The materials currently used in soft tissue regeneration, which include collagen, hyaluronic acid, silicon, and other filler materials, have several disadvantages such as high cost, immunogenicity/allergenicity, and the risk of transmitting infectious diseases. Meanwhile, autologous fat grafts are more widely available; however, one limitation of this technique is the poor long-term graft retention in current clinical practice (Min et al., 2010). The transplanted fat grafts can lose volume over time due to tissue resorption that can result in the loss of 20-90% of the original graft volume (Cherubino et al., 2009). The ideal solution for soft tissue regeneration would promote the regeneration of vascularized adipose tissue to completely fill the defect volume (Brayfield et al., 2010).

Recently, Frerich et al. (2005) reported an in vitro co-culture model using human adipose stromal cells and human umbilical vein ECs, where perfused tubes formed capillary-like networks that sprouted from the central lumen wall. Kang et al. (2009) developed an in vitro 3D model of tissue regeneration in which human vascularized adipose tissue, human ASCs, and human umbilical vein ECs were co-cultured on 3D aqueous silk scaffolds. After two weeks of co-culture, continuous endothelial lumens formed. Furthermore, Min et al. (2010) demonstrated in an in vivo murine model that the transplantation of fat tissue with non-cultured ASCs improved long-term graft retention. Compared with transplanted fat tissue alone, fat tissue transplanted with non-cultured ASCs had a higher density of capillaries six and nine months after transplantation. The reasons for these successful results might be the pro-angiogenic growth factors secreted by ASCs, as described previously.

Wound healing might be interrupted by a variety of pathological conditions, such as diabetes, radiation and immunosuppression, resulting in refractory chronic wounds (Lorens et al., 2006). Growth factors involved in wound healing have been individually applied to the wound to promote wound healing in unfavorable conditions. However, the theoretical promise of this approach was unfulfilled due to the complex nature of wound healing, which involves a number of different growth factors (Ebrahimian et al., 2009; Brem et al., 2009). To achieve optimal results, all these growth factors should be applied continuously, as opposed to the intermittent applications of individual growth factors (Brem et al., 2009; Blanton et al., 2009).

ASCs secrete nearly all of the growth factors that take part in normal wound healing (Ebrahimian et al., 2009; Blanton et al., 2009; Kim et al., 2007; Rehman et al., 2004). After application, ASCs may remain viable at the wound site and secrete growth factors in a continuous and regulated manner in response to environmental cues, just as occurs in the natural wound healing process (Badillo et al., 2007). ASCs promote wound healing by increasing vessel density, granulation tissue thickness, and collagen deposition (Ebrahimian et al., 2009), and they also improve the cosmetic appearance of resultant scars (Blanton et al., 2009).

A ready blood supply is crucial for wound healing. VEGF secreted from ASCs induces the migration and proliferation of ECs, increasing the vascularity of the wound bed (Lorens et al., 2006; Rehman et al., 2004). It was both experimentally and clinically shown that the topical administration of ASCs to full-thickness radiated wounds increase the healing rate of the wound (Ebrahimian et al., 2009; Rigotti et al., 2007). Kim et al. (2007) demonstrated that ASCs stimulate fibroblast proliferation and migration and type I collagen secretion in an in vitro wound model. These findings suggest that ASCs may promote in vivo wound healing.

Musculoskeletal Regeneration

Current therapeutic approaches for muscle loss cannot restore muscle function effectively. ASCs can differentiate into chondrogenic, osteogenic, and myogenic cells in vitro, and thus could potentially be used to regenerate tissue in musculoskeletal system disorders (Zuk et al., 2001; Mizuno et al., 2002).

Muscle tissue contains muscle progenitor cells called satellite cells that lie underneath the basal lamina (Kim et al., 2006; Di Rocco et al., 2006; Mizuno et al., 2002). These cells can divide and fuse to repair or replace damaged fibers in response to acute muscle injury or in chronic degenerative myopathies (Kim et al., 2006; Mizuno et al., 2002). However, continuous muscle degeneration-regeneration cycles in chronic cases lead to a depletion of the satellite cell pool. Moreover, it is difficult to expand satellite cells in vitro and they rapidly undergo senescence (Di Rocco et al., 2006; Mizuno et al., 2002).

ASCs may provide an easily accessible and expandable alternative cell source for the cellular therapy of muscular disorders. ASCs were successfully differentiated into skeletal muscle cells and smooth muscle cells in vitro (Jeon et al., 2010; Mizuno et al., 2002; Di Rocco et al., 2006). Differentiated ASCs even exhibited a contractile function similar to that of smooth muscle cells in vivo (Rodríguez et al., 2006). ASCs have also shown a capacity for myogenic differentiation in vivo. Allogeneic ASCs injected intravenously or directly into the affected muscle could restore muscle function in a murine muscular dystrophy model without any signs of immune rejection (Di Rocco et al., 2006). In another study, poly lactic-co glycolic acid (PLGA) spheres attached to myogenically-induced ASCs were injected subcutaneously into athymic nude mice. Injected ASCs differentiated into muscle cells and regenerated into new muscular tissue (Kim et al., 2006). However, it is still unclear whether ASCs directly differentiate into myogenic lineage cells or whether they become incorporated into muscle fibers via cell fusion. It is likely that ASCs contain different subsets of cells capable of either function (Di Rocco et al., 2006).

ASCs can form osteoid in vitro and in vivo (Hattori et al., 2004). ASCs combined with biomaterials were successfully used to repair critical bone defects (Di Bella et al., 2008; Yoon et al., 2007). Moreover, ASCs secrete osteoinductive growth factors, which may potentially recruit host bone-forming cells and induce osteogenesis when implanted in vivo (Hao et al., 2010). ASCs genetically modified to secrete bone morphogenic protein-2 (BMP-2) may also be an effective method for enhancing bone healing (Peterson et al., 2005).

Use of ASCs in intervertebral disc regeneration has also been reported (Hoogendoorn et al., 2008). Other applications of ASCs in musculoskeletal system are periodontal tissue regeneration and tendon regeneration. Tobita et al. (2008) reported that implanted ASCs were differentiated into the periodontal tissues including alveolar bone, cementum, and periodontal ligament in a rat model. In addition, topical administration of ASCs to tendon repair sites in rabbits accelerated tendon repair and significantly increased tensile strength (Uysal et al., 2011).

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