Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, School of Rehabilitation, Kunming Medical University, Kunming, 650500, China.
Department of Stomatology, The First People's Hospital of Yunnan Province, Kunming, 650032, China.
J Nanobiotechnology. 2024 Nov 20;22(1):722. doi: 10.1186/s12951-024-02886-7.
The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146 host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration.
骨质疏松性骨缺损的再生仍然具有挑战性，因为炎症微环境会损害关键的干细胞功能。具有内在诱导成骨分化而非募集干细胞自我更新功能的合成材料代表了一种有前途的内源性骨形成的替代策略。因此，设计了一种微环境优化的聚氨酯（PU）/n-HA 支架，以实现天麻素的持续释放，研究其对干细胞成骨命运的影响。它具有相互连接的多孔网络和升高的连续天麻素释放模式，以匹配免疫-骨级联反应，同时与材料的渐进降解相匹配。在骨质疏松大鼠股骨缺损模型中，5%天麻素-PU/n-HA 强力促进新骨再生，促进 M2 巨噬细胞极化和 CD146 宿主干细胞募集到缺陷部位。植入时间依赖性地增加了骨髓间充质干细胞（BMSC）的数量，进一步培养 BMSC 显示出强大的增殖、迁移和线粒体复苏能力。值得注意的是，一些细胞对产生一个干细胞样子细胞，而另一个以不对称细胞分裂（ACD）的方式向成骨谱系分化，当植入 5%天麻素-PU/n-HA 时，触发了更强的 ACD 反应。进一步的研究表明，在分裂细胞中，蛋白激酶 C（PKC）的单侧集中表达和β-连环蛋白有效地诱导了不对称分布，使 PKC 偏向于使子细胞对 Wnt 信号做出反应。骨骼干细胞（SSCs）中的不对称细胞分裂在机械上与 BMSC 相似，并且也受独特的 PKC 和β-连环蛋白偏向的控制。同时，植入物附近的骨丢失延迟部分缓解了骨质疏松症的发展。总之，我们的研究结果为调节巨噬细胞极化以及募集干细胞以 ACD 方式成骨提供了新的认识，为内源性骨再生的支架设计策略提供了新的思路。
