Tropical Weight Loss
Tropical Weight Loss
Photo: Polina Tankilevitch
Skin tissue regeneration processes Superficial burns recover within two weeks and cause minimal scarring. The re-epithelization of partial thickness burns is ensured by keratinocyte migration from skin dermal appendages within a few hours of the injury.
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Read More »Cells are the main component of the tissue-engineered skin used for burn therapies (Table 1). They include both stem and somatic cells and can be divided into three main groups: autologous, allogeneic, and xenogeneic. One of the main trends in choosing a cell type for patient treatment is the use of autologous cells as they do not cause immune rejection and their tumorigenicity is low due to the absence of epigenetic manipulations. Nowadays, animal cells are not widely used for skin tissue regeneration, only ECM or its components that they synthesize. Plant stem cells, which are commonly applied in cosmetics, can be interesting as they have no use limitations when compared to animal and human cells. Of course, they cannot be used in skin substitute development as a cell component; but they can provide bioactive substances, which can improve the wound healing process [40]. Table 1 Somatic and stem cells used in skin tissue regeneration Full size table Fibroblasts and keratinocytes are common cells used in products for wound and burn healing [41]. Keratinocytes are the major cell component of the epidermis and responsible for its stratified structure and form numerous tight intercellular junctions. Fibroblasts are the main cell type of the dermis and produce ECM components and secrete various growth factors (TGF-β), cytokines (TNF-α), and matrix metalloproteinases, which ensure the ECM formation and keratinocyte proliferation and differentiation [16]. Commercial products such as Epicel, Cryoskin, and BioSeed-S contain keratinocytes; Dermagraft, TransCyte and Hyalograft 3D—fibroblasts; and Apligraf, Theraskin, and OrCell—a combination. The use of these cells enables the large-scale production of standardized product batches. However, these materials are mostly non-permanent bioactive dressings, which provide cytokines, ECM, and growth factors for the successful skin reparation [41,42,43]. Immune rejection is commonly reported with allogeneic fibroblasts and keratinocytes, [44] but this is mostly shown for allogeneic keratinocytes that can be explained by the difference in HLA expression and cytokine production [45]. Fetal fibroblasts are of particular interest because they can significantly improve skin repair due to the high expansion ability, low immunogenicity, and intense secretion of bioactive substances such as basic fibroblast growth factor, vascular endothelial growth factor, and keratinocyte growth factor. However, ethical issues limit their application [46,47,48,49]. Epidermal stem cells (ESC) are of particular interest for skin tissue regeneration as they have favorable features such as high proliferation rate and easy access and keep their potency and differentiation potential for long periods [65, 82]. They are one of the skin stem cell types, either heterogeneous or autogenous origins (Table 2). ESC are mostly connected to the process of skin regeneration [17]. They are rare, infrequently divide and generate short-lived and rapidly dividing cells, which are involved in the regeneration process [65]. Their main population, responsible for skin repair, is located in the basal layer of the epidermis; however, they can also be revealed in the base of sebaceous glands and the bulge region of hair follicles [6, 65, 82]. However, while working with ESC culture, we may face progressive aneuploidy or polyploidy and mutation accumulation after several passages. Moreover, as they can be easily derived from the patient’s skin and transplanted to the same patient, ESC are not restricted by ethical issues. Grafts containing autologous holoclones ESC have proven to be effective in treating vast skin defects: epidermolysis, skin and ocular burns, etc. [83, 84].
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Read More »Mesenchymal stromal cells (MSC) have similar (not identical) features as ESC and can be derived from various tissues, even the skin as mentioned previously [98]. They have a high differentiation potential and a certain degree of plasticity and may generate cells of mesodermal, ectodermal, and endodermal lineages [99]. Moreover, paracrine, trophic, and immunomodulatory MSC properties enable their clinical use [100, 101]. MSC can migrate to the injured tissues, differentiate, and regulate the tissue regeneration by the production of growth factors, cytokines, and chemokines [102]. Their immunomodulatory activity is based on the release of anti-inflammatory cytokines and the inhibition of proliferation of CD4+ and CD8+ natural killer cells, T cells, and B cells. MSC are considered to be hypoimmunogenic because they do not express class I and II molecules of the major histocompatibility complex (MHC) and co-stimulatory proteins (e.g., CD40, CD80, CD86). Therefore, the transplantation of allogenic MSC has a low risk of the immune rejection [103,104,105]. In burn therapy, adipose-derived stromal cells refined from the stromal vascular fraction are widely applied because of their easy access and isolation procedure and inspiring improvement of the healing processes [106,107,108]. They are showed to preserve their therapeutic effects after freezing that ensures their multiple use [109]. It is worth mentioning that even the freshly isolated stromal vascular fraction is showed to be effective in burn therapy [110], but compared to adipose-derived stromal cells, it can release high concentrations of inflammatory mediators [111]. However, the number of randomized controlled preclinical and clinical trials remains insufficient [106]. Among the MSC derived from other tissues (adipose tissue, umbilical cord, etc.) the MSC derived from bone marrow (BMSC) requires special attention. They also possess plasticity and can differentiate into tissues of mesodermal, ectodermal, and endodermal origin [112, 113]. BMSC are considered to participate in the skin development. It has been reported that bone marrow can generate not only hematopoietic and mesenchymal cells but also fibroblast-like cells that are located in the dermis and actively proliferate in the skin during the regeneration processes [69, 114, 115]. The possible disadvantages of BMSC are that the tumor microenvironment may induce changes in the angiogenesis ability and anti-tumor response. Moreover, they may generate tumor-associated fibroblasts and shift a normal immune cell phenotype to an immunosuppressive and tumor promoting one [116]. However, nowadays, the greatest interest in tissue regeneration belongs to induced pluripotent stem cells (iPSC); using somatic cell reprogramming like a magic wand, we can develop patient-specific cells with a tailored phenotype and apply them in clinics [117]. The most commonly used cells for cell reprogramming are dermal fibroblasts, melanocytes, and keratinocytes since they can be easily accessed and isolated from punch biopsies [118]. Research has shown that both murine and human iPSC can be differentiated into dermal fibroblasts [119], keratinocytes [120], and melanocytes [121], opening a door for iPSC technology into dermatology applications. The interesting fact is that fibroblasts achieved via this technique may show increased properties compared to those of the parental fibroblasts, e.g., the exceeded ECM production [122]. This might be related to the changed epigenetic signature that occurs during iPSC differentiation and is critical for their use in skin tissue regeneration. However, when cells are reprogrammed with tumorigenic c-Myc and this transgene remains in iPSC, the risk of tumor formation increases, because c-Myc might be reactivated [123]. Since modern methods for cell purification cannot ensure the full separation of differentiated cells from iPSC, undifferentiated and partly differentiated cells may be implanted into a patient and increase the possibility of tumor formation [124].
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