Glycosaminoglycan content of a mineralized collagen scaffold promotes mesenchymal stem cell secretion of factors to modulate angiogenesis and monocyte differentiation
Glycosaminoglycan content of a mineralized collagen scaffold promotes mesenchymal stem cell secretion of factors to modulate angiogenesis and monocyte differentiation
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DOI：
10.1016/j.mtla.2021.101149
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发表时间：
2021-06-30
期刊：
影响因子：
3.4
通讯作者：
Harley, Brendan A. C.
中科院分区：
文献类型：
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作者：
Dewey, Marley J.;Kolliopoulos, Vasiliki;Harley, Brendan A. C.
有效设计生物材料以帮助颅颌面(CMF)骨缺损的再生修复需要调控外源性增加的祖细胞与伤口微环境中的细胞(如成骨细胞、破骨细胞、内皮细胞和免疫细胞)之间的复杂相互作用。我们正在探索一类矿化胶原支架中糖胺聚糖(GAG)含量的作用，这种支架最近被证明可以促进颅面部骨缺损的成骨和愈合。我们之前的研究表明，加入软骨素-6-硫酸盐或肝素可以改善种植的人骨髓间充质干细胞(HMSCs)的矿物质沉积。在这里，我们研究了不同的支架GAG含量对hMSC行为的影响，以及它们调节破骨细胞生成、血管生成和免疫反应的能力。我们报道了在含有软骨素-6-硫酸盐(CS6)、软骨素-4-硫酸盐(CS4)或肝素(肝素)的支架中产生的hMSC条件培养液在内皮管形成和单核细胞分化中的作用。值得注意的是，hMSCs在肝素支架内的内源性产生通过分泌的骨保护素(OPG)最显著地抑制破骨细胞的形成，而CS6支架产生的分泌体减少了促炎免疫反应并增加了内皮管的形成。所有条件培养液均下调多种促炎和抗炎细胞因子，如IL-6、IL-1β、CCL18和CCL17。总之，这些发现表明，改变矿化胶原支架的GAG含量可以直接(hMSC活性)和间接(分泌因子的产生)影响整体成骨潜力和矿物生物合成，以及血管生成潜力和单核细胞向破骨细胞和巨噬细胞系的分化。因此，支架GAG含量是一种强大的刺激，可以调节骨愈合微环境中多个细胞群体之间的相互信号。
Effective design of biomaterials to aid regenerative repair of craniomaxillofacial (CMF) bone defects requires approaches that modulate the complex interplay between exogenously added progenitor cells and cells in the wound microenvironment, such as osteoblasts, osteoclasts, endothelial cells, and immune cells. We are exploring the role of the glycosaminoglycan (GAG) content in a class of mineralized collagen scaffolds recently shown to promote osteogenesis and healing of craniofacial bone defects. We previously showed that incorporating chondroitin-6-sulfate or heparin improved mineral deposition by seeded human mesenchymal stem cells (hMSCs). Here, we examine the effect of varying scaffold GAG content on hMSC behavior, and their ability to modulate osteoclastogenesis, vasculogenesis, and the immune response. We report the role of hMSC-conditioned media produced in scaffolds containing chondroitin-6-sulfate (CS6), chondroitin-4-sulfate (CS4), or heparin (Heparin) GAGs on endothelial tube formation and monocyte differentiation. Notably, endogenous production by hMSCs within Heparin scaffolds most significantly inhibits osteoclastogenesis via secreted osteoprotegerin (OPG), while the secretome generated by CS6 scaffolds reduced pro-inflammatory immune response and increased endothelial tube formation. All conditioned media down-regulated many pro- and anti-inflammatory cytokines, such as IL6, IL-1 beta and CCL18 and CCL17 respectively. Together, these findings demonstrate that modifying mineralized collagen scaffold GAG content can both directly (hMSC activity) and indirectly (production of secreted factors) influence overall osteogenic potential and mineral biosynthesis as well as angiogenic potential and monocyte differentiation towards osteoclastic and macrophage lineages. Scaffold GAG content is therefore a powerful stimulus to modulate reciprocal signaling between multiple cell populations within the bone healing microenvironment.