Potential of stem cells for skin regeneration following burns

Burn injury has been reported to be an important cause of morbidity and mortality in many countries. It leads to a loss of integrity of the skin, which protects us from water loss, temperature change, radiation, trauma and infection. The burn wound is defined in terms of the evolving injury that occurs. In adults, the normal repair of massive full-thickness burns is fibrosis and scarring without any appendages, including hair follicles, sweat and sebaceous glands. Autologous skin grafting followed by application of an elastic bandage has been considered to be a better treatment for excised burn wounds. However, donor sites for autografts are limited in those patients with very large burns. Recently, great progress has been achieved in the research of artificial skin substitutes, however, creating a viable skin substitute by assembling individual components in vitro has not been successful [1]. Furthermore, during the healing process of deep partial or full-thickness burns treated by the known skin substitutes, wound contraction and scar formation are still unavoidable. At present, the substitutes containing stem cells do not only temporarily prevent the loss of body fluids and bacterial infection, but also achieve satisfactory repairing effects [2]. Optimum healing of a burn wound requires a well-orchestrated integration of the complex biological and molecular events of cell migration and proliferation, and of extracellular matrix deposition and remodeling [3]. Stem cell therapy can improve the quality of burn wound healing, reduce the formation of scars and re-establish the normal function of the skin and its appendages.

The main sources of stem cells that might be used for repair and regeneration of injured skin tissue are embryonic stem cells (ESCs) and adult stem cells. ESCs have a great capacity for self-renewal and pluripotency, but their clinical applications are limited because of the political and ethical considerations. In 2007, Yamanaka and coworkers successfully produced induced pluripotent stem cells from adult human dermal fibroblasts and other human somatic cells [4], which have similar characteristics as ESCs [5]. However, whether induced pluripotent stem cells can be used in burn treatment is remains questionable.

Encouragingly, the use of adult stem cells, especially mesenchymal stem cells (MSCs), is becoming more realistic in burn treatment. MSCs can be isolated from bone marrow and other tissues, such as adipose tissue, umbilical cord blood and skin tissue. For instance, rapid regeneration of burn wounds can be achieved after the transplantation of allogenic or autologous bone marrow MSCs (BMSCs) in Wistar rats [6]. Furthermore, BMSCs have the potential to differentiate into epidermal cells and fibroblasts in vitro, and combined with a scaffold can accelerate the skin wound repair significantly in vivo, demonstrating the clinical feasibility of BMSCs acting as the seed cells in skin tissue engineering [7]. Stem cells from umbilical cord blood are able to differentiate into keratinocytes under in vitro conditions [8]. We can obtain stem cells not only from the outside of the skin but also from the local skin. Roh and Lyle have proved that stem cells extracted from the human bulge region can differentiate into hair follicle, epidermal and sebaceous cells in vitro[9]. Moreover, adipose-derived stem cells (ADSCs) can promote human dermal fibroblast proliferation and the re-epithelialization of cutaneous wounds [10]. These studies indicate the definite contribution of stem cells in skin wound repair. However, questions regarding whether patients with a burn will accommodate stem cell therapy and what the benefit of stem cell therapy in burn wound healing may be still need to be answered. Stem cell research for skin regeneration following burns may have important clinical significance.

Cell therapy is the transplantation, through local delivery or systemic infusion, of autologous or allogeneic cells to restore the viability or function of deficient tissues [11]. The use of stem cell treatment for burn wounds is an extremely difficult challenge, in which several key issues of stem cells in wound healing must be illuminated.

First, stem cells have properties of self-renewal and multipotency. Adult stem cells can produce differentiated skin cells. BMSCs can differentiate into multiple skin cell types and contribute to wound repair [12]. Labeled BMSCs can be observed in the epidermis [13], hair follicles, sebaceous glands, blood vessels and dermis in full-thickness wounds. The incorporated cells in hair follicles and sebaceous glands are positive for pan-cytokeratin [14–16]. ADSCs, which are delivered via the acellular dermal matrix, can survive after in vivo engraftment, spontaneously differentiate along the vascular endothelial, fibroblastic and epidermal epithelial lineages and significantly improve wound healing [17]. A few scholars think that the plasticity of stem cells is due to the cell fusion between adult stem cells and skin cells [18], but we think that the plasticity of stem cells is definite, and the stem cell niche (microenvironment) plays an important role in regulating the balance of self-renewal and differentiation in all stem cells. Thus, it is important to note that creating a suitable microenvironment is the key issue for stem cells to survive and participate in regeneration and repair of a burn wound.

