Journal of Stem Cells Research Development & Therapy Category: Medical Type: Research Article
Use of Stem Cells in Intervention Dermatology and Trichology: A New Hope
- Suruchi Garg1*, Himabindu Saginatham2, Ami Badheka2
- 1 Department Of Dermatology, Aesthetic Surgery And Intervention Dermatology, Aura Skin Institute, Chandigarh, India
- 2 Department Of Dermatology, Aesthetic Surgery And Intervention Dermatology, Aura Skin Institute, India
*Corresponding Author:Suruchi Garg
Department Of Dermatology, Aesthetic Surgery And Intervention Dermatology, Aura Skin Institute, Chandigarh, India
Received Date: Mar 20, 2019 Accepted Date: Apr 05, 2019 Published Date: Apr 12, 2019
Properties of stem cells
Adult stem cells are defined by specific properties [3,4]:
• They are relatively undifferentiated both morphologically and functionally
• They provide a source for continuous renewal of cells and long-term tissue maintenance
• In vivo, they have a slow generation time, but the process can be triggered by various stimuli like injury and growth factors
• Adult stem cells are located in a specialized micro environment called ‘niche’, which contributes to stem cell activity and behavior
The most appealing feature of a stem cell is plasticity, also called trans differentiation, which implies its ability to cross the germ lines and differentiate into cells types other than germ line lineage or tissue they were derived from . Based on their ability to regenerate, stem cells can be classified as follows:
• Totipotent, as in they can differentiate into all cell lineages and embryonic tissue. Blastocyst up to 8 cell stage has this capacity
• Pluripotent cells which have the capacity to differentiate into all the 3 germ cell lineages, but not the extra-embryonic tissue
• Multipotent stem cells that can differentiate into different cells of same lineage
• Monopotent cells, as the name indicates can regenerate only one cell type
Functionally, a stem cell represents an undifferentiated cell that divides asymmetrically in to a stem cell, retaining its self-renewal capacity and a smaller cell called transient amplifying cells. Transient amplifying cells which have lost their capacity of continuous self-renewal, differentiates down a certain pathway. In mammals adult stem cells are identified in various locations of which common sites include hematopoietic system, central nervous system, cornea, skin. Among these, skin is the major source of stem cells due to its vast area, being the largest organ in the body and ease of accessibility. There are many different types of cells residing in the skin and these originate from multiple different embryonic sources . The epidermis originates from neuroectodermal cells that remain at the surface of the embryo after gastrulation. The epidermis usually begins as a single layer of cells which then gives rise to the hair follicle, sebaceous glands and inters follicular epidermis. Dermal fibroblasts, vessels, nerves, arrector pili muscles, immune cells in the dermis, and mature adipocytes in the subcutis are derived from mesoderm. Melanocytes and sensory nerve endings originate from neural crest. During adult life, the maintenance of these various types of cells is the function of stem cells located at their particular ‘niches.’
Identification of epidermal stem cells:
• All stem cells have the property of quiescence at normal conditions, and the multiplication rate triggered by various stimuli and growth factors [3,4], and this property has been utilized in their identification. Using this method all actively dividing cells within the epidermis are pulse-labelled with injections of a DNA precursor, such as tritiated thymidine or bromodeoxyuridine. This is then followed by a chase period (4–10 weeks) during which the label is lost from rapidly proliferating cells such as the transient amplifying cells as a result of proliferation-associated dilution, while the rarely dividing stem cells retain the label for prolonged periods and are therefore called label- retaining cells.
• The other method which makes use of this high proliferative capacity of epidermal stem cells is Colony Forming assay. Using this method the proliferative potential of cultured cells is assessed by examining the clonogenicity of individual cells through serial passage or colony forming efficacy. Based on this method, cells with a clonogenic or high proliferative capacity (stem cells) have been identified.
• Although these two methods help in the identification of epidermal stem cells, they do not allow for the easy isolation of living stem cells for further analysis therefore several epidermal stem cell markers have been identified.
Epidermal stem cells
Hair follicle stem cells
In each hair cycle, at the transition from the anagen to catagen phase, melanocytes in the hair bulb matrix undergo apoptosis with their reconstitution occurring at the beginning of the next anagen phase. Evidence from murine and human studies indicates that this reconstitution process is made possible by a population of follicular bulge stem cells committed to melanocyte differentiation. These melanocyte stem cells are usually quiescent but become activated and proliferate at the onset of the anagen phase leading to the repopulation of the hair follicle matrix with melanocytes that generate melanin leading to pigmentation of the hair shaft. In addition, the defective self-maintenance of these melanocytes stem cells, which is thought to be part of physiological ageing, may be the underlying cause of hair greying.
