Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells NATURE COMMUNICATIONS Gao, Y., Yang, P., Shen, H., Yu, H., Song, X., Zhang, L., Zhang, P., Cheng, H., Xie, Z., Hao, S., Dong, F., Ma, S., Ji, Q., Bartlow, P., Ding, Y., Wang, L., Liu, H., Li, Y., Cheng, H., Miao, W., Yuan, W., Yuan, Y., Cheng, T., Xie, X. 2015; 6

Abstract

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 signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.

View details for DOI 10.1038/ncomms7328

View details for Web of Science ID 000350291300004

View details for PubMedID 25692908