Intercellular Adhesion Molecule-1 Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells and Impairs Bio-Scaffold-Mediated Bone Regeneration In Vivo
Intercellular Adhesion Molecule-1 Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells and Impairs Bio-Scaffold-Mediated Bone Regeneration In Vivo
复制标题
细胞间粘附分子-1 抑制间充质干细胞的成骨分化，并损害体内生物支架介导的骨再生。
DOI：
10.1089/ten.tea.2014.0007
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发表时间：
2014-10-01
影响因子：
4.1
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Xu, Fen-Fen;Zhu, Heng;Zhang, Yi
骨髓间充质干细胞（MSC）负载生物支架移植是一种很有前途的骨再生和修复治疗方法。然而，越来越多的证据表明，来自损伤组织的促炎介质抑制成骨分化并损害骨形成。为了提高MSC为基础的骨再生，重要的是要了解炎症介导的成骨抑制的机制。在本研究中，我们发现类风湿关节炎患者的滑液和促炎细胞因子，包括白细胞介素-1 α，白细胞介素-1 β和肿瘤坏死因子α，刺激细胞间粘附分子-1（ICAM-1）的表达和受损的成骨分化的MSC。有趣的是，使用遗传方法在MSC中过表达ICAM-1也抑制骨生成。相反，ICAM-1敲低显著逆转了成骨抑制。此外，在大鼠颅骨缺损中移植可追踪的MSC-聚（乳酸-共-乙醇酸）结构后，我们发现ICAM-1抑制了体内MSC成骨分化和基质矿化。从机制上讲，我们发现ICAM-1促进MSC增殖，但导致干细胞标志物丢失。此外，ICAM-1的过表达稳定地激活了MAPK和NF-κ B通路，但抑制了MSC中的PI 3 K/AKT通路。更重要的是，特异性抑制ERK/MAPK和NF-κ B通路或激活PI 3 K/AKT通路可部分挽救成骨分化，而抑制p38/MAPK和PI 3 K/AKT通路则导致更严重的成骨抑制。总之，我们的研究结果揭示了ICAM-1在骨生成中的新功能，并提出了一个新的分子靶点，以改善炎症微环境中的骨再生和修复。
Mesenchymal stem cell (MSC) loaded bio-scaffold transplantation is a promising therapeutic approach for bone regeneration and repair. However, growing evidence shows that pro-inflammatory mediators from injured tissues suppress osteogenic differentiation and impair bone formation. To improve MSC-based bone regeneration, it is important to understand the mechanism of inflammation mediated osteogenic suppression. In the present study, we found that synovial fluid from rheumatoid arthritis patients and pro-inflammatory cytokines including interleukin-1 alpha, interleukin-1 beta, and tumor necrosis factor alpha, stimulated intercellular adhesion molecule-1(ICAM-1) expression and impaired osteogenic differentiation of MSCs. Interestingly, overexpression of ICAM-1 in MSCs using a genetic approach also inhibited osteogenesis. In contrast, ICAM-1 knockdown significantly reversed the osteogenic suppression. In addition, after transplanting a traceable MSC-poly(lactic-co-glycolic acid) construct in rat calvarial defects, we found that ICAM-1 suppressed MSC osteogenic differentiation and matrix mineralization in vivo. Mechanistically, we found that ICAM-1 enhances MSC proliferation but causes stem cell marker loss. Furthermore, overexpression of ICAM-1 stably activated the MAPK and NF-kappa B pathways but suppressed the PI3K/AKT pathway in MSCs. More importantly, specific inhibition of the ERK/MAPK and NF-kappa B pathways or activation of the PI3K/AKT pathway partially rescued osteogenic differentiation, while inhibition of the p38/MAPK and PI3K/AKT pathway caused more serious osteogenic suppression. In summary, our findings reveal a novel function of ICAM-1 in osteogenesis and suggest a new molecular target to improve bone regeneration and repair in inflammatory microenvironments.