The melanocyte stem cell markers include Pax3 and MITF, also known as melanocyte master transcriptional regulator. Pax3 has been shown to maintain the undifferentiated state of stem cells while simultaneously functioning in initiation of the melanogenic cascade. MITF, which may play a role in stem cell maintenance within the bulge through an antiapoptotic effect mediated by induction of Bcl-2 expression, has been shown to be highly expressed in the human bulge and is believed to serve as a potential marker of this stem cell population.
A hair growth hypothesis has been proposed by Garg et al depicting the model of ‘Golden anchorage and molecular locking of ectodermal and mesenchymal components for hair follicle integrity and survival.’ The ‘Golden anchorage’comprises of stem cells, ectodermal basement membrane and portion of arrector pili muscle attached to bulge region. After stimulatory nephronectin signals from basement membrane, the ‘molecular locking’ of α8B1 integrin receptor with nephronectin takes place in stem cell and bulge portion of arrector pili muscle,which is essentialfor further migration of stem cells towards dermal papilla and aid in hairfollicle formation in anagen phase. The lock and key arrangement of nephronectin-integrin molecules also helps in holding the ectodermal and mesenchymal components together for follicular integrity and survival as depicted in figure 1.
A new population of stem cells, Bulge neural crest-derived stem cells, has been identified within the murine hair follicle bulge. These stem cells, with markers that differentiate them from other stem cells in the bulge, apparently have the ability to differentiate in vitro to keratinocytes, neurons, melanocytes, glial cells, smooth muscle cells and adipocytes. One of the markers which helped in the identification of this stem cell population is nestin, an intermediate filament protein expressed in the neuroepithelial stem cell cytoplasm and known to be a marker for neural stem cells. Although these nestin-positive cells do not contribute to the keratinocyte compartment in homeostatic conditions, they have been shown to enhance blood vessel formation during hair follicle growth.
Sebaceous gland progenitor cells
Stem cells in the interfollicular epidermis
Sweat gland stem cells
Skin Mesenchymal Stem Cells (MSCs)
Adipose Tissue Derived Stem Cells (AdSCs)
Extracutaneous sources of stem cells probably play a role in skin homeostasis and should be considered with respect to regenerative cell therapies in dermatology. These include mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, placenta, haematopoietic stem cells. Induced Pluripotent Stem Cells (iPSCs) are primary keratinocytes that can be reprogrammed into pluripotent stem cells, with at least 100-fold higher efficiency and twice as quickly compared with fibroblasts.
Method of preparation of follicular stem cell suspension
Post traumatic scar
He was given a cocktail therapy of pixel erbium YAG laser, platelet rich plasma therapy and autologous fat transplantation at our institute with the idea of scar revision .
Various treatment modalities have been used for the management of patterned hair loss like topical minoxidil solution, oral finasteride, peptide based therapies, Low Level Light Therapy (LLLT), Platelet Rich Plasma Therapy (PRP) etc, out of which minoxidil and finasteride have been approved by USFDA [9,23-25]. Since the response to these treatments is often inadequate, the hope lies on the regenerative medicine which uses the therapeutic potential of stem cell therapy.
Stem cells of various origins like follicular stem cells, bone marrow stem cells, adipose tissue, skin stem cells have been used in the management of alopecia. However, multipotent stem cells from the hair follicle and sebaceous glands are most commonly used, and are known by several therapeutic strategies that they help in reversing the pathological mechanisms contributing to hair loss, regeneration of complete hair follicle from bulge derived stem cells, and neogenesis of hair follicle from a stem cell culture using tissue engineering techniques [27-29]. Occipital hair, which are resistant to hormonal influences in androgenetic alopecia are considered the best source for extraction of stem cells .
Gentile et al., evaluated the effect of autologous hair follicle stem cell suspension over placebo in 11 patients, aged from 38-61 years with androgenetic alopecia and found that there was 29 ± 5% increase in the hair density in the treatment group as compared to < 1% in the group treated with placebo .
A double blinded, randomized controlled trial compared the efficacy of single session of intradermal injections of autologous bone marrow derived mononuclear cells versus follicular stem cell culture in resistant cases of alopecia areata and androgenetic alopecia of 20 patients each. There was very good improvement in both the groups, which is classified as >50-75% improvement in hair density, along with significant improvement in immunohistochemistry for stem cell markers and digital dermoscopy, at the end of 23 weeks after the session .