Second, the paracrine effect of adult stem cells can promote the progress of wound healing. An in vitro study indicated that collagen synthesis and levels of bFGF and VEGF were much higher in BMSCs than those in dermal fibroblasts. Fathke et al. showed that the BMSCs were able to transcribe types I and III collagen, whereas the wound-resident cells transcribed only type I collagen [14]. In an excisional wound splinting model in diabetic mice, wounds to which allogeneic BMSCs were applied demonstrated accelerated closure and high levels of VEGF and angiopoietin-1, suggesting that BMSCs had promoted wound healing through a direct contribution and release of proangiogenic factors [19]. ADSCs promote human dermal fibroblast proliferation by direct cell-to-cell contact and by induced paracrine activation, which significantly accelerates the re-epithelialization of cutaneous wounds [10]. These studies suggest that the ability of adult stem cells to alter the tissue microenvironment via secretion of soluble factors may contribute more significantly than their multipotential differentiation to tissue repair [20,21].

Finally, adult stem cells can modulate the immune and inflammatory responses to promote wound healing. The transplantation of autologous and allogeneic MSCs on the surface of deep burn wounds in rats decreases inflammatory cell infiltration into the wound, and accelerates the formation of new vessels and granulation tissue [6]. After skin tissue injury, multipotent stem cells mobilize from the bone marrow into the pool of circulating cells. These cells migrate to the site of injury, and regulate the proliferation and migration of epithelial cells/dermal mesenchymal cells (MCs) during the early inflammatory phase [14]. It has also been identified that MSC subpopulations can express high levels of the IL-1 receptor antagonist [22] and inhibit inflammatory and immune responses [23]. A subpopulation of bone marrow-derived cells that integrate into the healed wound often play a useful role as antigen-presenting cells [14]. Adult stem cell therapy reduces the intensity of inflammatory cell infiltration and activates the vessel formation. Thus, it promotes normal interactions between cell assemblies during the regeneration of burn wounds, which prevents the formation of cicatrix or the deformation of tissues [24,25].

Taken together, it has been demonstrated that stem cells contribute to wound repair via several of their properties, including multipotency, the paracrine effect and immunosuppression. Stem cell therapy may be an attractive therapeutic tool for future burn treatment.

Although the treatment of burn wounds with adult stem cell therapy has been much improved [26], there are still many problems that need to be resolved before stem cells can be widely used clinically [27]. Data from the preliminary studies are not sufficient to show whether these new skin cells and appendages (including keratinocytes, the sebaceous glands and sweat glands) regenerated by stem cells are functional. Furthermore, the plasticity of stem cells may be a double-edged sword and instability of cellular phenotypes may lead to the deterioration of the structure and/or function of tissues, and may eventually give rise to malignant cells. In addition, the mechanisms of controlling stem cell aging largely remain a mystery. Some data suggest that bone marrow-derived cells from older patients may be poor candidates for therapeutic use and could actually harm them [28].

Currently, there are several approaches for utilizing stem cells, including cell suspension injection, cell sheet or tissue-engineered skin. Which one is the optimum approach and which type of stem cell (autologous or allogenic stem cells) is suitable for clinical practice? Further clinical studies are required to determine the effectiveness of these approaches.

It would certainly be a big mistake to underestimate the complexity of stem cell biological behavior and the clinical applications. Nevertheless, research progress in this field will undoubtedly have many more implications in the burns practice throughout the world.

Financial & competing interests disclosure

This editorial is supported by funding from the Development of High and New Science and Technology (863 Project) of China (2006AA02A119). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.