Laboratory investigation of METTL7A driving MSC osteogenic differentiation through YAP1 translation enhancement via eIF4F recruitment.

Aim: Effective control of mesenchymal stem cell (MSC) differentiation towards osteogenic lineages is fundamental for bone regeneration. This study elucidates the regulatory role of methyltransferase like 7A (METTL7A) in the osteogenic differentiation of MSCs.

Methodology: Alkaline phosphatase staining, Alizarin Red S staining, western blotting, and in vivo studies were conducted to determine the effects of METTL7A depletion or overexpression on the osteogenic differentiation of various types of MSCs. Then the downstream signalling pathways regulated by METTL7A in MSCs were further investigated.

Results: Our findings indicate that METTL7A expression significantly increases during the osteogenic differentiation of MSCs. Furthermore, depletion of METTL7A hindered, whereas its overexpression enhanced, the osteogenic differentiation of MSCs. Mechanistically, METTL7A influences MSC osteogenic differentiation by activating the YAP1-TEAD1 signalling pathway. It enhances YAP1 expression not only by stabilising YAP1 mRNA but also, crucially, by recruiting the eIF4F complex, thereby boosting the translation efficiency of YAP1 mRNA. Additionally, the YAP1/TEAD1 complex transcriptionally regulates METTL7A expression, creating a positive feedback loop that amplifies osteogenic differentiation.

Conclusions: Overall, our study uncovers a previously unknown molecular mechanism of MSC osteogenic differentiation and suggests that activating METTL7A could offer new avenues for enhancing bone regeneration.