Fat-Derived Mesenchymal Stem Cells Aid Wound Healing

Breaches in the skin produce wounds that have the ability to heal, but take time to do so. During the time prior to healing, the wound is subject to irritation, pain, and infection. Speeding up wound healing is a necessary to prevent wound infections and other wound-related morbidities.

Wound healing requires a somewhat complicated chain of events that includes interactions with nearby cells and tissues. Wound healing is slower in patients with conditions such as type 1 diabetes mellitis. New therapeutic methods are available for chronic wounds, but there are no satisfactory methods for treating chronic wounds that stubbornly refuse to heal.

Stem cell treatments have been tested as potential treatments for chronic wounds. Mesenchymal stem cells (MSCs) from bone marrow can accelerate wound healing in a rodent model system (see Wu Y, et al., “Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648-2659, & Chen L, et al., “Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing.” PLoS One 2008;3:e1886). However, the acquisition of a patient’s bone marrow MSCs requires bone marrow aspirations, and if a patient already has a chronic wound that refuses to heal, introducing anther lesion is probably not a good idea.

Therefore, a South Korean research group as tried to use fat-based MSCs, or adipose tissue-derived MSCs (ADSCs) to accelerate wound healing in a rodent model system. The paper reference is Seung Ho Lee, et al., “Effects of Human Adipose-derived Stem Cells on Cutaneous Wound Healing in Nude Mice,” Ann Dermatol Vol. 23, No. 2, 2011 DOI: 10.5021/ad.2011.23.2.150, and it can be found at this link.

In this work, Lee and his team counted on earlier work that showed that ADSCs improved wound healing in mice that suffered from an inherited form of type 2 diabetes mellitis (Nambu M, et al., “Accelerated wound healing in healing-impaired db/db mice by autologous adipose tissue-derived stromal cells combined with atelocollagen matrix,” Ann Plast Surg 2009;62:317-321.). In other experiments, human ADSCs accelerated the closure of wounds in nude mice (Kim WS, et al., “Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts,” J Dermatol Sci 2007;48:15-24). Nude mice have a mutation in the FOXN1 gene, which causes them to be born without a thymus gland or body fur. The lack of a thymus gland means that they do not have T cells and this makes them unable to reject tissues that are transplanted into them.

In this study Lee and his colleagues determined the benefits of human ADSCs in wound healing on a nude mice. They used a contraction-preventing splint method, and covered each wound with either ADSC-populated collagen gels (CG), human dermal fibroblast (DFs)-populated CG, or CG alone. They measured the size and thickness of the wounds after healing, and examined the histology of the wounds once they had healed.

The results were rather clear. Wound sizes after ASC treatment was significantly smaller than those wounds that were treated with CG alone (28.63±5.05 mm2, 54.63±5.69 mm2, p<0.05). Wounds treated with DFs healed significantly faster than wounds treated with either ASCs and CG alone (11.09±2.71 mm2, p<0.05). However, when the healed tissue was excised and examined under the microscope, the dermal portion of ASCs-treated wounds was thicker than the others, but the DF-treated wounds was thicker than those treated with CG alone (84.50±4.39μm, 75.78±4.52μm, 51.61±2.31μm, p<0.05).

Dermal fibroblasts (DFs) accelerated wounds faster than ADSCs.   Several reports in the literature have shown that DFs can accelerate cutaneous wound healing.  When seeded in a collagen sponge matrix, DFs facilitated dermal and epidermal wound healing better than wounds treated with the collagen sponge only.  Skin substitutes with dermal components that contain DFs induce the proliferation and differentiation of skin cells (keratinocytes) and increase formation of basement membrane.  Both of these accelerate wound re-epithelialization (Okamoto E, Kitano Y. Expression of basement membrane components in skin equivalents–influence of dermal fibroblasts. J Dermatol Sci 1993;5:81-88; Maruguchi T, Maruguchi Y, Suzuki S, Matsuda K, Toda K, Isshiki N. A new skin equivalent: keratinocytes proliferated and differentiated on collagen sponge containing fibroblasts. Plast Reconstr Surg 1994;93:537-546; Medalie DA, Eming SA, Collins ME, Tompkins RG, Yarmush ML, Morgan JR. Differences in dermal analogs influence subsequent pigmentation, epidermal differentiation, basement membrane, and rete ridge formation of transplanted composite skin grafts. Transplantation 1997;64:454-465).

Thus, the Lee paper supports this previous work, but other work suggests that DFs may not help patients with diabetes mellitis and have chronic wounds (Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648-2659).  Therefore, even though DFs seem to accelerate wound healing in non-diabetic mice, ADSCs are able to accelerate wound healing in diabetic mice, and therefore might be even more useful for patients.

Furthermore, DFs have other clinical limitations in that they must be isolated from a patient’s own skin.  Also, the ability of DFs to be detected by the immune system could also limit their ability to heal wounds.  ADSCs, on the other hand, are easily isolated by liposuction, are poorly recognized by the immune system, and might accelerate wound healing.  In conclusion, ADSCs might provide a treatment regime for chronic wounds and help those who suffer from such things experience wound closure.