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Citation: Zhang Y,Han F,He T,et al.Effects and mechanism of hepatocyte growth factor-modified human adipose mesenchymal stem cells on wound healing of full-thickness skin defects in diabetic rats[J].Chin J Burns,2021,37(9):860-868.DOI: 10.3760/cma.j.cn501120-20200626-00329.

Effects and mechanism of hepatocyte growth factor-modified human adipose mesenchymal stem cells on wound healing of full-thickness skin defects in diabetic rats

doi: 10.3760/cma.j.cn501120-20200626-00329
Funds:

General Program of National Natural Science Foundation of China 81871561

Youth Science Foundation of National Natural Science Foundation of China 82002039

More Information
  •   Objective  To investigate the effects and mechanism of hepatocyte growth factor (HGF)-modified human adipose mesenchymal stem cells (ADSCs) on the wound healing of full-thickness skin defects in diabetic rats.  Methods  The experimental research method was adopted. The discarded abdominal adipose tissue was collected from a 35-year-old healthy female who underwent abdominal liposuction in the Department of Plastic Surgery of the First Affiliated Hospital of Air Force Medical University in December 2019. The long spindle-shaped primary ADSCs were obtained by collagenase digestion, and the third passage of cells were identified by flow cytometry to positively express ADSCs surface markers CD29 and CD90 and negatively express CD34 and CD45. The third passage of ADSCs were used for the subsequent experiments. ADSCs were transfected with lentivirus-mediated HGF for 4 h (obtaining HGF modified ADSCs) and then routinely cultured for 24 h. The cell morphology was observed under an inverted phase contrast microscope, and the transfection rate was calculated. Eighty-one male Sprague-Dawley rats aged 4 weeks were induced into diabetic rat model by high glucose and high fat diet combined with streptozotocin injection. A full-thickness skin defect wound of 1.5 cm×1.5 cm was made on the back of each rat. The injured rats were divided into phosphate buffer solution (PBS) group, ADSCs alone group, and HGF-modified ADSCs group according to the random number table, with 27 rats in each group. The rats were injected with the same volume of corresponding substances around the wound on post injury day (PID) 1, 3, and 7, respectively. Nine rats in each group were selected according to the random number table, the wound area of whom was measured on PID 0 (immediately), 3, 7, 10, and 14 (after injection on injection day), and the wound healing rates on PID 3, 7, 10, and 14 were calculated. Nine remaining rats in each group were sacrificed after injection on PID 3 and 7, respectively, and the skin tissue around the wound were collected. The mRNA expressions of inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-10 on PID 3 and collagen type Ⅰ and Ⅲ on PID 7 were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction. The expression level of vascular endothelial growth factor (VEGF) was detected by enzyme-linked immunosorbent assay on PID 7. The protein expression of nuclear factor κb-p65 on PID 3 and phosphorylation level of protein kinase B (Akt) on PID 7 were detected by Western blotting. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, least significant difference t test, and Bonferroni correction.  Results  After 24 h of culture, the HGF-transfected human ADSCs showed good morphology, which was not different with the non-transfected ADSCs, and the transfection rate reached 90%. On PID 3, 7, 10, and 14, the wound healing rates of rats in HGF-modified ADSCs group were (31.5±1.0)%, (75.2±2.0)%, (92.2±1.3)%, and (99.1±1.8)%, respectively, being significantly higher than (21.4±1.3)%, (61.4±1.5)%, (80.1±2.1)%, and (92.4±1.8)% in PBS group and (25.1±2.1)%, (67.2±1.3)%, (89.3±1.4)%, and (95.1±2.1)% in ADSCs alone group (t=1.452, 0.393, 0.436, 0.211, 4.982, 3.011, 4.211, 7.503, P<0.05 or P<0.01). On PID 3, compared with those in PBS group and ADSCs alone group, the mRNA expressions of TNF-α and IL-1β and protein expression of nuclear factor κb-p65 in the skin tissue around the wound of rats in HGF-modified ADSCs group were significantly decreased (t=7.281, 17.700, 9.447, 6.231, 13.083, 7.783, P<0.01), and the mRNA expression of IL-10 in the skin tissue around the wound of rats in HGF-modified ADSCs group was significantly increased (t=-6.644, -6.381, P<0.01). On PID 7, compared with those in PBS group and ADSCs alone group, the mRNA expressions of collagen type Ⅰ and Ⅲ, the expression level of VEGF, and the phosphorylation level of Akt in the skin tissue around the wound of rats in HGF-modified ADSCs group were significantly increased (t=-5.126, -4.347, -5.058, -3.367, -10.694, -19.876, -4.890, -6.819, P<0.05 or P<0.01).  Conclusions  HGF-modified human ADSCs can significantly promote the wound healing of full-thickness skin defects in diabetic rats. The mechanism may be related to the inhibition of TNF-α and IL-1β expression, the promotion of IL-10, collagen type Ⅰ and Ⅲ, and VEGF expression, which could be related to the inhibition of nuclear factor κB signaling pathway, and the promotion of Akt signaling pathway.