Sixty patients of androgenetic alopecia were randomized in to 2 groups to receive 3 monthly sessions of either autologous adipose tissue derived stem cell versus platelet rice plasma (PRP) therapy by Kadry et al. It was shown that the mean increase in hair density as evaluated by increase in the terminal and intermediate hair count was significantly higher compared to baseline in the group treated with adipose tissue derived stem cells (p<0.001 and p<0.001 respectively). However, terminal hair count was significantly higher in PRP therapy group (p=0.037), but no significant improvement in intermediate hair count. Mild side effects with post session headache, erythema and pain were more in the group treated with adipose tissue derived stem cells .
An open labelled pilot study evaluating the efficacy of follicular stem cell suspension in eight patients of alopecia areata showed excellent (>50%) improvement in 62.5% patients, good (10-50%) improvement in 25% patients and poor (<10%) improvement in 1 patient at the end of 6 months of therapy .
It has been reported as a coincidental finding that a treatment resistant, long-lasting case of alopecia universals in a 40 year old male, completely recovered after allogeneic hematopoietic stem cell transplantation given to treat chronic myeloid leukemia .
A retrospective study of 20 patients with alopecia areata, used autologous stromal vascular fraction showed that there was increased hair growth and decreased pull test 3 and 6 months after the treatment [hair density (85.1 ± 8.7 vs 121.1 ± 12.5 hair/cm2, P< 0.0001), hair diameter (60.5 ± 1.8 vs 80.8 ± 2.4μ, P < 0.0001) and pull-test values (4.4 ± 0.3 vs 0.8 ± 0.2, P < 0.0001), untreated versus 6 months post-operative)] .
Park et al demonstrated that combined ADSCs with autologous lipoaspirate cells administered intradermally to an aged skin patient resulted in an improvement in the texture of the skin and wrinkles and dermal thickness 8 weeks after treatment .
In a study by Amirkhani et al., 16 patients aged from 38-56 years underwent transplantation of autologous stromal vascular fraction in the nasolabial folds. They were assessed at the end of 6 months, and showed increased elasticity and density of dermis along with enrichment of vascular bed in the subcutis .
Kim et al. showed that co-culturing of melanocytes with Adipose Tissue Derived Stem Cells (AdSCs) had a better survival effect on melanocytes. Immunomodulatory properties of stem cells, owing to their ability to inhibit CD4/CD8 T cell infiltration and inflammatory cytokines have been suggested as a possible explanation for the above phenomenon .
An intrapatient comparison evaluating the efficacy of combined epidermal cell suspension and follicular cell suspension versus epidermal suspension alone in 5 patients with stable vitiligo, showed that the repigmentation was better with combination therapy, with 100% lesions showing >90% repigmentation in combination arm at the end of 16 weeks. Whereas, in the lesions treated with epidermal cell suspension alone, 80% lesions showed >75% repigmentation and 20% lesions had >90% repigmentation .
An observer blinded, randomized controlled, intrapatient trial in 30 patients of stable vitiligo, where in the lesions were divided in to 2 groups, to receive a combination of epidermal cell suspension and follicular cell suspension transplant versus epidermal cell suspension alone. At the end of 16 weeks following therapy, the results were better with combination therapy in terms of mean repigmentation (76% vs 57%), rapidity of repigmentation (48% vs. 31%) and color match (73% vs. 61%) .
Ismail et al., studied the effect of autologous bone marrow stem cell therapy in 20 patients with reconstructable chronic critical lower limb ischemia with no distal run off, and showed that 55% patients had decrease in rest pain at the end of 1 month after therapy, and this increased to 75% after 1 year and 80% after 2 years of therapy. Also, there was a 80% limb salvage rate at the end of 1 year .
An open labelled, pilot study of 15 patients with chronic non healing ulcers secondary to peripheral arterial disease and diabetes, were treated with stromal vascular fraction derived from abdomen as local intramuscular injections in 2 sessions, 2 months apart. When followed up at the end of 12 months, all ulcers were healed with 86.7% improvement in walking distance .
Raposio et al., evaluated the efficacy of enriched PRP (PRP mixed with adipose tissue derived stem cells) versus standard wound care therapy in an open labelled, case control study in which a single session of 5 ml injection of e-PRP were given around and base of the ulcer. At the end of 18 month follow up period both groups showed similar healing rates, however, wound closure was higher in the group treated with e-PRP .
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Citation:Garg S, Saginatham H, Badheka A (2019) Use of Stem Cells in Intervention Dermatology and Trichology: A New Hope. J Stem Cell Res Dev Ther: S1004.
Copyright: © 2019 Suruchi Garg, 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.