Wound healing studies have subsequently focused on MSCs as the potential cell population within bone marrow that can contribute to cutaneous regeneration. Studies in both mice and humans have consistently demonstrated enhanced wound repair following treatment with bone marrow-derived MSCs (Table ).
Study design and results for treatment of cutaneous wounds with mesenchymal stem cell therapy.
The use of murine models has been crucial for advancing the understating of wound healing, however, fundamental differences exist between the mouse and human skin. Murine skin lacks apocrine sweat glands and rete ridges/dermal papillae, which are both found in human skin. However, rete ridge-like structures may become apparent during mouse wound healing and are often described as “pseudoepitheliomatous” or “pseudocarcinomatous hyperplasia” (Sundberg, 2004
). Mouse skin also has a panniculosus carnosus layer, a thin subcutaneous muscle layer only found in the human neck (platysma). This muscle layer produces rapid wound contraction following injury which is the primary method of wound healing in the mouse as opposed to granulation tissue formation and re-epithelialization in humans. Mouse skin has also been shown to be thinner and more compliant than human skin (Aarabi et al., 2007
). A more complete summary of murine wound healing models is reviewed here (Wong et al., 2011b
Experiments with diabetic murine models have been particularly useful in assessing the clinical utility of MSCs in wound repair. Many non-healing ulcers are caused by diabetic pathology which has been shown to attenuate the recruitment of inflammatory cells and down-regulate expression of various growth factors (Falanga, 2005
). Local delivery of MSCs significantly increased granulation tissue formation and decreased wound healing time in leptin receptor-deficient db/db diabetic mice compared to those treated with either PBS or non-cell type-specific bone marrow aspirate (Javazon et al., 2007
). Analysis of the mechanical properties of treated wounds revealed that administration of MSCs not only accelerated wound closure but also enhanced wound repair quality, resulting in healed tissue with increased tensile strength. This effect is thought to be secondary to increased collagen composition within the healed tissue (McFarlin et al., 2006
; Kwon et al., 2008
). The mechanism for this observed increase in collagen secretion is currently under investigation.
Promising findings in animal models have led to a very limited number of small-scale human trials examining the effects of autologous MSCs on chronic wounds. Injection of primary bone marrow cells into the wound edge followed by topical application of cultured MSCs resulted in the complete closure of three chronic wounds which had failed traditional therapy including autologous skin grafting (Badiavas and Falanga, 2003
). Hallmarks of the healing wounds were a massive influx of mature and immature inflammatory cells, increased vascularity, and increased dermal thickness. It must be noted that this study utilized the injection of whole bone marrow aspirate which includes a large and mixed population of hematopoietic stem cells and inflammatory cells.
Dash et al. conducted the only randomized controlled trial investigating the use of MSCs in 24 patients with non-healing lower extremity ulcers secondary to diabetes or vasculitis. Autologous MSCs expanded in culture were injected intramuscularly into the wound edges of the treatment group. Twelve weeks after implantation, ulcer size in the MSC-treated group decreased 73% while those receiving standard wound care only decreased 23%. In addition, subjects receiving MSC injections increased their pain-free walking distance 7.5-fold compared to 2.2-fold in the control group with no reported adverse effects (Dash et al., 2009
). Increased numbers of mature immune cells in the dermis of wound biopsies in the treatment group suggest an augmented inflammatory response as a possible mechanism for enhanced repair.