Burn injure caused by heat, friction, electricity, or exposure to chemicals results severe damage to tissues (1). According to the World Health Organization report, approximately 11 million cases of various types of burns occur worldwide each year and cause approximately 180,000 deaths (2). Approximately 90% of burns are caused by thermal injury, while less than 5% are electrical and 3% are chemical (3). However, chemical burn injuries can have a disproportionately large physical and psychosocial impact on patients (4), due to that protein denaturation in acid burns and deeper tissue penetration in alkaline burns (5).

Immediately after injury, inflammatory reaction was initiated with infiltration of neutrophils and later, macrophages (6). However, long lasting infiltration of these inflammatory cells leads to persisting and accumulative expression of inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) within wound area, resulting delayed wound healing (7). Healing of wounds largely dependents on quick neovascularization to restore oxygen and nutrient supply to the injured tissue 8, 9. Under pathological circumstances, such as diabetes mellitus, process of angiogenesis was impaired as a consequence of damaged function of endothelial cells, which contributes to delayed healing of wounds or even results non-healing(10). Adipose-derived stem cells (ADSCs) represent a promising cellular candidate for tissue repair due to their nature in modulation of angiogenesis. The ability of ADSCs to promote tissue repair has also been confirmed by several in vitro and in vivo experiments 11, 12. It was shown by Fujiwara (13) et al that expression of VEGF was increased nearly by 4-fold with topical application of ADSCs in burn wounds. However, the abnormal accumulation of oxidative stress, highly activation of inflammation and poor supply of blood and nutrition within wound greatly decrease the survival and maintenance of transplanted ADSCs in the damaged tissue (14). To this end, pretreating ADSCs prior to transplantation have been proposed in an attempt to enhance ADSCs survival. For example, pretreatment with stromal cell-derived factor-1 (SDF-1) resulted approximately 2-fold increase in survival of ADSCs in diabetic wounds (15). By suppressing intracellular level of reactive oxygen species (ROS) via pretreatment with salidroside, apoptotic rate of engrafted MSCs in wound was reduced by 13.93% in the context of hyperglycemia as compared with that of without pretreatment (16). Moreover, healing of acid burn wound was reduced from 11.9 ± 0.67 to 9.1 ± 0.68 days with local administration of ADSCs preconditioned with ascorbic acid (17). Together, these results suggest that preconditioning approaches improved the ability of ADSCs to heal wounds via enhanced survival and paracrine production.

Alpha-ketoglutarate (α-KG) is a key intermediate of the tricarboxylic acid cycle and plays an important role in a variety of biological processes, including energy metabolism, antioxidant and anti-inflammation (18). α-KG supplementation was shown to reduce the levels of systemic inflammatory cytokines (such as interleukin IL-6, and tumor necrosis factor-alpha (TNF-α) in aging mice (19). These pushed us to question whether preconditioning ADSCs with α-KG could prolong survival of engrafted ADSCs and thus accelerate healing of acid burn wound.

In the present study, we explored the therapeutic effects of α-KG preconditioning ADSCs on chemical burn wounds. We found that ADSCs preconditioned with α-KG significantly promoted the healing of burn wounds, with concomitant increase in cell survival rate and expression of pro-angiogenic factors. These results suggest that injection of α-KG preconditioned ADSCs may provide a therapeutic avenue for treating cutaneous wounds.