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中华关节外科杂志(电子版) ›› 2025, Vol. 19 ›› Issue (05) : 560 -569. doi: 10.3877/cma.j.issn.1674-134X.2025.05.006

基础论著

微孔水凝胶与双细胞因子协同促软骨分化的实验研究
黄宇阳1, 李永生2,3, 罗程1, 何奕君1, 潘骞4,†()   
  1. 1511400　广州医科大学附属番禺中心医院骨关节与运动医学科
    2510663　广东省脐带血造血干细胞库
    3510663　广州市天河诺亚生物工程有限公司
    4510120　广州医科大学第一附属医院关节外科
  • 收稿日期:2025-05-09 出版日期:2025-10-01
  • 通信作者: 潘骞
  • 基金资助:
    广东省中医药局科研项目(20251302); 广州市卫生科技项目(20241A010112); 广州市卫健委一般科研项目(20241A011115)

Experimental study on synergistic promotion of cartilage differentiation by microporous hydrogel combined with dual cytokines

Yuyang Huang1, Yongsheng Li2,3, Cheng Luo1, Yijun He1, Qian Pan4,†()   

  1. 1Department of Osteoarthropathy and Sports Medicine, The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou 511400, China
    2Guangdong Cord Blood Bank, Guangzhou 510663, China
    3Guangzhou Municipality Tianhe Nuoya Bio-engineering Co, Ltd., Guangzhou 510663, China
    4Department of Joint Surgery, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, China
  • Received:2025-05-09 Published:2025-10-01
  • Corresponding author: Qian Pan
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引用本文：

黄宇阳, 李永生, 罗程, 何奕君, 潘骞. 微孔水凝胶与双细胞因子协同促软骨分化的实验研究[J/OL]. 中华关节外科杂志(电子版), 2025, 19(05): 560-569.

Yuyang Huang, Yongsheng Li, Cheng Luo, Yijun He, Qian Pan. Experimental study on synergistic promotion of cartilage differentiation by microporous hydrogel combined with dual cytokines[J/OL]. Chinese Journal of Joint Surgery(Electronic Edition), 2025, 19(05): 560-569.

目的

探讨转化生长因子β3（TGF-β3）和基质细胞衍生因子（SDF-1α）联合微孔水凝胶对软骨损伤修复的作用。

方法

通过腺病毒将TGF-β3转染至大鼠骨髓间充质干细胞（BMSCs）中，获得携带TGF-β3基因的骨髓间充质干细胞（Ad-BMSCs）。将京尼平交联的明胶微球（GMs）浸入含SDF-1α的溶液中，制备负载SDF-1α的明胶微球（GMs-S）。随后，将Ad-BMSCs和BMSCs分别悬浮于海藻酸钠溶液中，与GMs-S混合，通过钙离子交联反应制备两组水凝胶微球（HMs）：S+T组（含SDF-1α和TGF-β3）和S组（仅含SDF-1α）。另两组细胞海藻酸钠溶液与空白GMs混合，分别得到T组（含TGF-β3）和空白组。各组HMs在相同条件下培养，通过细胞计数试剂盒-8（CCK-8）法检测细胞增殖，酶联免疫吸附测定（ELISA）法检测SDF-1α和/或TGF-β3的释放，聚合酶链式反应（PCR）法检测Ⅰ型胶原、Ⅱ型胶原、X型胶原和蛋白聚糖（ACAN）的基因表达，western blotting（WB）法检测Y染色体性别决定区盒转录因子9（SOX9）蛋白表达。本研究所有实验重复3次；定量数据以±s表示，两组数据比较采用t检验，多组数据采用单因素方差分析。P<0.05为差异有统计学意义。