     

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    Created with Highcharts 5.0.7Chart context menuAccess Area Distribution其他: 1.0 %其他: 1.0 %其他: 0.5 %其他: 0.5 %China: 0.3 %China: 0.3 %Seattle: 0.0 %Seattle: 0.0 %United States: 0.0 %United States: 0.0 %[]: 0.3 %[]: 0.3 %三明: 0.4 %三明: 0.4 %三门峡: 0.5 %三门峡: 0.5 %上海: 0.1 %上海: 0.1 %东莞: 0.2 %东莞: 0.2 %丽水: 1.0 %丽水: 1.0 %乐山: 0.3 %乐山: 0.3 %佛山: 0.1 %佛山: 0.1 %保定: 0.6 %保定: 0.6 %信阳: 0.0 %信阳: 0.0 %克拉玛依: 0.0 %克拉玛依: 0.0 %六安: 0.4 %六安: 0.4 %六盘水: 0.2 %六盘水: 0.2 %兴安: 0.1 %兴安: 0.1 %兴安盟: 0.0 %兴安盟: 0.0 %凉山彝族自治州: 0.0 %凉山彝族自治州: 0.0 %包头: 0.2 %包头: 0.2 %北京: 0.2 %北京: 0.2 %北方邦: 0.0 %北方邦: 0.0 %南京: 0.3 %南京: 0.3 %南充: 0.1 %南充: 0.1 %南平: 1.6 %南平: 1.6 %南昌: 0.1 %南昌: 0.1 %南通: 0.9 %南通: 0.9 %厦门: 0.2 %厦门: 0.2 %台北: 0.1 %台北: 0.1 %台州: 0.5 %台州: 0.5 %合肥: 0.1 %合肥: 0.1 %吉林: 0.4 %吉林: 0.4 %呼和浩特: 0.1 %呼和浩特: 0.1 %咸阳: 0.1 %咸阳: 0.1 %哈尔滨: 0.3 %哈尔滨: 0.3 %哥伦布: 0.1 %哥伦布: 0.1 %唐山: 0.6 %唐山: 0.6 %商丘: 0.0 %商丘: 0.0 %喀什: 0.0 %喀什: 0.0 %嘉兴: 1.7 %嘉兴: 1.7 %大连: 1.9 %大连: 1.9 %天津: 0.3 %天津: 0.3 %宁德: 3.2 %宁德: 3.2 %宁波: 0.9 %宁波: 0.9 %安庆: 0.1 %安庆: 0.1 %安康: 1.6 %安康: 1.6 %宜春: 0.3 %宜春: 0.3 %宣城: 0.0 %宣城: 0.0 %宿迁: 3.4 %宿迁: 3.4 %山景城: 0.1 %山景城: 0.1 %常德: 0.9 %常德: 0.9 %广元: 0.3 %广元: 0.3 %广安: 0.3 %广安: 0.3 %广州: 1.6 %广州: 1.6 %廊坊: 0.1 %廊坊: 0.1 %延安: 4.4 %延安: 4.4 %延边朝鲜族自治州: 0.1 %延边朝鲜族自治州: 0.1 %张家口: 0.7 %张家口: 0.7 %徐州: 1.5 %徐州: 1.5 %德州: 0.1 %德州: 0.1 %德阳: 0.7 %德阳: 0.7 %怀化: 0.1 %怀化: 0.1 %成都: 0.1 %成都: 0.1 %扬州: 0.5 %扬州: 0.5 %抚州: 1.0 %抚州: 1.0 %抚顺: 0.3 %抚顺: 0.3 %拉贾斯坦邦: 0.1 %拉贾斯坦邦: 0.1 %无锡: 0.6 %无锡: 0.6 %日照: 1.2 %日照: 1.2 %昆明: 0.0 %昆明: 0.0 %普赖恩维尔: 0.1 %普赖恩维尔: 0.1 %朝阳: 0.2 %朝阳: 0.2 %杭州: 1.7 %杭州: 1.7 %枣庄: 0.0 %枣庄: 0.0 %株洲: 0.1 %株洲: 0.1 %榆林: 0.7 %榆林: 0.7 %武汉: 0.2 %武汉: 0.2 %汉中: 0.8 %汉中: 0.8 %汕头: 0.6 %汕头: 0.6 %池州: 0.9 %池州: 0.9 %沃思堡: 0.2 %沃思堡: 0.2 %沈阳: 1.2 %沈阳: 1.2 %泉州: 1.1 %泉州: 1.1 %泰州: 1.4 %泰州: 1.4 %泸州: 0.5 %泸州: 0.5 %济南: 1.3 %济南: 1.3 %海得拉巴: 