not just as vector to in improving the delivery of targeted agents (adipose derived mesenchymal stem cells expressing TRAIL, interferon-α/γ, pigment epithelium-derived factor and cytosine deaminase) but also express a distinct set of biologically functional chemokines and tumor supressing agents. MSCs can also be genetically modified with tumor suppressive genes to stop the pathways that cause progression and metastasis of melanoma [46-48].
Aging is natural phase of life and every organ of our body goes through it. Reduced function is one of the main changes seen due to aging. Physical changes seen in skin just highlight this phase. Usually the cell in our body wears out and gets replaced continuously with the help of stem cells. Decrease in ability of the stem cells to regenerate and repair is the main causation of aging. Xu et al.,  , compared adipose stem cell and placental stem cell in secretion characteristics and facial anti-aging. The study shows that the protein secreted from adipose stem cells were more versed towards cell adhesion and migration, and were more helpful in would healing and tissue repair. Also the improvement of melanin index was more pronounced with the injection of the adipose stem cell conditioned medium. Similarly, the proteins from placental stem cells were found to be defter towards angiogenesis, cell proliferation and differentiation, cell survival, degradation of collagen and in immunomodulation. Both of these conditioned medium helped improve the facial index.
Improvement in this ability of regeneration and repair can be made by using stem cell therapy which helps delay the process of aging and help manage aged diseases .
In any new discipline of study, there will always be intricate relationship between knowledge and hypothesis of the intrinsic mechanism with development of new clinical plans. Many studies have shown that stem cells have the capability to transform itself into any mature cell type. This feature of stem cells has led many researchers to conduct studies on certain dermatological conditions, such as, treating chronic wound repair with MSCs and epidermal stem cell. Studies have also been conducted in conditions like alopecia and vitiligo where use of epidermal and dermal stem cells has shown great benefits. Similarly, in condition like melanoma, stem cells have been used along with other agents like anticancer drugs with MSCs acting as vector thereby improving the delivery of targeted agents. Studies in antiaging with stem cells have shown great promise in improving the body’s ability to increase the repair and regeneration of aged cells and as such delaying aging.
Despite these positive results with stem cell therapy, the need for further study will always be there. Till date our knowledge regarding the complex signaling cascades, environmental influence on the stem cells or its epigenetic modulation is still limited and much work is still needed. Stem cells also show some adverse events particularly when it comes to characterize graft versus host stem cell immune interactions, tumorigenesis, metastasis and potential drug resistance, which too needs to be addressed.
In the field of dermatology, due to readily accessible topical approach towards the epidermal and dermal stem cells, it seems easier to obtain the samples of stem cells from cutis and subcutis. Also the dermatological conditions are easily reachable without using any interventions, for example, using stem cell laden fibrin spray in chronic wound so as to modulate rapid wound healing without scarring.
Though the studies till date show mostly promising results, however the subjects and controls are usually too small to allow for proper assessment of the efficacy of the therapies. Therefore, further research and large, controlled clinical trials are required to obtain necessary data regarding the outcome, safety and efficacy of the stem cell therapies. Despite these limitations, there is still hope that safe and efficient approach is forthcoming and there will be safe and sophisticated treatment modalities with stem cells.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
- Chagastelles PC, Nardi NB (2011) Biology of stem cells: An overview. Kidney Int Suppl 1: 63-67.
- Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37: 614-636.
- Ogliari KS, Marinowic D, Brum DE, Loth F (2014) Stem cells in dermatology. An Bras Dermatol 89: 286-292.
- Colter DC, Class R, DiGirolamo CM, Prockop DJ (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci USA 97: 3213-3218.
- Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145-1147.
- Keller GM (1995) In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 7: 862-869.
- Wu DC, Boyd AS, Wood KJ (2007) Embryonic stem cell transplantation: Potential applicability in cell replacement therapy and regenerative medicine. Front Biosci 12: 4525-4535.
- Fortier LA (2005) Stem Cells: Classifications, Controversies, and Clinical Applications. Vet Surg 34: 415-423.
- Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.
- Bilousova G, Roop DR (2014) Induced pluripotent stem cells in dermatology: Potentials, advances, and limitations. Cold Spring Harb Perspect Med 4: 015164.
- Niezgoda A, Niezgoda P, Nowowiejska L, Bia?ecka A, M?ci?ska-Jundzi?? K, et al. (2017) Properties of skin stem cells and their potential clinical applications in modern dermatology. Eur J Dermatol 27: 227-236.
- Sunil P, Manikandhan R, Muthu M, Abraham S (2012) Stem cell therapy in oral and maxillofacial region: An overview. J Oral Maxillofac Pathol 16: 58-63.
- Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102: 3483-3494.
- Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini Fc, et al. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315-317.
- Blanpain C, Fuchs E (2006) Epidermal Stem Cells of the Skin. Annu Rev Cell Dev Biol 22: 339-373.
- Abbas O, Mahalingam M (2009) Epidermal stem cells: Practical perspectives and potential uses. Br J Dermatol 161: 228-236.
- Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, et al. (2001) p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 98: 3156-3161.
- Suzuki D, Senoo M (2012) Increased p63 phosphorylation marks early transition of epidermal stem cells to progenitors. J Invest Dermatol 132: 2461-2464.
- Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia. Cell 129: 523-536.
- Nishikawa-Torikai S, Osawa M, Nishikawa SI (2011) Functional characterization of melanocyte stem cells in hair follicles. J Invest Dermatol 131: 2358-2367.
- Li A (2014) The biology of melanocyte and melanocyte stem cell. Acta Biochim Biophys Sin (Shanghai) 46: 255-260.
