Cell-secreted matrices perpetuate the bone-forming phenotype of differentiated mesenchymal stem cells.
Cell-secreted matrices perpetuate the bone-forming phenotype of differentiated mesenchymal stem cells.
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DOI：
10.1016/j.biomaterials.2015.10.003
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发表时间：
2016-01
期刊：
影响因子：
14
通讯作者：
Leach JK
中科院分区：
文献类型：
--
作者：
Hoch AI;Mittal V;Mitra D;Vollmer N;Zikry CA;Leach JK
移植前，可以使用可溶性补充剂混合物将间充质干细胞/基质细胞 (MSC) 诱导成成骨细胞表型。然而，几乎没有证据表明分化的间充质干细胞直接参与骨形成，这表明间充质干细胞在移植后可能会死亡或恢复表型。细胞分泌的脱细胞细胞外基质（DM）是一个有前途的平台，可以通过呈现复杂且生理相关的环境来赋予生物活性并指导细胞命运。因此，我们研究了仿生 DM 在撤消诱导刺激后保留矿物质产生表型的能力。无论诱导持续时间长短（最长 6 周），MSC 在刺激撤消后 24 小时内表现出成骨标志物减少多达 5 倍。我们发现，在 DM 上接种成骨诱导的 MSC 产生的钙沉积量比组织培养塑料多 2 倍，并且这种改善至少部分是通过 ROCK II 途径增加肌动蛋白细胞骨架张力来介导的。 DM 上的 MSC 还分泌多出 25% 的血管内皮生长因子 (VEGF)，这是一种重要的内源性促血管生成因子，在 MSC 成骨分化过程中被消除。将 DM 部署到皮下异位部位，与不使用 DM 输送的 MSC 相比，MSC 的持久性提高了 5 倍，血管密度提高了 3 倍，骨形成提高了 2 倍。这些结果强调了使用 DM 等生物材料平台部署 MSC 的必要性，以保留体外获得的矿物质生成表型并加速骨修复过程。
Prior to transplantation, mesenchymal stem/stromal cells (MSCs) can be induced toward the osteoblastic phenotype using a cocktail of soluble supplements. However, there is little evidence of differentiated MSCs directly participating in bone formation, suggesting that MSCs may either die or revert in phenotype upon transplantation. Cell-secreted decellularized extracellular matrices (DMs) are a promising platform to confer bioactivity and direct cell fate through the presentation of a complex and physiologically relevant milieu. Therefore, we examined the capacity of biomimetic DMs to preserve the mineral-producing phenotype upon withdrawal of the induction stimulus. Regardless of induction duration, ranging up to 6 weeks, MSCs exhibited up to a 5-fold reduction in osteogenic markers within 24 hours following stimulus withdrawal. We show that seeding osteogenically induced MSCs on DMs yields up to 2-fold more calcium deposition than tissue culture plastic, and this improvement is at least partially mediated by increasing actin cytoskeletal tension via the ROCK II pathway. MSCs on DMs also secreted 25% more vascular endothelial growth factor (VEGF), a crucial endogenous proangiogenic factor that is abrogated during MSC osteogenic differentiation. The deployment of DMs into a subcutaneous ectopic site enhanced the persistence of MSCs 5-fold, vessel density 3-fold, and bone formation 2-fold more than MSCs delivered without DMs. These results underscore the need for deploying MSCs using biomaterial platforms such as DMs to preserve the in vitro-acquired mineral-producing phenotype and accelerate the process of bone repair.