Potential Osteoinductive Effects of Hydroxyapatite Nanoparticles on Mesenchymal Stem Cells by Endothelial Cell Interaction

Nano-hydroxyapatite (nano-HA) has attracted substantial attention in the field of regenerative medicine. Endothelial cell (EC)-mesenchymal stem cell (MSC) interactions are necessary for bone reconstruction, but the manner in which nano-HA interacts in this process remains unknown. Herein, we investigated the cytotoxicity and osteoinductive effects of HA nanoparticles (HANPs) on MSCs using an indirect co-culture model mediated by ECs and highlighted the underlying mechanisms. It was found that at a subcytotoxic dose, HANPs increased the viability and expression of osteoblast genes, as well as mineralized nodules and alkaline phosphatase production of MSCs. These phenomena relied on HIF-1 alpha secreted by ECs, which triggered the ERK1/2 signaling cascade. In addition, a two-stage cell-lineage mathematical model was established to quantitatively analyze the impact of HIF-1 alpha on the osteogenic differentiation of MSCs. It demonstrated that HIF-1 alpha exerted a dose-dependent stimulatory effect on the osteogenic differentiation rate of MSCs up to 1500 pg/mL, which was in agreement with the above results. Our data implied that cooperative interactions between HANPs, ECs, and MSCs likely serve to stimulate bone regeneration. Furthermore, the two-stage cell-lineage model is helpful in vitro system for assessing the potential influence of effector molecules in bone tissue engineering.

Automated summary

Nano-hydroxyapatite (nano-HA) has attracted attention in regenerative medicine, and its interaction with endothelial cells (ECs) and mesenchymal stem cells (MSCs) for bone reconstruction has been studied. The study found that HA nanoparticles (HANPs) could increase the viability and osteogenic gene expression of MSCs at subcytotoxic doses, with effects mediated by HIF-1 alpha secreted by ECs and triggering the ERK1/2 signaling cascade. A mathematical model showed a dose-dependent stimulatory effect of HIF-1 alpha on MSC osteogenic differentiation. These cooperative interactions may stimulate bone regeneration.