We have recently demonstrated that c-Jun N-terminal kinase 3 (JNK3) is a key modulator of the enhanced osteogenic potential of stem cells derived from children when compared to those derived from adults. In this study, we formulated a JNK3-activator nanoparticle (JNK3*) that recapitulates the immense osteogenic potential of juvenile cells in adult stem cells by facilitating JNK3 activation. Moreover, we aimed to functionalize a collagen-based scaffold by incorporating the JNK3* in order to develop an advanced platform capable of accelerating bone healing by recruitment of host stem cells. Our data, in vitro and in vivo, demonstrated that the immense osteogenic potential of juvenile cells could be recapitulated in adult stem cells by facilitating JNK3 activation. Moreover, our results revealed that the JNK3* functionalized 3D scaffold induced the fastest bone healing and greatest blood vessel infiltration when implanted in critical-size rat calvarial defects in vivo. JNK3*scaffold fastest bone healing in vivo was associated with its capacity to recruit host stem cells to the site of injury and promote angiogenic-osteogenic coupling (e.g. Vegfa, Tie1, Runx2, Alp and Igf2 upregulation). In summary, this study has demonstrated the potential of harnessing knowledge of age-altered stem cell mechanobiology in order to develop a materials-based functionalization approach for the repair of large tissue defects.

我们最近证明，与来自成人的干细胞相比，c-Jun N 末端激酶 3 (JNK3) 是增强儿童干细胞成骨潜能的关键调节剂。在这项研究中，我们配制了一种 JNK3 激活剂纳米颗粒 (JNK3*)，它通过促进 JNK3 激活来概括成体干细胞中幼年细胞的巨大成骨潜力。此外，我们旨在通过整合 JNK3* 来功能化基于胶原蛋白的支架，以开发能够通过募集宿主干细胞来加速骨愈合的先进平台。我们的数据，体外和体内，证明了幼年细胞的巨大成骨潜力可以通过促进 JNK3 激活在成体干细胞中重现。此外，我们的研究结果表明，JNK3* 功能化 3D 支架在体内植入临界大小的大鼠颅骨缺损时可诱导最快的骨愈合和最大的血管浸润。JNK3*支架体内最快的骨愈合与其将宿主干细胞募集到损伤部位并促进血管生成-成骨偶联（例如， Vegfa、Tie1、Runx2、Alp和Igf2 ）的能力有关上调）。总之，这项研究证明了利用年龄改变的干细胞机械生物学知识开发一种基于材料的功能化方法来修复大组织缺损的潜力。