2. Academic Validation
  3. Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells

Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells

  • Nat Commun. 2015 Feb 18:6:6328. doi: 10.1038/ncomms7328.
Yingdai Gao 1,  Peng Yang 2,  Hongmei Shen 3,  Hui Yu 3,  Xianmin Song 4,  Liyan Zhang 1,  Peng Zhang 2,  Haizi Cheng 2,  Zhaojun Xie 2,  Sha Hao 1,  Fang Dong 1,  Shihui Ma 1,  Qing Ji 1,  Patrick Bartlow 2,  Yahui Ding 1,  Lirong Wang 2,  Haibin Liu 2,  Yanxin Li 1,  Hui Cheng 1,  Weimin Miao 1,  Weiping Yuan 1,  Youzhong Yuan 1,  Tao Cheng 1,  Xiang-Qun Xie 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
  • 2 1] Department of Pharmaceutical Sciences, Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute, Pittsburgh, Pennsylvania 15260, USA [2] Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
  • 3 Department of Radiation Oncology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
  • 4 Department of Hematology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, China.
PMID: 25692908 DOI: 10.1038/ncomms7328
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.

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