METTL1 limits differentiation and functioning of EPCs derived from human-induced pluripotent stem cells through a MAPK/ERK pathway

Transplantation of endothelial progenitor cells (EPCs) has high therapeutic potential for ischemia-related ailments like heart attacks and claudication. Due to limited EPC sources, direct reprogramming is a fast-developing way to convert human-induced pluripotent stem cells (hiPSCs) into EPCs fit for transplantation. However, the procedural efficacy was affected by multiple factors, including epigenetic modifications. Recent studies have shown that m7G methylation mediated by Methyltransferase like 1 (METTL1) is required for mouse embryonic stem cells (mESCs) to differentiate normally. Yet, its contributions to EPC differentiation still require elucidation. Here, using immunofluorescence microscopy and Fluorescence-activated Cell Sorting (FACS), we found that the typical EPC markers were significantly increased in METTL1 knockdown (METTL1-KD) hiPSCs-derived EPCs compared to those of control types. In addition, we found that METTL1 knockdown activates the MAPK/ERK signaling pathway during EPCs differentiation from hiPSCs. Furthermore, functional properties of METTL1-KD EPCs were significantly raised above those of control hiPSCs-derived EPCs. Moreover, we proved that METTL1-KD hiPSCs-derived EPCs significantly accelerate vascular smooth muscle cell proliferation and ‘phenotype switching’ through a co-culture system. To sum up, our results demonstrate that METTL1-KD significantly promotes the differentiation of EPCs along with their in vitro functions, and this effect may be achieved through activation of the MAPK/ERK signaling pathway. This enhances current knowledge of EPC generation from hiPSCs and presents a new therapeutic target of vascular diseases.