Accelerating bone healing in vivo by harnessing the age-altered activation of c-Jun N-terminal kinase 3

Abstract

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.