Xu Song, Cecilia Santini Gaia, De Veirman Kim, Vande Broek Isabelle, Leleu Xavier, De Becker Ann, Van Camp Ben, Vanderkerken Karin, Van Riet Ivan
Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, P.R.China ; Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium ; Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels, Brussels, Belgium.
PLoS One. 2013 Nov 6;8(11):e79752. doi: 10.1371/journal.pone.0079752. eCollection 2013.
Previous studies have demonstrated that mesenchymal stem cells from multiple myeloma (MM) patients (MM-hMSCs) display a distinctive gene expression profile, an enhanced production of cytokines and an impaired osteogenic differentiation ability compared to normal donors (ND-hMSCs). However, the underlying molecular mechanisms are unclear. In the present study, we observed that MM-hMSCs exhibited an abnormal upregulation of miR-135b, showing meanwhile an impaired osteogenic differentiation and a decrease of SMAD5 expression, which is the target of miR-135b involved in osteogenesis. By gain and loss of function studies we confirmed that miR-135b negatively regulated hMSCs osteogenesis. We also found that MM cell-produced factors stimulated ND-hMSCs to upregulate the expression of miR-135b. Importantly, treatment with a miR-135b inhibitor promoted osteogenic differentiation in MM-hMSCs. Finally, we observed that MM cell-derived soluble factors could induce an upregulation of miR-135b expression in ND-hMSCs in an indirect coculture system and the miR-135b expression turned to normal level after the removal of MM cells. Collectively, we provide evidence that miR-135b is involved in the impaired osteogenic differentiation of MSCs derived from MM patients and might therefore be a promising target for controlling bone disease.
先前的研究表明，与正常供体的间充质干细胞（ND-hMSCs）相比，多发性骨髓瘤（MM）患者的间充质干细胞（MM-hMSCs）表现出独特的基因表达谱、细胞因子产生增加和成骨分化能力受损。然而，其潜在的分子机制尚不清楚。在本研究中，我们观察到MM-hMSCs中miR-135b异常上调，同时成骨分化受损且SMAD5表达降低，而SMAD5是参与成骨的miR-135b的靶标。通过功能获得和缺失研究，我们证实miR-135b负向调节hMSCs的成骨作用。我们还发现MM细胞产生的因子刺激ND-hMSCs上调miR-135b的表达。重要的是，用miR-135b抑制剂处理可促进MM-hMSCs的成骨分化。最后，我们观察到在间接共培养系统中，MM细胞衍生的可溶性因子可诱导ND-hMSCs中miR-135b表达上调，去除MM细胞后miR-135b表达恢复正常水平。总体而言，我们提供的证据表明，miR-135b参与了MM患者来源的MSCs成骨分化受损，因此可能是控制骨疾病的一个有前景的靶点。
