Zhang Xiao-Hui, He Yi-De, Wang Hao, Cao Yuan, Ying Si-Qi, Liu Jia-Ning, Lei Xiao, Liu Lu, Cai Xin-Yue, Mu Shi-Han, Zhang Kai-Chao, Yuan Yuan, Liu Yi-Han, Xu Hao-Kun, Chen Ji, Liang Jian-Fei, Jin Yan, Jin Fang, Sui Bing-Dong, Zheng Chen-Xi
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Adv Healthc Mater. 2025 Jun;14(16):e2501550. doi: 10.1002/adhm.202501550. Epub 2025 May 16.
Harnessing natural developmental programs to repair and replace damaged organs represents promising approaches in regenerative medicine. However, effective strategies are still lacking for tissue regeneration in complicated conditions, such as the periodontal bone defect. Here, human dental follicle stem cells (hDFSCs) and their aggregates (hDFSCA) are cultured and characterized, which are formed based on the inherent property of these stem cells self-assembly into compact spheroid-like structures, mimicking mesenchymal condensation in development. A periodontal tissue-specific microenvironment simulation material is then established, human decellularized alveolar bone matrix particles (hDABMPs), which possess favorable physicochemical and biological properties for regenerative use. hDFSCs co-cultured with hDABMPs exhibit improved cell function, and hDFSCA-hDABMP co-aggregates are subsequently constructed, which activate the developmental gene expression in hDFSCA and initiate hypoxic adaptation mechanisms for tissue regeneration. Indeed, hDFSCA-hDABMP co-aggregates significantly promote regeneration after implantation in alveolar bone defects with good biosafety. Interestingly, during the early stages of implantation, hDABMPs enhance hDFSC survival and expansion, thereby providing a sufficient source of cells for tissue regeneration. Collectively, this study reveals a development-inspired, engineered cell-niche co-aggregation strategy for enhancing CA therapeutic potential by simulating tissue-specific microenvironments, offering novel insights for functional tissue regeneration.
利用自然发育程序来修复和替换受损器官是再生医学中很有前景的方法。然而，对于复杂条件下的组织再生，如牙周骨缺损，仍缺乏有效的策略。在此，培养并表征了人牙囊干细胞（hDFSCs）及其聚集体（hDFSCA），它们基于这些干细胞自组装成紧密的类球体结构的固有特性形成，模拟发育过程中的间充质凝聚。然后建立了一种牙周组织特异性微环境模拟材料，即人脱细胞牙槽骨基质颗粒（hDABMPs），其具有有利于再生利用的理化和生物学特性。与hDABMPs共培养的hDFSCs表现出改善的细胞功能，随后构建了hDFSCA-hDABMP共聚集体，其激活了hDFSCA中的发育基因表达并启动了组织再生的缺氧适应机制。事实上，hDFSCA-hDABMP共聚集体在植入牙槽骨缺损后显著促进再生，且具有良好的生物安全性。有趣的是，在植入早期，hDABMPs增强了hDFSC的存活和扩增，从而为组织再生提供了充足的细胞来源。总体而言，本研究揭示了一种受发育启发的、工程化的细胞-微环境共聚集策略，通过模拟组织特异性微环境来增强CA治疗潜力，为功能性组织再生提供了新的见解。
