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Abstract: Since 3D printed hard materials could match the shape of bone, cell survival and fate determination towards osteoblasts in such materials have become a popular research target. In this study, a scaffold of hard material for 3D fabrication was designed to regulate developmental signal (Notch) transduction guiding osteoblast differentiation. We established a polycaprolactone (PCL) and cell-integrated 3D printing system (PCI3D) to reciprocally print the beams of PCL and cell-laden hydrogel for a module. This PCI3D module holds good cell viability of over 87%, whereas cells show about sixfold proliferation in a 7-day culture. The osteocytic MLO-Y4 was engineered to overexpress Notch ligand Dll4, making up 25% after mixing with 75% stromal cells in the PCI3D module. osteocytic Dll4, unlike other delta-like family members such as Dll1 or Dll3, promotes osteoblast differentiation and the mineralization of primary mouse and a cell line of bone marrow stromal cells when cultured in a PCI3D module for up to 28 days. Mechanistically, osteocytic Dll4 could not promote osteogenic differentiation of the primary bone marrow stromal cells (BMSCs) after conditional deletion of the Notch transcription factor RBPjκ by Cre recombinase. These data indicate that osteocytic Dll4 activates RBPjκ-dependent canonical notch signaling in BMSCs for their oriented differentiation towards osteoblasts. Additionally, osteocytic Dll4 holds a great potential for angiogenesis in human umbilical vein endothelial cells within modules. Our study reveals that osteocytic Dll4 could be the osteogenic niche determining cell fate towards osteoblasts. This will open a new avenue to overcome the current limitation of poor cell viability and low bioactivity of traditional orthopedic implants.

重庆医科大学涂小林等 | 构建硬材料和细胞一体化3D打印新技术和发现骨细胞Dll4调控骨髓基质细胞成骨分化

本研究论文聚焦如何提高3D打印硬材料里细胞的存活率和控制细胞命运问题。3D打印硬材料可以适配骨的形状和加强力学支撑，本文设计了一种硬材料和细胞一体化3D打印技术体系，构建调控骨发育信号（Notch），引导骨髓基质细胞成骨分化的硬材料支架。建立了聚己内酯（PCL）和细胞集成3D打印系统（PCI3D），交互打印PCL束和负载细胞的水凝胶束，并形成网络通道，递送营养。PCI3D模块中细胞存活率超过87%，培养7天细胞增殖6倍。骨细胞MLO-Y4过表达Notch配体Dll4，在PCI3D模块中与75%的基质细胞混合后占25%。与Dll1或Dll3等其他delta样家族成员不同，骨细胞Dll4促进小鼠原代和骨髓基质细胞系成骨分化和矿化（长达28天）。机制研究上，使用Cre重组酶条件性敲除原代骨髓基质细胞（BMSCs）Notch转录因子RBPjκ后，失去对骨细胞Dll4的应答，因而不能产生成骨分化。研究结果表明，骨细胞Dll4激活BMSCs的依赖于RBPjκ的经典Notch信号，促使BMSCs定向分化。此外，骨细胞Dll4显示促血管生成的潜力。骨细胞Dll4是决定细胞朝向成骨细胞分化的成骨微环境，将打破传统骨科植入物的生物活性低的局限，开辟应用新途径。