Park Hyoeun, Cho Woong Jin, Kim Jiseong, Choi Hyejong, Baek Inho, Kim Youngjin, Kim Deogil, Kim Byoung Ju, Arai Yoshie, Lee Soo-Hong
Department of Biomedical Engineering, Dongguk University, Seoul, South Korea.
Department of Research & Development Team, ATEMs, Seoul, Republic of Korea.
Tissue Eng Regen Med. 2025 Jun 24. doi: 10.1007/s13770-025-00738-5.
The ultimate goal of regenerative medicine is to restore damaged tissues to a healthy state in the body. Direct reprogramming, also referred to as transdifferentiation, holds significant therapeutic potential by converting abundant somatic cells, such as fibroblasts, into functionally distinct cell types for tissue regeneration. Despite its potential applications in regenerative medicine, direct reprogramming faces major challenges, including low efficiency and poor In vivo applicability. In this study, we propose a novel therapeutic strategy for osteoporosis based on In vivo direct reprogramming using a stepwise delivery approach that first enhances cellular stemness and subsequently induces osteogenic transdifferentiation. Enhancing stemness in lineage-committed cells facilitates their conversion into other functional cell types.
To investigate the efficiency of direct reprogramming via stepwise delivery, we utilized valproic acid (VPA) and tauroursodeoxycholic acid (TUDCA) as reprogramming and bone-stimulating factors, respectively. VPA increased the expression of stemness genes, including Oct4, Nanog, and Sox2, and subsequent treatment of TUDCA enhanced the expression of osteogenic genes in the mouse fibroblast. Targeted delivery of these factors to fibroblasts surrounding bone tissue, enabling subsequent direct reprogramming into osteoblasts, was achieved using bisphosphonate (BP)-conjugated lipid nanoparticles as carriers.
Our findings demonstrate that sequential induction of cell reprogramming and tissue regeneration through stepwise administration of VPA and TUDCA significantly enhances therapeutic efficacy in a mouse model of osteoporosis compared to their simultaneous administration.
This stepwise bone-targeted drug delivery system presents a promising strategy for osteoporosis treatment via In vivo direct reprogramming.
再生医学的最终目标是将体内受损组织恢复到健康状态。直接重编程，也称为转分化，通过将丰富的体细胞（如成纤维细胞）转化为功能不同的细胞类型用于组织再生，具有巨大的治疗潜力。尽管直接重编程在再生医学中有潜在应用，但它面临着重大挑战，包括效率低和体内适用性差。在本研究中，我们基于体内直接重编程提出了一种治疗骨质疏松症的新策略，采用逐步递送方法，首先增强细胞干性，随后诱导成骨转分化。增强谱系定向细胞的干性有助于它们转化为其他功能细胞类型。
为了研究通过逐步递送进行直接重编程的效率，我们分别使用丙戊酸（VPA）和牛磺熊去氧胆酸（TUDCA）作为重编程和骨刺激因子。VPA增加了包括Oct4、Nanog和Sox2在内的干性基因的表达，随后用TUDCA处理增强了小鼠成纤维细胞中成骨基因的表达。使用双膦酸盐（BP）偶联的脂质纳米颗粒作为载体，将这些因子靶向递送至骨组织周围的成纤维细胞，从而实现随后直接重编程为成骨细胞。
我们的研究结果表明，与同时给药相比，通过逐步给予VPA和TUDCA顺序诱导细胞重编程和组织再生，在骨质疏松症小鼠模型中显著提高了治疗效果。
这种逐步骨靶向药物递送系统为通过体内直接重编程治疗骨质疏松症提供了一种有前景的策略。
