我重点实验室高瀛岱研究员等在Nature Communications发表文章“Small-molecule inhibitors targeting INK4 protein ?p18INK4C enhance ex vivoexpansion of haematopoietic stem cells”,该文章于2015年2月18日发表,其中共同第一作者为高瀛岱、杨鹏、沈红梅,通讯作者为程涛教授和解向群教授。
Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signaling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.