Xu Jun, E Xiao-Qiang, Wang Nan-Xiang, Wang Mo-Nan, Xie Huan-Xin, Cao Yan-Hui, Sun Li-Hua, Tian Jun, Chen Hua-Jiang, Yan Jing-Long
Department of Orthopaedics, The Second Affiliated Hospital of Harbin Medical University, China.
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, China.
FEBS J. 2016 May;283(9):1689-700. doi: 10.1111/febs.13695. Epub 2016 Mar 28.
Intervertebral discs (IVDs) provide stability and flexibility to the spinal column; however, IVDs, and in particular the nucleus pulposus (NP), undergo a degenerative process characterized by changes in the disc extracellular matrix (ECM), decreased cell viability, and reduced synthesis of proteoglycan and type II collagen. Here, we investigated the efficacy and feasibility of stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) over-expressing bone morphogenetic protein 7 (BMP7) to promote ECM remodeling of degenerated IVDs. Lentivirus-mediated BMP7 over-expression induced differentiation of BMSCs into an NP phenotype, as indicated by expression of the NP markers collagen type II, aggrecan, SOX9 and keratins 8 and 19, increased the content of glycosaminoglycan, and up-regulated β-1,3-glucuronosyl transferase 1, a regulator of chondroitin sulfate synthesis in NP cells. These effects were suppressed by Smad1 silencing, indicating that the effect of BMP7 on ECM remodeling was mediated by the Smad pathway. In vivo analysis in a rabbit model of disc degeneration showed that implantation of BMSCs over-expressing BMP7 promoted cell differentiation and proliferation in the NP, as well as their own survival, and these effects were mediated by the Smad pathway. The results of the present study indicate the beneficial effects of BMP7 on restoring ECM homeostasis in NP cells, and suggest potential strategies for improving cell therapy for the treatment of disc diseases.
椎间盘（IVD）为脊柱提供稳定性和灵活性；然而，椎间盘，尤其是髓核（NP）会经历一个退化过程，其特征为椎间盘细胞外基质（ECM）发生变化、细胞活力下降以及蛋白聚糖和II型胶原蛋白合成减少。在此，我们研究了使用过表达骨形态发生蛋白7（BMP7）的骨髓间充质干细胞（BMSC）进行干细胞治疗以促进退变椎间盘ECM重塑的疗效和可行性。慢病毒介导的BMP7过表达诱导BMSC向NP表型分化，这通过NP标志物II型胶原蛋白、聚集蛋白聚糖、SOX9以及角蛋白8和19的表达得以体现，增加了糖胺聚糖的含量，并上调了β-1,3-葡糖醛酸基转移酶1，该酶是NP细胞中硫酸软骨素合成的调节因子。Smad1沉默可抑制这些效应，表明BMP7对ECM重塑的作用是由Smad通路介导的。在兔椎间盘退变模型中的体内分析表明，植入过表达BMP7的BMSC可促进NP中的细胞分化和增殖以及它们自身的存活，并且这些效应是由Smad通路介导的。本研究结果表明BMP7对恢复NP细胞中ECM稳态具有有益作用，并提示了改善椎间盘疾病细胞治疗的潜在策略。