结果

CCK-8数据显示，S+T组的细胞增殖能力显著优于其他组（F=6.904，R2=0.533，P<0.05）。S+T组和S组的SDF-1α（P>0.05）和TGF-β3（P>0.05）释放曲线基本一致。其他结果表明，S+T组的Ⅱ型胶原（空白组及S组与S+T组对比，P<0.05）和ACAN（空白组及S组与S+T组对比，P<0.05）表达更高，软骨细胞外基质合成更多。此外，WB分析显示S+T组的SOX9蛋白表达最高（各组与S+T组对比，P<0.05）。

结论

在微孔水凝胶中，SDF-1α与TGF-β3的协同作用可增强BMSCs的软骨分化效果。

关键词: 趋化因子CXCL12, 转化生长因子β3, 软骨细胞, 水凝胶类, 藻酸盐, 明胶
Objective

To explore the effect of the combined application of transforming growth factor-β3 (TGF-β3) and stromal cell-derived factor 1α (SDF-1α) with microporous hydrogel on the repair of cartilage injury.

Methods

TGF-β3 was transfected into rat bone marrow mesenchymal stem cells (BMSCs) by adenovirus to obtain bone marrow mesenchymal stem cells carrying the TGF-β3 gene (Ad-BMSCs). Genipin crosslinked gelatin microspheres (GMs) were infiltrated into cytokine SDF-1α solution to obtain GMs containing SDF-1α (GMs-S). Then the Ad-BMSCs and BMSCs were suspending in alginate solution, respectively, and mixed with GMs-S, to obtain two groups of hydrogel microspheres (HMs) after calcium in crosslinking reaction as group S+T (containing SDF-1α and TGF-β3) and group S (containing only SDF-1α). Similarly, these two cells alginate solution mixed with GMs respectively to obtain two groups of gelatin microsphere hydrogel as group T (containing TGF-β3) and the blank group.The HMs of each group were cultured in cell incubators under the same conditions,and cell proliferation was detected by cell counting kit-8 assay (CCK-8), the release of SDF-1α and/or TGF-β3 were detected by enzyme-linked immunosorbent assay (ELISA). The gene expression of type I collagen, type Ⅱ collagen, type X collagen and aggrecan (ACAN) were detected by polymerase chain reaction assay (PCR), and expression of sex related Y-box transcription factor 9 (SOX9) protein was detected by western blotting analysis (WB). All the tests in this study were repeated for three times; the quantitative data were described as ±s, t test was used to compare the difference between two groups, and single factor variance analysis was applied for multipe groups comparison. P<0.05 indicated the difference was statistically significant.

Results

CCK-8 data indicated that group S+T had an outstanding ability of cell growth (F=6.904, R2=0.533, P<0.05). SDF-1α (P>0.05) and TGF-β3 (P>0.05) release curves of group S+T and group S were generally consistent. Other results demonstrated that group S+T had greater expression of typeⅡcollagen (comparing the blank group and the group S with the group S+T, P<0.05) and aggrecan (comparing the blank group and the group S with the group S+T, P<0.05) and more synthesized cartilaginous extracellular matrix. Moreover, the WB analysis suggested that the expression of SOX9 protein in group S+T was the highest (each group was compared with the group S+T, P<0.05).

Conclusion

Synergistic effect of SDF-1α and TGF-β3 on BMSCs cultured in microcavitary hydrogel can improve the effect of chondrogenesis.

