Loss and rescue of osteocalcin and osteopontin modulate osteogenic and angiogenic features of mesenchymal stem/stromal cells
Loss and rescue of osteocalcin and osteopontin modulate osteogenic and angiogenic features of mesenchymal stem/stromal cells
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DOI：
10.1002/jcp.29653
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发表时间：
2020-03-11
影响因子：
5.6
通讯作者：
Vashishth, Deepak
中科院分区：
文献类型：
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作者：
Carvalho, Marta S.;Silva, Joao C.;Vashishth, Deepak
骨细胞外基质中的非胶原蛋白，如骨钙素（OC）和骨桥蛋白（OPN），是骨作为骨骼组织进化所固有的，已知调节骨形成和矿化。然而，这一调节作用的根本基础仍然不明。在这里，我们首次使用同时缺乏OC和OPN的小鼠间充质干/基质细胞（MSC）来研究OC和OPN对MSC增殖能力和分化能力的机制作用。我们发现OC和OPN的缺失降低了干细胞的自我更新潜力和多能性，影响其分化成成骨谱系，并损害其血管生成潜力，同时维持软骨形成和脂肪形成谱系。此外，OC和OPN的损失损害了细胞外基质的完整性和成熟，这通过与更原始的骨骼结缔组织相关的糖胺聚糖含量的意外增强以及所产生的矿物质种类的成熟延迟来观察。有趣的是，外源性补充的OC和OPN能够拯救MSC增殖和成骨潜能，沿着基质完整性和矿物质质量。总之，这些结果突出了OC和OPN在增强原始结缔组织的骨生成和血管生成方面的关键贡献，并支持基于其外源性补充的潜在治疗方法。
Noncollagenous proteins in the bone extracellular matrix, such as osteocalcin (OC) and osteopontin (OPN), inherent to evolution of bone as a skeletal tissue, are known to regulate bone formation and mineralization. However, the fundamental basis of this regulatory role remains unknown. Here, for the first time, we use mouse mesenchymal stem/stromal cells (MSC) lacking both OC and OPN to investigate the mechanistic roles of OC and OPN on the proliferation capacity and differentiation ability of MSC. We found that the loss of OC and OPN reduces stem cells self-renewal potential and multipotency, affects their differentiation into an osteogenic lineage, and impairs their angiogenic potential while maintaining chondrogenic and adipogenic lineages. Moreover, loss of OC and OPN compromises the extracellular matrix integrity and maturation, observed by an unexpected enhancement of glycosaminoglycans content that are associated with a more primitive skeletal connective tissue, and by a delay on the maturation of mineral species produced. Interestingly, exogenously supplemented OC and OPN were able to rescue MSC proliferative and osteogenic potential along with matrix integrity and mineral quality. Taken together, these results highlight the key contributions of OC and OPN in enhancing osteogenesis and angiogenesis over primitive connective tissue, and support a potential therapeutic approach based on their exogenous supplementation.