- Osawa M, Egawa G, Mak SS, Moriyama M, Freter R, et al. (2005) Molecular characterization of melanocyte stem cells in their niche. Development 132: 5589-5599.
- Harris ML, Buac K, Shakhova O, Hakami RM, Wegner M, et al. (2013) A Dual Role for SOX10 in the Maintenance of the Postnatal Melanocyte Lineage and the Differentiation of Melanocyte Stem Cell Progenitors. PLoS Genet 9: 1003644.
- Lavker RM, Miller S, Wilson C, Cotsarelis G, Wei ZG, et al. (1993) Hair follicle stem cells: their location, role in hair cycle, and involvement in skin tumor formation. J Invest Dermatol 101: 16-26.
- Nowak JA, Polak L, Pasolli HA, Fuchs E (2008) Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3: 33-43.
- Niemann C (2009) Differentiation of the sebaceous gland. Dermatoendocrinol 1: 64-67.
- Frances D, Niemann C (2012) Stem cell dynamics in sebaceous gland morphogenesis in mouse skin. Dev Biol 363: 138-146.
- Horsley V, O'Carroll D, Tooze R, Ohinata Y, Saitou M, et al. (2006) Blimp1 Defines a Progenitor Population that Governs Cellular Input to the Sebaceous Gland. Cell 126: 597-609.
- Chu GY, Chen YF, Chen HY, Chan MH, Gau CS, et al. (2018) Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues. J Food Drug Anal 26: 14-20.
- Sisakht MM, Kheirkhah MS, Sharifzad F, Nilforoushzadeh MA (2015) Skin stem cells in skin cell therapy. Journal of Skin and Stem Cell 2: 38698.
- Hu MS, Borrelli MR, Lorenz HP, Longaker MT, Wan DC (2018) Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential. Stem Cell Int 2018: 6901983.
- Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, et al. (2007) Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng13: 1299-1312.
- Navsaria HA, Ojeh NO, Moiemen N, Griffiths MA, Frame JD (2004) Reepithelialization of a full-thickness burn from stem cells of hair follicles micrografted into a tissue-engineered dermal template (integra). Plast Reconstr Surg 113: 978-981.
- Zakine G, Mimoun M, Pham J, Chaouat M (2012) Reepithelialization from stem cells of hair follicles of dermal graft of the scalp in acute treatment of third-degree burns: First clinical and histologic study. Plast Reconstr Surg 130: 42-50.
- Ito M, Liu Y, Yang Z, Nguyen J, Liang F, et al. (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11: 1351-1354.
- Falabella R (2009) Vitiligo and the melanocyte reservoir. Indian J Dermatol 54: 313-318.
- Zhu L, Lin X, Zhi L, Fang Y, Lin K, et al. (2020) Mesenchymal stem cells promote human melanocytes proliferation and resistance to apoptosis through PTEN pathway in vitiligo. Stem Cell Res Ther 11:
- Zhou MN, Zhang ZQ, Wu JI, Lin FQ, Fu LF, et al. (2013) Dermal Mesenchymal Stem Cells (DMSCs) Inhibit Skin-Homing CD8+ T Cell Activity, a Determining Factor of Vitiligo Patients’ Autologous Melanocytes Transplantation Efficiency. PLoS One 8: 60254.
- Nilforoushzadeh M, Jameh ER, Jaffary F, Abolhasani E, Keshtmand G, et al. (2017) Hair follicle generation by injections of adult human follicular epithelial and dermal papilla cells into nude mice. Cell J 19: 259-268.
- Gentile P, Scioli MG, Bielli A, Orlandi A, Cervelli V (2017) Stem cells from human hair follicles: first mechanical isolation for immediate autologous clinical use in androgenetic alopecia and hair loss. Stem Cell Investig 4: 58-58.
- Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu J, et al. (2006) Melanoma, a Tumor Based on a Mutant Stem Cell? J Invest Dermatol 126: 142-153.
- Hoerter JD, Bradley P, Casillas A, Chambers D, Weiswasser B, et al. (2012) Does Melanoma Begin in a Melanocyte Stem Cell? Journal of Skin Cancer 2012: 571087.
- Vicari AP, Caux C (2002) Chemokines in cancer. Cytokine Growth Factor Rev 13: 143–154.
- Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F (2008) Inflammation and tumor microenvironments: Defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15: 730-738.
- Pessina A, Leonetti C, Artuso S, Benetti A, Dessy E, et al. (2005) Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model. J Exp Clin Cancer Res 34: 82.
- Loebinger MR, Janes SM (2010) Stem cells as vectors for antitumour therapy. Thorax 65: 362-369.
- Petrella F, Rimoldi I, Rizzo S, Spaggiari L (2017) Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery. Medicines (Basel) 4: 87.
- Mirzaei H, Sahebkar A, Avan A, Jaafari MR, Salehi R, et al. (2016) Application of Mesenchymal Stem Cells in Melanoma: A Potential Therapeutic Strategy for Delivery of Targeted Agents. Curr Med Chem 23: 455-463.
- Xu Y, Guo S, Wei C, Li H, Chen L, et al. (2016) The Comparison of Adipose Stem Cell and Placental Stem Cell in Secretion Characteristics and in Facial Antiaging. Stem Cells Int 2016: 7315830.
- Yu Y (2018) Application of stem cell technology in antiaging and aging-related diseases. In Advances in Experimental Medicine and Biology1086: 255-265.
Citation: Bhattarai E, Almutawa YM, Gautam N, Zhao J (2020) Stem Cells and Their Potential Applications in Dermatology. J Stem Cell Res Dev Ther 6: 043.
Copyright: © 2020 Emma Bhattarai, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.