Inorganic biomaterials shape the transcriptome profile to induce endochondral differentiation

Minerals play a vital role, working synergistically with enzymes and other cofactors to regulate physiological functions including tissue healing and regeneration. The bioactive characteristics of mineral-based nanomaterials can be harnessed to facilitate in situ tissue regeneration by attracting endogenous progenitor and stem cells and subsequently directing tissue-specific differentiation. Here, we investigate cellular responses of human mesenchymal stem/stromal cells (hMSCs) to traditional bioactive mineral-based nanomaterials, such as hydroxyapatite (nHA), whitlockite (nWH), silicon-dioxide (nSiO2), and the emerging synthetic 2D nanosilicates (nSi). We utilized transcriptome sequencing (RNA-seq) to probe the cellular response and determine the significantly affected signaling pathways due to exposure to these inorganic nanomaterials. Transcriptome profiles of stem cells treated with nanosilicates revealed a stabilized skeletal progenitor state suggestive of endochondral differentiation. This observation is bolstered by enhanced deposition of matrix mineralization in nanosilicate treated stem cells compared to control or other treatments. Specifically, use of 2D nanosilicates directs osteogenic differentiation of stem cells via activation of bone morphogenetic proteins (BMP) and hypoxia-inducible factor 1-alpha (HIF-1a) signaling pathway. This study provides a holistic transcriptomic insight into nanomaterial-cell interactions and predicts downstream effects of nanomaterial induction of endochondral differentiation.