Gao Dongyun, Gu Chengwei, Wu Yan, Xie Jiangfan, Yao Bin, Li Jiwei, Feng Changjiang, Wang Jin, Wu Xu, Huang Sha, Fu Xiaobing
Department of Thoracic and Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China; Key Laboratory of Wound Repair and Regeneration of Chinese People's Liberation Army (PLA), The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, PR China; Department of Oncology, Dongtai People's Hospital, Dongtai, PR China.
Department of Thoracic and Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China; Key Laboratory of Wound Repair and Regeneration of Chinese People's Liberation Army (PLA), The First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing, PR China; Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, PR China.
Cytotherapy. 2014 Nov;16(11):1467-1475. doi: 10.1016/j.jcyt.2014.05.014.
Mesenchymal stromal cells (MSCs) have been documented to improve delayed wound healing in diabetes, but the underlying mechanism remains obscure. We aimed to investigate whether the therapeutic effects on wounds was associated with metabolic alterations by paracrine action of MSCs.
MSCs from mice with high-fat diet/streptozotocin-induced diabetes or wild-type C57BL/6 mice were evaluated for their paracrine potential in vitro using enzyme-linked immunosorbent assay and immunohistochemical staining assay. MSCs were then evaluated for their therapeutic potential in vivo using an excisional cutaneous wound model in mice with diabetes. Metabolic alterations and glucose transporter four (GLUT4) as well as PI3K/Akt signaling pathway expression after wounding were also examined.
MSCs from normal mice expressed even more insulin-like growth factor-1 (IGF-1) than mice with diabetes, suggesting putative paracrine action. Furthermore, compared with IGF-1 knockdown MSCs, normal MSCs markedly accelerated wound healing, as revealed by higher wound closure rate and better healing quality at 21 days post-wound. By contrast, MSCs administration increased the level of insulin as well as GLUT4 and PI3K/Akt signaling pathway expression but repressed the biochemical indexes of glucose and lipid, resulting in obvious metabolic improvement.
These findings suggest that IGF-1 is an important paracrine factor that mediates the therapeutic effects of MSCs on wound healing in diabetes, and the benefits of MSCs may be associated with metabolism improvements, which would provide a new target for treatment.
间充质基质细胞（MSCs）已被证明可改善糖尿病患者延迟的伤口愈合，但其潜在机制仍不清楚。我们旨在研究MSCs对伤口的治疗作用是否与通过旁分泌作用引起的代谢改变有关。
使用酶联免疫吸附测定和免疫组织化学染色测定法，在体外评估高脂饮食/链脲佐菌素诱导的糖尿病小鼠或野生型C57BL/6小鼠的MSCs的旁分泌潜力。然后，使用糖尿病小鼠的切除性皮肤伤口模型在体内评估MSCs的治疗潜力。还检查了伤口后代谢改变以及葡萄糖转运蛋白4（GLUT4）和PI3K/Akt信号通路的表达。
正常小鼠的MSCs比糖尿病小鼠表达更多的胰岛素样生长因子-1（IGF-1），提示可能存在旁分泌作用。此外，与IGF-1基因敲低的MSCs相比，正常MSCs显著加速了伤口愈合，伤口后21天时伤口闭合率更高，愈合质量更好。相比之下，给予MSCs可提高胰岛素水平以及GLUT4和PI3K/Akt信号通路的表达，但可降低血糖和血脂的生化指标，从而导致明显的代谢改善。
这些发现表明，IGF-1是介导MSCs对糖尿病伤口愈合治疗作用的重要旁分泌因子，MSCs的益处可能与代谢改善有关，这将为治疗提供新的靶点。