Key words: Chemokine CXCL12, Transforming growth factor beta3, Chondrocytes, Hydrogels, Alginates, Gelatin
图1 微球培养实验分组情况注：S+T-含SDF-1α因子与TGF-β3因子；T-含TGF-β3因子；S-含SDF-1α因子
Figure 1 Experimental microsphere culture groupsNote: S+T-containing the SDF-1α factor and the TGF-β3 factor; T- containing the TGF-β3 factor; S- containing the SDF-1αfactor
图4 腺病毒转染后倒置相差显微镜下BMSCs（骨髓间充质干细胞）情况（比例尺=100 μm）。图A为BMSCs在的显微镜明场下的状态；图B为携带TGF-β3基因的腺病毒转染48 h后细胞的荧光情况
Figure 4 Views of BMSCs under the inverted phase-contrast microscope after adenovirus transfection (scale = 100 μm). A shows BMSCs under the bright field; B shows the fluorescence image of the cells 48 h after adenovirus transfection with the TGF-β3 gene
图5 BMSCs（骨髓间充质干细胞）在微孔水凝胶中存活情况。图A为BMSCs在微孔水凝胶的明场图片；图B为BMSCs在微孔水凝胶的荧光图片（比例尺100 μm）
Figure 5 The survival status of BMSCs in microporous hydrogel. A shows the bright-field image of BMSCs in the microporous hydrogel; B shows the fluorescence image of BMSCs in the microporous hydrogel (scale 100 μm)
图2 BMSCs（骨髓间充质干细胞） Q-PCR（实时定量PCR）所用引物序列注：COLⅠ-Ⅰ型胶原蛋白；COL Ⅱ-Ⅱ型胶原蛋白；COL X-X型胶原蛋白；ACAN-蛋白聚糖；GAPDH-甘油醛-3-磷酸脱氢酶
Figure 2 Primer sequences of target genes of BMSCs used for Q-PCRNote: COL I-type I collagen; COLⅡ-TypeⅡcollagen; COL X-type X collagen; ACAN-aggrecan; GAPDH- glyceraldehyde-3-phosphate dehydrogenase
图3 干燥和溶胀状态下的明胶微球显微镜下观（比例尺100 μm）。图A为干燥状态下交联明胶微球；图B为溶胀状态下交联明胶微球
Figure 3 Microscopic views of gelatin microspheres in dry state and swollen state(scale 100 μm). A is the cross-linked gelatin microspheres in the dry state; B is the cross-linked gelatin microspheres in the swollen state
图6 各实验组细胞增殖活性曲线图注：S+T-含SDF-1α和TGF-β3；T-含TGF-β3；S-含SDF-1α
Figure 6 Curves showing the proliferation activity of cells in each experimental groupNote: S+T- containing SDF-1α and TGF-β3; T- containing TGF-β3; S- containing SDF-1α
图7 S+T组和S组的SDF-1α（基质细胞衍生因子-1α）释放曲线注：S+T-含SDF-1α和TGF-β3；S-含SDF-1α
Figure 7 Release curves of SDF-1α in the group S+T and the group SNote: S+T- containing SDF-1α and TGF-β3; S- containing SDF-1α
图8 S+T组和T组的TGF-β3（转化生长因子-β3）释放曲线注：S+T-含SDF-1α和TGF-β3；T-含TGF-β3
Figure 8 Release curves of TGF-β3 in the group S+T and the group SNote: S+T- containing SDF-1α and TGF-β3; T- containing TGF-β3
图9 各水凝胶微球组第28天软骨相关基因表达。图A为Ⅰ型胶原基因；图B为X型胶原基因；图C为Ⅱ型胶原基因；图D为ACAN（蛋白聚糖）基因注：*-P<0.05；S+T-含SDF-1α和TGF-β3；T-含TGF-β3；S-含SDF-1α
Figure 9 Expressions of cartilage-related genes in different hydrogel-microsphere groups at day 28. A is the expression of type I collagen gene; B is the expression of type X collagen gene; C is the expression of type II collagen gene; D is the expression of ACAN geneNote: *-P<0.05; S+T- containing SDF-1α and TGF-β3; T- containing TGF-β3; S- containing SDF-1α
图10 各水凝胶微球组第14天SOX9蛋白表达情况。图A为蛋白条带；图B为Image J分析灰度值后的柱状图注：*-P<0.05；S+T-含SDF-1α和TGF-β3；T-含TGF-β3；S-含SDF-1α
Figure 10 Expression of SOX9 protein in different hydrogel-microsphere groups at day 14. A represents the protein band; B is the bar graph obtained after Image J analysisNote: *-P<0.05; S+T- containing SDF-1α and TGF-β3; T- containing TGF-β3; S- containing SDF-1α
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