Interaction between fibroblasts and keratinocytes in the wound edge skin tissue of a diabetic foot patient and the mechanism
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摘要:
目的 探讨糖尿病足患者创缘皮肤组织中成纤维细胞（Fb）与角质形成细胞（KC）的相互作用及其机制。 方法 该研究为实验研究。取华中科技大学同济医学院附属梨园医院创面修复科2021年8月收治的1例糖尿病足患者（男,33岁）和该院手外科2021年9月收治的1例急性足外伤患者（男,50岁）创缘皮肤组织,行单细胞转录组测序,分析Fb亚群中趋化因子配体和KC亚群中趋化因子受体的相互作用。收集常规培养和用高浓度葡萄糖培养7 d的人包皮Fb（HFF）的上清液,分别作为正常条件培养基（CM）和高糖CM。取HaCaT细胞,分为用正常CM培养的正常CM组和用高糖CM培养的高糖CM组,进行划痕试验,并计算划痕后24、48 h细胞迁移率（样本数为3）。利用液相悬浮芯片检测2种CM中细胞因子含量（样本数为5）。取HFF,分为常规培养的正常组和用高浓度葡萄糖培养的高糖组,培养7 d,采用实时荧光定量反转录PCR法检测CXC趋化因子配体1（CXCL1）、CXCL2、CXCL8和CXCL12的mRNA表达（样本数为6）。取正常CM组和高糖CM组HaCaT细胞,采用蛋白质印迹法检测培养48 h细胞中CXC趋化因子受体4（CXCR4）的蛋白表达（样本数为3）。取HaCaT细胞,分为正常CM组、高糖CM组、正常CM+CXCL12组、高糖CM+CXCL12组,前2组细胞处理同前,后2组细胞分别采用含重组人CXCL12的正常CM和高糖CM培养,行划痕试验并计算划痕后24、48 h细胞迁移率,采用蛋白质印迹法检测培养48 h细胞中CXCR4蛋白表达（样本数均为3）。 结果 相较于急性足外伤创缘皮肤组织,糖尿病足创缘皮肤组织Fb亚群中的趋化因子配体（CXCL1、CXCL2、CXCL3、CXCL8、CXCL12）和KC亚群中的趋化因子受体（CXCR2和CXCR4）间的相互作用明显减弱。划痕后24、48 h,高糖CM组HaCaT细胞迁移率均明显低于正常CM组（t值分别为23.50、15.65,P<0.05）。相较于正常CM,高糖CM中的CXCL1含量明显增多（P<0.05）,CXCL12含量明显减少（P<0.05）。培养7 d,相较于正常组,高糖组HFF中CXCL1、CXCL2和CXCL8的mRNA表达均明显升高（t值分别为4.25、4.98、10.04,P<0.05）,CXCL12的mRNA表达明显降低（t=4.10,P<0.05）。培养48 h,高糖CM组HaCaT细胞中CXCR4的蛋白表达明显低于正常CM组（t=5.13,P<0.05）。划痕后24、48 h,高糖CM组HaCaT细胞迁移率较正常CM组和高糖CM+CXCL12组明显降低（P值均<0.05）；划痕后24 h,正常CM+CXCL12组HaCaT细胞迁移率较正常CM组明显降低（P<0.05）；划痕后48 h,正常CM+CXCL12组HaCaT细胞迁移率较高糖CM+CXCL12组明显升高（P<0.05）。培养48 h,高糖CM+CXCL12组HaCaT细胞中CXCR4蛋白表达为0.446±0.050,明显高于高糖CM组的0.247±0.010（P<0.05）,与正常CM+CXCL12组的0.522±0.082相近（P>0.05）；正常CM组HaCaT细胞中CXCR4蛋白表达为0.509±0.055,明显高于高糖CM组（P<0.05）。 结论 糖尿病足创缘皮肤组织Fb亚群中的趋化因子配体和KC亚群中的趋化因子受体间的相互作用明显减弱。高糖抑制HFF分泌CXCL12,其细胞培养上清液刺激导致HaCaT细胞迁移能力减弱、CXCR4表达降低。给予外源性CXCL12蛋白可增加HaCaT细胞中CXCR4的蛋白表达,增强细胞迁移能力。 Abstract:Objective To investigate the interaction between fibroblasts (Fb) and keratinocytes (KC) in the wound edge skin tissue of a diabetic foot patient and the mechanism. Methods This was an experimental research. The wound edge skin tissue from a diabetic foot patient (male and 33 years old) admitted to the Department of Wound Repair of Liyuan Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in August 2021 and from an acute foot injury patient (male and 50 years old) admitted to the Department of Hand Surgery of the hospital in September 2021 was collected. The single-cell transcriptome sequencing was performed to analyze the interaction between chemokine ligands of Fb subgroup and chemokine receptors of KC subgroup. The supernatant was collected after human foreskin fibroblast (HFF) was cultured routinely and with high concentration of glucose for 7 days as normal conditioned medium (CM) and high glucose CM, respectively. HaCaT cells were collected and divided into normal CM group cultured with normal CM and high glucose CM group cultured with high glucose CM, the scratch test was performed to calculate the cell migration rates at 24 and 48 h after scratch (n=3). The content of cytokines in the two kinds of CM was detected by liquid suspension chip (n=5). HFF was collected and divided into normal group cultured routinely and high glucose group cultured with high concentration of glucose for 7 days, and the mRNA expressions of C-X-C motif chemokine ligand 1 (CXCL1), CXCL2, CXCL8, and CXCL12 were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (n=6). HaCaT cells in normal CM group and high glucose CM group were collected to detect the protein expressions of C-X-C motif chemokine receptor 4 (CXCR4) in cells cultured for 48 h by Western blotting (n=3). HaCaT cells were collected and divided into normal CM group, high glucose CM group, normal CM+CXCL12 group, and high glucose CM+CXCL12 group. The first two groups of cells were treated as before, and the latter two groups of cells were cultured with normal CM and high glucose CM containing recombinant human CXCL12, respectively. Scratch test was performed, and cell migration rates were calculated at 24 and 48 h after scratch (n=3); the protein expression of CXCR4 in cells cultured for 48 h was detected by Western blotting (n=3). Results Compared with those in the wound edge skin tissue of acute foot injury, the interactions between chemokine ligands (CXCL1, CXCL2, CXCL3, CXCL8, and CXCL12) of Fb subgroup and chemokine receptors (CXCR2 and CXCR4) of KC subgroup were significantly weakened in the wound edge skin tissue of diabetic foot. At 24 and 48 h after scratch, the migration rates of HaCaT cells in high glucose CM group were significantly lower than those in normal CM group (with t values of 23.50 and 15.65, respectively, P<0.05). Compared with that in normal CM, the content of CXCL1 in high glucose CM was significantly increased (P<0.05), and the content of CXCL12 was significantly decreased (P<0.05). After 7 days of culture, compared with those in normal group, the mRNA expressions of CXCL1, CXCL2, and CXCL8 in HFF in high glucose group were significantly increased (with t values of 4.25, 4.98, and 10.04, respectively, P<0.05), while the mRNA expression of CXCL12 was significantly decreased (t=4.10, P<0.05). After 48 h of culture, the CXCR4 protein expression in HaCaT cells in high glucose CM group was significantly lower than that in normal CM group (t= 5.13, P<0.05). At 24 and 48 h after scratch, the migration rates of HaCaT cells in high glucose CM group were significantly lower than those in normal CM group and high glucose CM+CXCL12 group (with P values all <0.05); at 24 h after scratch, the migration rate of HaCaT cells in normal CM+CXCL12 group was significantly lower than that in normal CM group (P<0.05); at 48 h after scratch, the migration rate of HaCaT cells in normal CM+CXCL12 group was significantly higher than that in high glucose CM+CXCL12 group (P<0.05). At 48 h of culture, the CXCR4 protein expression of HaCaT cells in high glucose CM+CXCL12 group was 0.446±0.050, which was significantly higher than 0.247±0.010 in high glucose CM group (P<0.05) and similar to 0.522±0.082 in normal CM+CXCL12 group (P>0.05); the CXCR4 protein expression in HaCaT cells in normal CM group was 0.509±0.055, which was significantly higher than that in high glucose CM group (P<0.05). Conclusions The interactions between chemokine ligands of Fb subgroup and chemokine receptors of KC subgroup were significantly weakened in the wound edge skin tissue of diabetic foot. High glucose can inhibit CXCL12 secretion of HFF, and the stimulation of its cell culture supernatant can decrease HaCaT cell migration ability and CXCR4 expression. Exogenous CXCL12 protein can increase the CXCR4 protein expression in HaCaT cells and enhance the cell migration ability. -
Key words:
- Cell communication /
- Chemokines, CXC /
- Receptors, chemokine /
- Fibroblasts /
- Keratinocytes /
- Cell migration /
- Wound repair
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参考文献
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图 1 基于单细胞转录组测序分析急性足外伤患者创缘皮肤组织和糖尿病足患者创缘皮肤组织Fb亚群中趋化因子配体与KC亚群中趋化因子受体的相互作用
注：图中最左侧字母A表示急性足外伤创缘皮肤组织,D表示糖尿病足创缘皮肤组织；CXCL为CXC趋化因子配体,CXCR为CXC趋化因子受体,ACKR3为非典型趋化因子受体3,Fb为成纤维细胞,KC为角质形成细胞；从左至右各列依次为Fb亚群1与Fb亚群5、Fb亚群1与KC亚群2、Fb亚群1与KC亚群4、Fb亚群1与KC亚群6、Fb亚群2与Fb亚群5、Fb亚群2与KC亚群2、Fb亚群2与KC亚群4、Fb亚群2与KC亚群6、Fb亚群3与Fb亚群1、Fb亚群3与Fb亚群3、Fb亚群3与Fb亚群5、Fb亚群3与Fb亚群6、Fb亚群3与KC亚群2、Fb亚群3与KC亚群4、Fb亚群3与KC亚群6、Fb亚群4与Fb亚群5、Fb亚群4与KC亚群2、Fb亚群4与KC亚群4、Fb亚群4与KC亚群6、Fb亚群5与Fb亚群5、Fb亚群5与KC亚群2、Fb亚群5与KC亚群4、Fb亚群5与KC亚群6、Fb亚群6与Fb亚群5、Fb亚群6与KC亚群2、Fb亚群6与KC亚群4、Fb亚群6与KC亚群6
图 2 2组HaCaT细胞划痕后各时间点迁移情况 倒置相差显微镜×200。2A、2B、2C.分别为正常CM组细胞划痕后0（即刻）、24、48 h的划痕面积,划痕面积逐渐变小；2D、2E、2F.分别为高糖CM组细胞划痕后0、24、48 h的划痕面积,图2E和2F剩余划痕面积分别较图2B和2C明显增大
