**1. Introduction**

In the United Kingdom, around 200,000 patients experience a chronic wound of varying type, ranging between ulcerations, scars, trauma and burns. Unfortunately, patient morbidity and in some cases mortality may result from such injuries for which chronic ulceration is a major factor [1–3]. One of these impacts is the reduced contribution to society by the individuals suffering from these chronic wounds including their inability to work [3]. In addition, healthcare treatment and hospitalisation for chronic wounds are costly [2] involving lengthy treatment and nursing care. In 2005 and 2006, the care of patients with a chronic wound costs the UK NHS approximately £2.3bn–£3.1bn each year, with £6.08 million in England lone being attributed to nursing care [4]. In the United States, approximately 6.5 million patients suffered from chronic wounds with expenses for wound care management exceeding US \$25 billion in 2009 [5]. Furthermore, infection is inevitable, which not only negatively affect wound healing but can also be life threatening, requiring more hospitalisation and increased healthcare expenditure [6] and repetitive treatment [7]. Consequently, both the society and the health sector are negatively affected by the burden of chronic wounds. Moreover, despite great progress in wound treatment including the implementation of growth factors and biological engineering of skin equivalents, present treatment options for burns and non‐healing chronic wounds are restricted and not always effective [8]. Engineered skin to aid the development of novel wound care strategies is limited by their construction from substances that are hard to be degraded, and do not always result in complete replication into normal uninjured skin. Furthermore, complete renewal of this model requires the alteration of immune responses to reduce fibrotic reactions in order to diminish scar production [9]. Gene therapy may also be limited by insufficient selection of target cells, the identification of the factors which may affect the introduction of genes or the inability to produce stable prolonged specific gene product which is the main problem with systemic gene therapy [10]. Additionally, biofilms give rise to hypoxic conditions. Therefore, there is an urgent need for new therapies for wounds with delayed healing [8]. Specific extracellular matrix (ECM) proteins equivalent to the skin, specific growth factors, mesenchymal stem cells (MSCs), fibroblasts or viable epithelial cells may, however, aid the wound‐healing process, and their addition to potential wound‐healing treatments may improve the efficacy of current therapeutic strategies [11]. The availability of MSCs in normal human skin [12], and their vital function in wound healing suggests that the exogenous application of such cells may represent a promising solution for the treatment of non‐healing wounds [13].

Mesenchymal stem cells (MSCs) are generally defined as self‐renewable, multi‐potent pro‐ genitor adult stem cells present in peripheral blood. *In vivo*, they have the ability to differentiate widely into many mesenchymal lineages such as cartilage, bone, muscle and adipose tissues [14]. Furthermore, MSCs have the ability to migrate from the bone marrow to an injured site and differentiate into functional skin cells [15]. *In vitro* they can be defined as fibroblast‐like cells capable of self‐renewal with the ability to adhere to plastic and subsequently differentiate into adipose, bone, cartilage tissue [16] as well as a multi‐layered epidermis‐like structure [17]. Paracrine factors secreted by MSCs are considered the principle factors with therapeutic potential for tissue wound healing [18] including growth factors, cytokines and chemokines which promote angiogenesis and wound repair [19–22]. Moreover, MSCs produce soluble factors that regulate cellular responses, angiogenesis formation and tissue remodelling [23] and play a vital role in each of the five phases of wound‐healing process including haemostasis, inflammation, proliferation, contraction and remodelling [11]. In addition, MSCs exert antimicrobial activity via the secretion of the antimicrobial peptide LL‐37 thereby preventing wound infection [24]. Furthermore, Tamama and Kerpedjieva [25] report that conditioned medium derived from the cell culture of MSCs (MSC‐CM) contains all the effector molecules secreted by MSCs which could be effectively utilised in tissue regeneration and wound healing. Collectively these data thus suggest that MSC‐CM may represent a novel therapeutic strategy for wound therapy, but the mechanisms mediating these events and exactly how MSCs contribute in skin regeneration remain undefined.
