Understanding the molecular basis of mesenchymal stem cell stemness: implications for clinical applications

Human mesenchymal stem cells (MSCs) have been studied in over 1500 clinical trials to treat over 30 diseases. However, the understanding towards MSC stemness remains under studied. So far, little is known about how MSCs maintain undifferentiated state or commit to specific lineages under different microenvironmental cues. The lack of comprehensive understanding regarding MSC stemness greatly hampers the translation of research findings into successful clinical application due to unclear mechanism of action. Emerging evidence shows that a variety of genetic factors delicately regulate MSC self-renewal and differentiation. In this review, we summarize the role of transcriptional factors, cell cycle regulators, genomic stability genes, cellular quality control, epigenetic regulators, non-coding RNAs, mitochondrial function, growth factors and m6A modification in regulating the stemness of MSCs. Strategies to maintain MSC stemness during ex-vivo expansion are also discussed. This review will deepen understanding of MSC stemness for advancing clinical applications and provide insights into future directions for research aimed at improving MSC-based therapies.