注：CM为条件培养基；用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞
图 3 采用液相悬浮芯片检测常规培养人包皮成纤维细胞7 d的上清液（即正常CM）和用高浓度葡萄糖培养人包皮成纤维细胞 7 d的上清液（即高糖CM）中细胞因子含量
注：第1~5列为正常CM,第6~10列为高糖CM；CM为条件培养基,IL为白细胞介素,CXCL为CXC趋化因子配体,CCL为CC趋化因子配体,TNF为肿瘤坏死因子,GM-CSF为粒细胞-巨噬细胞集落刺激因子
图 4 蛋白质印迹法检测的2组HaCaT细胞培养48 h的CXCR4的蛋白表达
注：用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞；CM为条件培养基,CXCR4为CXC趋化因子受体4,GAPDH为3-磷酸甘油醛脱氢酶；条带图上方1和2分别表示正常CM组和高糖CM组
图 5 4组HaCaT细胞划痕后各时间点迁移情况 倒置相差显微镜×200。5A、5B、5C、5D.分别为正常CM组、正常CM+CXCL12组、高糖CM组和高糖CM+CXCL12组划痕后0（即刻）h划痕面积；5E、5F、5G、5H.分别为正常CM组、正常CM+CXCL12组、高糖CM组和高糖CM+CXCL12组划痕后24 h划痕面积,图5E剩余划痕面积最小,图5E、5F、5H剩余划痕面积小于图5G；5I、5J、5K、5L.分别为正常CM组、正常CM+CXCL12组、高糖CM组和高糖CM+CXCL12组划痕后48 h划痕面积,图5I、5J中基本未见划痕,图5K剩余划痕面积明显大于图5L
注：用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞,分别在正常CM组和高糖CM组处理的基础上用重组人CXCL12处理正常CM+CXCL12组和高糖CM+CXCL12组细胞；CM为条件培养基,CXCL12为CXC趋化因子配体12
图 6 蛋白质印迹法检测的4组HaCaT细胞培养48 h的CXCR4的蛋白表达
注：用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞,分别在正常CM组和高糖CM组处理的基础上用重组人CXCL12处理正常CM+CXCL12组、高糖CM+CXCL12组细胞；CM为条件培养基,CXCL12为CXC趋化因子配体12,CXCR4为CXC趋化因子受体4,GAPDH为3-磷酸甘油醛脱氢酶；条带图上方1、2、3、4分别表示正常CM组、正常CM+CXCL12组、高糖CM组和高糖CM+CXCL12组
引物名称 引物序列（5'→3'） 产物大小（bp） CXCL1 上游：GGGAATTCACCCCAAGAACATC 121 下游：GGATGCAGGATTGAGGCAAGC CXCL2 上游：CAAACCGAAGTCATAGCCACA 157 下游：TCCTTCAGGAACAGCCACCA CXCL8 上游：CATACTCCAAACCTTTCCACCC 164 下游：CATACTCCAAACCTTTCCACCC CXCL12 上游：TGAGCTACAGATGCCCATGC 103 下游：ACAATCTGAAGGGCACAGTTTG β肌动蛋白 上游：CACCCAGCACAATGAAGATCAAGAT 317 下游：CCAGTTTTTAAATCCTGAGTCAAGC 注：HFF为人包皮成纤维细胞,CXCL为CXC趋化因子配体 
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Table 2. 2组HaCaT细胞划痕后各时间点迁移率比较（%,
组别 样本数 24 h 48 h 正常CM组 3 54.06±1.95 82.66±2.75 高糖CM组 3 17.53±1.85 47.72±2.71 t值 23.50 15.65 P值 <0.001 <0.001 注：CM为条件培养基；用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞；时间因素主效应,F=4 592.04,P<0.001；处理因素主效应,F=363.46,P<0.001；两者交互作用,F=3.36,P=0.140
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Table 3. 4组HaCaT细胞划痕后各时间点迁移率比较（%,
组别 样本数 24 h 48 h 高糖CM组 3 16.27±1.10 26.33±3.02 正常CM组 3 55.95±5.73 100 高糖CM+CXCL12组 3 42.05±0.55 86.65±0.24 正常CM+CXCL12组 3 41.49±3.23 100 F值 73.22 1 622.80 P值 <0.001 <0.001 P1值 <0.001 <0.001 P2值 <0.001 <0.001 P3值 0.004 >0.999 P4值 >0.999 <0.001 注：用常规培养人包皮成纤维细胞的上清液培养正常CM组细胞,用高浓度葡萄糖培养的人包皮成纤维细胞的上清液培养高糖CM组细胞,分别在正常CM组和高糖CM组处理的基础上用重组人CXCL12处理正常CM+CXCL12组、高糖CM+CXCL12组细胞；CM为条件培养基,CXCL12为CXC趋化因子配体12；时间因素主效应,F=1 242.82,P<0.001；处理因素主效应,F=646.70,P<0.001；两者交互作用,F=85.46,P<0.001；F值、P值为组间各时间点总体比较所得；P1值、P2值分别为高糖CM组与正常CM组、高糖CM+CXCL12组比较所得,P3值、P4值分别为正常CM+CXCL12组与正常CM组、高糖CM+CXCL12组比较所得
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