Li Yanjiao, Jiang Bin, Wu Zhen, Ma Zhaoxia, Qiu Lihua, Cui Wen, Zhao Yunhui, Yan Jinghe, Ma Daiping, Wu Xingfei, Liang Shu, Wang Sitao, Zhao Yanqun, Wang Mengting, Hu Min
Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China.
R&D Division, Eureka Biotech Inc., Philadelphia, PA, United States.
Bioact Mater. 2025 Apr 23;50:414-431. doi: 10.1016/j.bioactmat.2025.04.021. eCollection 2025 Aug.
Bone diseases profoundly affect patients, particularly the elderly, leading to severe health complications and disabilities. Osteoblasts play a crucial role in bone formation and are ideal candidates for treating bone diseases and engineering living materials. However, the stem and progenitor cells that give rise to osteoblasts, as well as osteoblasts themselves, exhibit dysfunction with aging. Although chemical reprogramming of fibroblasts into osteoblasts has been achieved, effective cell-based therapies or living materials have not been established in clinical practice. Here, we present a method to engineer fibroblasts through small molecule reprogramming and spheronization, achieving functional osteoblastic materials across all age groups. By primarily targeting the WNT signaling pathway and modularizing small molecules based on their effects on stage-specific genes, we optimized the temporal regulation of small molecules during reprogramming, acquiring a large number of healthy induced osteoblasts (iOBs). These iOBs with traits of functional native osteoblasts are ideal for forming transplantable tissue spheroids. As innovative living materials, the iOB spheroids (iOB-Sps) have demonstrated improved survival, significant self-bone formation, reduced ROS levels in the defect microenvironment, and accelerated endogenous osteogenesis and angiogenesis in vivo, promoting effective healing of bone defects. These material-free iOB-Sps function as self-scaffolding building blocks for biofunctional constructs, offering a promising avenue for clinical autologous bone defect repair, especially for the elderly.
骨疾病对患者，尤其是老年人影响深远，会导致严重的健康并发症和残疾。成骨细胞在骨形成过程中发挥着关键作用，是治疗骨疾病和构建生物活性材料的理想细胞来源。然而，产生成骨细胞的干细胞和祖细胞以及成骨细胞本身，都会随着衰老而出现功能障碍。尽管已经实现了将成纤维细胞化学重编程为成骨细胞，但基于细胞的有效治疗方法或生物活性材料在临床实践中尚未确立。在此，我们提出了一种通过小分子重编程和球化工程改造成纤维细胞的方法，在所有年龄组中都能获得功能性成骨细胞材料。通过主要靶向WNT信号通路并根据小分子对阶段特异性基因的影响进行模块化，我们优化了重编程过程中小分子的时间调控，从而获得了大量健康的诱导成骨细胞（iOBs）。这些具有功能性天然成骨细胞特征的iOBs是形成可移植组织球状体的理想选择。作为创新的生物活性材料，iOB球状体（iOB-Sps）在体内表现出提高的存活率、显著的自体骨形成、缺陷微环境中活性氧水平的降低以及内源性成骨和血管生成的加速，促进了骨缺损的有效愈合。这些无材料的iOB-Sps作为生物功能构建体的自支架构建模块，为临床自体骨缺损修复，尤其是针对老年人的修复，提供了一条有前景的途径。
