Efficacy and Mechanism of Highly Active Umbilical Cord Mesenchymal Stem Cells in the Treatment of Osteoporosis in Rats.

Chuan Tian, Guanke Lv, Li Ye, Xiaojuan Zhao, Mengdie Chen, Qianqian Ye, Qiang Li, Jing Zhao, Xiangqing Zhu, Xinghua Pan
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Abstract

Background: Osteoporosis increases bone brittleness and the risk of fracture. Umbilical cord mesenchymal stem cell (UCMSC) treatment is effective, but how to improve the biological activity and clinical efficacy of UCMSCs has not been determined.

Methods: A rat model of osteoporosis was induced with dexamethasone sodium phosphate. Highly active umbilical cord mesenchymal stem cells (HA-UCMSCs) and UCMSCs were isolated, cultured, identified, and infused intravenously once at a dose of 2.29 × 106 cells/kg. In the 4th week of treatment, bone mineral density (BMD) was evaluated via cross-micro-CT, tibial structure was observed via HE staining, osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) was examined via alizarin red staining, and carboxy-terminal cross-linked telopeptide (CTX), nuclear factor-κβ ligand (RANKL), procollagen type 1 N-terminal propeptide (PINP) and osteoprotegerin (OPG) levels were investigated via enzyme-linked immunosorbent assays (ELISAs). BMMSCs were treated with 10-6 mol/L dexamethasone and cocultured with HA-UCMSCs and UCMSCs in transwells. The osteogenic and adipogenic differentiation of BMMSCs was subsequently examined through directional induction culture. The protein expression levels of WNT, β-catenin, RUNX2, IFN-γ and IL-17 in the bone tissue were measured via Western blotting.

Results: The BMD in the healthy group was higher than that in the model group. Both UCMSCs and HA-UCMSCs exhibited a fusiform morphology; swirling growth; high expression of CD73, CD90 and CD105; and low expression of CD34 and CD45 and could differentiate into adipocytes, osteoblasts and chondrocytes, while HA-UCMSCs were smaller in size; had a higher nuclear percentage; and higher differentiation efficiency. Compared with those in the model group, the BMD increased, the bone structure improved, the trabecular area, number, and perimeter increased, the osteogenic differentiation of BMMSCs increased, RANKL expression decreased, and PINP expression increased after UCMSC and HA-UCMSC treatment for 4 weeks. Furthermore, the BMD, trabecular area, number and perimeter, calcareous nodule counts, and OPG/RANKL ratio were higher in the HA-UCMSC treatment group than in the UCMSC treatment group. The osteogenic and adipogenic differentiation of dexamethasone-treated BMMSCs was enhanced after the coculture of UCMSCs and HA-UCMSCs, and the HA-UCMSC group exhibited better effects than the UCMSC coculture group. The protein expression of WNT, β-catenin, and runx2 was upregulated, and IFN-γ and IL-17 expression was downregulated after UCMSC and HA-UCMSC treatment.

Conclusion: HA-UCMSCs have a stronger therapeutic effect on osteoporosis compared with that of UCMSCs. These effects include an improved bone structure, increased BMD, an increased number and perimeter of trabeculae, and enhanced osteogenic differentiation of BMMSCs via activation of the WNT/β-catenin pathway and inhibition of inflammation.

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高活性脐带间充质干细胞治疗大鼠骨质疏松症的功效和机制
背景:骨质疏松症会增加骨脆性和骨折风险。脐带间充质干细胞(UCMSC)治疗有效,但如何提高 UCMSCs 的生物活性和临床疗效尚未确定:方法:用地塞米松磷酸钠诱导大鼠骨质疏松症模型。分离、培养、鉴定高活性脐带间充质干细胞(HA-UCMSCs)和 UCMSCs,并以 2.29 × 106 cells/kg 的剂量静脉注射一次。在治疗的第四周,通过交叉显微 CT 评估骨矿物质密度(BMD),通过 HE 染色观察胫骨结构,通过茜素红染色检测骨髓间充质干细胞(BMMSCs)的成骨分化、并通过酶联免疫吸附试验(ELISA)检测羧基末端交联端肽(CTX)、核因子κβ配体(RANKL)、1 型胶原 N-末端前肽(PINP)和骨蛋白激酶(OPG)的水平。用 10-6 mol/L 地塞米松处理 BMMSCs,并将其与 HA-UCMSCs 和 UCMSCs 共同培养在转孔中。随后通过定向诱导培养检测了 BMMSCs 的成骨和成脂分化情况。通过 Western 印迹法测定骨组织中 WNT、β-catenin、RUNX2、IFN-γ 和 IL-17 的蛋白表达水平:结果:健康组的 BMD 高于模型组。UCMSCs和HA-UCMSCs均呈纺锤形形态,漩涡状生长,CD73、CD90和CD105高表达,CD34和CD45低表达,可分化为脂肪细胞、成骨细胞和软骨细胞,而HA-UCMSCs体积更小,核比例更高,分化效率更高。与模型组相比,UCMSC 和 HA-UCMSC 治疗 4 周后,BMD 增加,骨结构改善,骨小梁面积、数量和周长增加,BMMSCs 成骨分化增加,RANKL 表达减少,PINP 表达增加。此外,HA-UCMSC 治疗组的 BMD、骨小梁面积、数量和周长、钙化结节计数和 OPG/RANKL 比值均高于 UCMSC 治疗组。UCMSCs与HA-UCMSCs共培养后,地塞米松处理的BMMSCs的成骨和成脂分化能力增强,HA-UCMSC组的效果优于UCMSC共培养组。UCMSC和HA-UCMSC处理后,WNT、β-catenin和runx2蛋白表达上调,IFN-γ和IL-17表达下调:结论:与 UCMSCs 相比,HA-UCMSCs 对骨质疏松症有更强的治疗作用。结论:与 UCMSCs 相比,HA-UCMSCs 对骨质疏松症有更强的治疗作用,这些作用包括改善骨结构、增加 BMD、增加骨小梁的数量和周长,以及通过激活 WNT/β-catenin 通路和抑制炎症增强 BMMSCs 的成骨分化。
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