Stem Cells：研究发现骨桥蛋白对间充质干细胞成脂成骨分化的调节作用

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Stem Cells：研究发现骨桥蛋白对间充质干细胞成脂成骨分化的调节作用
8 _4 `) B4 C8 Z. c  w来源：中国科学院上海生命科学研究院 2013-11-01 19:19: x; J; p7 t, Y% R/ ^
近日，国际学术期刊《Stem Cells》在线发表了健康所时玉舫研究组题为“An Osteopontin-Integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells”的研究论文，报道了骨桥蛋白（Osteopontin，OPN）在MSCs（Mesenchymal stem cells， MSCs）成脂成骨分化平衡中的重要作用。. I: Y; E" Y9 j+ w) w2 I( o; O% k

7 N0 `9 R7 {5 z0 {% `0 rMSCs作为干细胞的一种，因其具有多向分化潜能，在损伤组织修复中发挥重要作用，并在再生医学领域中具有广泛的应用前景。近年来，众多研究一致认为骨髓中的MSCs是脂肪细胞和成骨细胞的共有前体细胞。因此，骨和脂肪之间存在竞争性平衡，这一平衡的打破与多种代谢疾病密切相关，例如：在骨质疏松和骨量减少患者的骨髓中，脂肪含量明显高于健康对照。然而，MSCs的成脂成骨分化平衡失调在这些疾病病理进程中的作用仍不清楚。因此，研究MSCs成脂成骨分化的调控机制具有重要生理意义。
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博士研究生陈箐、寿培舜等发现，缺失OPN的MSCs易于进行成脂分化，而成骨分化能力则明显减弱。由于OPN在小鼠整个胚胎发育过程中的缺失会引起许多生理变化，为了证明上述OPN缺失MSCs的分化表型是OPN直接作用的结果，他们利用shRNA特异性敲除OPN或在OPN缺失 MSCs中重新表达OPN等实验证明OPN缺失MSCs成脂成骨分化能力的变化来自于OPN的直接作用。结合OPN特异性中和抗体实验和补充外源性OPN实验，研究进一步证明胞外形式OPN在调控MSCs分化中发挥重要作用。这一作用依赖于OPN的受体-integrin ?v?1及其参与调控的C/EBPs信号通路，进而调节MSCs的成脂成骨分化。体内研究发现，尽管OPN 缺失小鼠的骨及骨髓中脂肪细胞含量正常，但是OPN 缺失小鼠的体脂比要明显高于野生型小鼠。至此，该研究首次揭示了OPN在调控MSCs成脂成骨分化平衡中的重要调节作用。
5 h# \, Y8 J8 a) m) M6 Q, @7 CStem Cells         DOI: 10.1002/stem.1567

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An Osteopontin-Integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells! D6 O% A6 J0 B, b' q& m8 A* o; z/ \; p
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Qing Chen, Peishun Shou, Liying Zhang, Chunliang Xu, Chunxing Zheng, Yanyan Han, Wenzhao Li, Yin Huang, Xiaoren Zhang, Changshun Shao, Arthur I. Roberts, Arnold B. Rabson, Guangwen Ren, Yanyun Zhang, Ying Wang, David T. Denhardt, Yufang Shi2 l. J5 \: x6 y! ?7 L$ x& m
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An imbalance between normal adipogenesis and osteogenesis by mesenchymal stem cells (MSCs) has been shown to be related to various human metabolic diseases, such as obesity and osteoporosis; however, the underlying mechanisms remain elusive. We found that the interaction between osteopontin (OPN), an arginine-glycine-aspartate-containing glycoprotein, and integrin αv/β1 plays a critical role in the lineage determination of MSCs. Although OPN is a well established marker during osteogenesis, its role in MSC differentiation is still unknown. Our study reveals that blockade of OPN function promoted robust adipogenic differentiation, while inhibiting osteogenic differentiation. Re-expression of OPN restored a normal balance between adipogenesis and osteogenesis in OPN-/- MSCs. Retarded bone formation by OPN-/- MSCs was also verified by in vivo implantation with hydroxyapatite-tricalcium phosphate (HA-TCP), a bone-forming matrix. The role of extracellular OPN in MSC differentiation was further demonstrated by supplementation and neutralization of OPN. Blocking well-known OPN receptors integrin αv/β1 but not CD44, also affected MSC differentiation. Further studies revealed that OPN inhibits the C/EBPs signaling pathway through integrin αv/β1. Consistent with these in vitro results, OPN-/- mice had a higher fat to total body weight ratio than did wild-type mice. Therefore, our study demonstrates a novel role for OPN-integrin αv/β1 in regulating MSC differentiation.