Dongyun Gao1, Chengwei Gu2, Yan Wu3, Jiangfan Xie4, Bin Yao4, Jiwei Li5, Changjiang Feng5, Jin Wang6, Xu Wu7, Sha Huang8, Xiaobing Fu9. 1. 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. 2. 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. 3. 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; Heilongjiang Key Laboratory of Anti-fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, PR China. 4. 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. 5. 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. 6. Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. 7. Department of Thoracic and Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. Electronic address: 13926402695@126.com. 8. 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; Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, PR China; Hainan Branch of the Chinese PLA General Hospital, Sanya, Hainan Province, PR China. Electronic address: stellarahuang@sina.com. 9. 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; Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, PR China. Electronic address: fuxiaobing@vip.sina.com.
Abstract
BACKGROUND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.