Shin Kyungha, Cha Yeseul, Ban Young-Hwan, Seo Da Woom, Choi Ehn-Kyoung, Park Dongsun, Kang Sung Keun, Ra Jeong Chan, Kim Yun-Bae
College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea.
Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, South Korea.
World J Stem Cells. 2019 Dec 26;11(12):1115-1129. doi: 10.4252/wjsc.v11.i12.1115.
Osteoarthritis (OA), a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage, is one of the leading causes of disability. As a new strategy for treatment of OA, mesenchymal stem cells (MSCs) have the potential for articular cartilage regeneration. Meanwhile, thrombospondin 2 (TSP2) promotes the chondrogenic differentiation of MSCs.
To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs (hADMSCs) and potentiates the therapeutic effects of hADMSCs in OA rabbits.
We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA (siRNA)-treated stem cells. Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits, and 8 wk later, hADMSCs (1.7 × 10 or 1.7 × 10 cells) were injected into the injured knees alone or in combination with intra-articular injection of TSP2 (100 ng/knee) at 2-d intervals. OA progression was monitored by gross, radiological, and histological examinations.
In hADMSC culture, treatment with TSP2 increased the expression of chondrogenic markers (SOX9 and collagen II) as well as NOTCH signaling genes (JAGGED1 and NOTCH3), which were inhibited by TSP2 siRNA treatment. , OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration, osteophyte formation, and extracellular matrix loss 8 wk after cell transplantation. Notably, such cartilage damage was further alleviated by the combination of hADMSCs and TSP2. In addition, synovial inflammatory cytokines, especially tumor-necrosis factor-α, markedly decreased following the combination treatment.
The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs JAGGED1/NOTCH3 signaling, and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.
骨关节炎（OA）是一种与年龄相关的慢性疾病，其特征是关节软骨缓慢进行性破坏，是导致残疾的主要原因之一。作为OA治疗的新策略，间充质干细胞（MSCs）具有促进关节软骨再生的潜力。同时，血小板反应蛋白2（TSP2）可促进MSCs的软骨形成分化。
研究TSP2是否能诱导人脂肪来源的间充质干细胞（hADMSCs）向软骨细胞分化，并增强hADMSCs对OA兔的治疗效果。
通过分析正常及经TSP2小干扰RNA（siRNA）处理的干细胞中软骨形成标志物以及NOTCH信号基因的表达，研究TSP2在hADMSCs中的软骨形成潜力。对雄性新西兰白兔进行前交叉韧带切断手术，8周后，将hADMSCs（1.7×10或1.7×10个细胞）单独或与关节腔内注射TSP2（100 ng/膝）以2天间隔联合注入受伤膝关节。通过大体、放射学和组织学检查监测OA进展。
在hADMSC培养中，TSP2处理增加了软骨形成标志物（SOX9和胶原蛋白II）以及NOTCH信号基因（JAGGED1和NOTCH3）的表达，而TSP2 siRNA处理则抑制了这些表达。单独用hADMSCs或TSP2处理的OA兔在细胞移植8周后软骨退变、骨赘形成和细胞外基质丢失程度较低。值得注意的是，hADMSCs与TSP2联合使用可进一步减轻这种软骨损伤。此外，联合治疗后滑膜炎症细胞因子，尤其是肿瘤坏死因子-α明显减少。
结果表明，TSP2通过JAGGED1/NOTCH3信号增强hADMSCs的软骨形成分化作用，hADMSCs与TSP2联合治疗在OA关节软骨再生中发挥协同作用。
