Trb3 controls mesenchymal stem cell lineage fate and enhances bone regeneration by scaffold-mediated local gene delivery.
Trb3 controls mesenchymal stem cell lineage fate and enhances bone regeneration by scaffold-mediated local gene delivery.
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Trb3通过支架介导的局部基因传递控制间充质干细胞谱系命运并增强骨再生。
DOI：
10.1016/j.biomaterials.2020.120445
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发表时间：
2021-01
期刊：
影响因子：
14
通讯作者：
Lee M
中科院分区：
文献类型：
--
作者：
Fan J;Lee CS;Kim S;Zhang X;Pi-Anfruns J;Guo M;Chen C;Rahnama M;Li J;Wu BM;Aghaloo TL;Lee M
骨髓间充质干细胞（MSC）的异常谱系定型导致骨形成异常，这是由于成骨能力降低和成脂能力增加。虽然在过去几十年中已经发现了与谱系分化相关的几个主要转录因子，但MSC命运决定的分子开关及其在骨骼再生中的作用在很大程度上仍然未知，限制了有效治疗方法的创造。Tribbles同源物3（Trb 3）是Tribbles家族假激酶的一员，在细胞分化过程中发挥着重要作用。在这里，我们研究了Trb 3在骨形成背景下调节MSCs成骨和成脂分化的相互作用，并研究了Trb 3控制脂肪-成骨平衡的机制。Trb 3促进MSCs向成骨细胞的定向分化，但以脂肪细胞分化为代价。Trb 3通过BMP/Smad和Wnt/β-catenin信号调节MSCs的细胞命运选择。重要的是，使用新型明胶缀合咖啡酸涂覆的磷灰石/PLGA（GelCA-PLGA）支架体内局部递送Trb 3刺激了啮齿动物非愈合下颌骨缺损模型中的稳健骨再生并抑制了脂肪填充的囊肿形成。这些研究结果表明，基于Trb 3的治疗策略有利于成骨细胞生成而不是脂肪生成，以改善骨骼再生和未来治疗骨丢失疾病。这种独特的方法实现了支架介导的局部基因转移，可能进一步拓宽靶向与谱系定型相关的特定治疗基因在临床骨治疗中的翻译用途。
Aberrant lineage commitment of mesenchymal stem cells (MSCs) in marrow contributes to abnormal bone formation due to reduced osteogenic and increased adipogenic potency. While several major transcriptional factors associated with lineage differentiation have been found during the last few decades, the molecular switch for MSC fate determination and its role in skeletal regeneration remains largely unknown, limiting creation of effective therapeutic approaches. Tribbles homolog 3 (Trb3), a member of tribbles family pseudokinases, is known to exert diverse roles in cellular differentiation. Here, we investigated the reciprocal role of Trb3 in the regulation of osteogenic and adipogenic differentiation of MSCs in the context of bone formation, and examined the mechanisms by which Trb3 controls the adipo-osteogenic balance. Trb3 promoted osteoblastic commitment of MSCs at the expense of adipocyte differentiation. Mechanistically, Trb3 regulated cell-fate choice of MSCs through BMP/Smad and Wnt/β-catenin signals. Importantly, in vivo local delivery of Trb3 using a novel gelatin-conjugated caffeic acid-coated apatite/PLGA (GelCA-PLGA) scaffold stimulated robust bone regeneration and inhibited fat-filled cyst formation in rodent non-healing mandibular defect models. These findings demonstrate Trb3-based therapeutic strategies that favor osteoblastogenesis over adipogenesis for improved skeletal regeneration and future treatment of bone-loss disease. The distinctive approach implementing a scaffold-mediated local gene transfer may further broaden the translational use of targeting specific therapeutic gene related to lineage commitment for clinical bone treatment.