0.1 %海得拉巴: 0.1 %淄博: 0.1 %淄博: 0.1 %淮北: 0.2 %淮北: 0.2 %淮安: 0.5 %淮安: 0.5 %温州: 1.2 %温州: 1.2 %渭南: 0.5 %渭南: 0.5 %湖州: 1.8 %湖州: 1.8 %湘潭: 0.4 %湘潭: 0.4 %湘西: 0.6 %湘西: 0.6 %湘西土家族苗族自治州: 0.3 %湘西土家族苗族自治州: 0.3 %滁州: 0.3 %滁州: 0.3 %漯河: 0.1 %漯河: 0.1 %漳州: 1.2 %漳州: 1.2 %烟台: 0.7 %烟台: 0.7 %白山: 0.3 %白山: 0.3 %盐城: 0.4 %盐城: 0.4 %盘锦: 0.9 %盘锦: 0.9 %石嘴山: 0.1 %石嘴山: 0.1 %石家庄: 0.8 %石家庄: 0.8 %福州: 0.2 %福州: 0.2 %科尼亚: 0.3 %科尼亚: 0.3 %秦皇岛: 0.2 %秦皇岛: 0.2 %绍兴: 0.5 %绍兴: 0.5 %绵阳: 0.4 %绵阳: 0.4 %罗奥尔凯埃: 0.1 %罗奥尔凯埃: 0.1 %自贡: 0.3 %自贡: 0.3 %舟山: 0.4 %舟山: 0.4 %芒廷维尤: 6.8 %芒廷维尤: 6.8 %芜湖: 0.5 %芜湖: 0.5 %芝加哥: 0.0 %芝加哥: 0.0 %苏州: 0.3 %苏州: 0.3 %荆门: 1.4 %荆门: 1.4 %莆田: 2.5 %莆田: 2.5 %营口: 1.4 %营口: 1.4 %葫芦岛: 0.2 %葫芦岛: 0.2 %蚌埠: 0.0 %蚌埠: 0.0 %衡水: 0.4 %衡水: 0.4 %衢州: 1.8 %衢州: 1.8 %襄阳: 0.4 %襄阳: 0.4 %西宁: 0.3 %西宁: 0.3 %西安: 2.5 %西安: 2.5 %西雅图: 0.0 %西雅图: 0.0 %许昌: 0.1 %许昌: 0.1 %辽阳: 1.1 %辽阳: 1.1 %达州: 0.2 %达州: 0.2 %运城: 0.1 %运城: 0.1 %连云港: 0.9 %连云港: 0.9 %通辽: 0.1 %通辽: 0.1 %遵义: 0.0 %遵义: 0.0 %邢台: 0.0 %邢台: 0.0 %邵阳: 0.2 %邵阳: 0.2 %郑州: 0.0 %郑州: 0.0 %郴州: 1.5 %郴州: 1.5 %鄂尔多斯: 0.5 %鄂尔多斯: 0.5 %重庆: 3.4 %重庆: 3.4 %金华: 1.1 %金华: 1.1 %铁岭: 0.9 %铁岭: 0.9 %铜川: 0.1 %铜川: 0.1 %铜陵: 1.6 %铜陵: 1.6 %银川: 0.1 %银川: 0.1 %锦州: 1.3 %锦州: 1.3 %长春: 0.1 %长春: 0.1 %长沙: 0.5 %长沙: 0.5 %雅安: 0.2 %雅安: 0.2 %鞍山: 2.2 %鞍山: 2.2 %韶关: 0.0 %韶关: 0.0 %马鞍山: 0.1 %马鞍山: 0.1 %驻马店: 0.0 %驻马店: 0.0 %鹰潭: 0.2 %鹰潭: 0.2 %黄山: 0.3 %黄山: 0.3 %黄石: 0.5 %黄石: 0.5 %黔西南: 0.4 %黔西南: 0.4 %齐齐哈尔: 0.0 %齐齐哈尔: 0.0 %其他其他ChinaSeattleUnited States[]三明三门峡上海东莞丽水乐山佛山保定信阳克拉玛依六安六盘水兴安兴安盟凉山彝族自治州包头北京北方邦南京南充南平南昌南通厦门台北台州合肥吉林呼和浩特咸阳哈尔滨哥伦布唐山商丘喀什嘉兴大连天津宁德宁波安庆安康宜春宣城宿迁山景城常德广元广安广州廊坊延安延边朝鲜族自治州张家口徐州德州德阳怀化成都扬州抚州抚顺拉贾斯坦邦无锡日照昆明普赖恩维尔朝阳杭州枣庄株洲榆林武汉汉中汕头池州沃思堡沈阳泉州泰州泸州济南海得拉巴淄博淮北淮安温州渭南湖州湘潭湘西湘西土家族苗族自治州滁州漯河漳州烟台白山盐城盘锦石嘴山石家庄福州科尼亚秦皇岛绍兴绵阳罗奥尔凯埃自贡舟山芒廷维尤芜湖芝加哥苏州荆门莆田营口葫芦岛蚌埠衡水衢州襄阳西宁西安西雅图许昌辽阳达州运城连云港通辽遵义邢台邵阳郑州郴州鄂尔多斯重庆金华铁岭铜川铜陵银川锦州长春长沙雅安鞍山韶关马鞍山驻马店鹰潭黄山黄石黔西南齐齐哈尔

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