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

Nature Communications

Volumn 6, Issue , 2015, Pages

  Gao, Yingdai ^a   Yang, Peng ^b,c   Shen, Hongmei ^c   Yu, Hui ^c   Song, Xianmin ^d   Zhang, Liyan ^a   Zhang, Peng ^b,c   Cheng, Haizi ^b,c   Xie, Zhaojun ^b,c   Hao, Sha ^a   Dong, Fang ^a   Ma, Shihui ^a   Ji, Qing ^a   Bartlow, Patrick ^b,c   Ding, Yahui ^a   Wang, Lirong ^b,c   Liu, Haibin ^b,c   Li, Yanxin ^a   Cheng, Hui ^a   Miao, Weimin ^a   Yuan, Weiping ^a   Yuan, Youzhong ^a   Cheng, Tao ^a   Xie, Xiang Qun ^b,c   more..

^a INSTITUTE OF HEMATOLOGY AND BLOOD DISEASES HOSPITAL   (China)

^b Universigy of Pittsburgh   (United States)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 [3 [[2 (BENZOYL) 4 CHLOROPHENYL]AMINO] 2 HYDROXYPROPOXY] 5 CHLOROPHENYL]ETHANONE; 1,2 BENZOXAZOL 3 YL 4 ACETAMIDOBENZENESULFONATE; 2 BUTYLAMINO 1 (4 METHOXYPHENYL) 2 PHENYLETHANONE; 4,5 BIS(4 METHOXYPHENYL) 1,5 DIHYDROIMIDAZOL 2 ONE; CYCLIN DEPENDENT KINASE INHIBITOR; CYCLIN DEPENDENT KINASE INHIBITOR 1B; CYCLIN DEPENDENT KINASE INHIBITOR 2C; N ACETYL 4,4' DIAMINO DIPHENYLSULFONE; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; PALBOCICLIB; SMALL MOLECULE TRANSPORT AGENT; UNCLASSIFIED DRUG; CDK6 PROTEIN, MOUSE; CDKN1B PROTEIN, MOUSE; CDKN2C PROTEIN, MOUSE; CYCLIN DEPENDENT KINASE 6;

ENZYME ACTIVITY; GENE EXPRESSION; INHIBITOR; LEAD; PROTEIN; RODENT; SIGNALING; SILICON;

ANIMAL EXPERIMENT; ARTICLE; CELL DIVISION; CELL RENEWAL; COMPUTER MODEL; CONTROLLED STUDY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SPECIFICITY; DRUG TARGETING; EX VIVO STUDY; FEMALE; GENE DELETION; HEMATOPOIETIC STEM CELL; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; MALE; MOUSE; NONHUMAN; PROTEIN FUNCTION; PROTEIN STRUCTURE; SIGNAL TRANSDUCTION; SINGLE CELL ANALYSIS; STEM CELL CULTURE; STEM CELL EXPANSION; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; C57BL MOUSE; CELL CULTURE TECHNIQUE; CELL CYCLE; CELL PROLIFERATION; CELL SEPARATION; COCULTURE; CYTOLOGY; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; KNOCKOUT MOUSE; METABOLISM; NEUTROPHIL; PHENOTYPE; STEM CELL;

ANIMALS; APOPTOSIS; CELL CULTURE TECHNIQUES; CELL CYCLE; CELL PROLIFERATION; CELL SEPARATION; COCULTURE TECHNIQUES; CYCLIN-DEPENDENT KINASE 6; CYCLIN-DEPENDENT KINASE INHIBITOR P18; CYCLIN-DEPENDENT KINASE INHIBITOR P27; FEMALE; GENE DELETION; GENE EXPRESSION REGULATION; HEMATOPOIETIC STEM CELLS; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; NEUTROPHILS; PHENOTYPE; SIGNAL TRANSDUCTION; SINGLE-CELL ANALYSIS; STEM CELLS;

EID: 84923658915     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms7328     Document Type: Article

References (37)

1. Cheng, T. Cell cycle inhibitors in normal and tumor stem cells. Oncogene 23, 7256-7266 (2004).
2. Boyer, M. J. & Cheng, T. The CDK inhibitors: potential targets for therapeutic stem cell manipulations? Gene Ther. 15, 117-125 (2008).
3. Matsumoto, A. et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell 9, 262-271 (2011).
4. Zou, P. et al. p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 9, 247-261 (2011).
5. Sherr, C. J. & Roberts, J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149-1163 (1995).
6. Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T. & Cheng, T. In vivo selfrenewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat. Cell. Biol. 6, 436-442 (2004).
7. Yu, H., Yuan, Y., Shen, H. & Cheng, T. Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 107, 1200-1206 (2006).
8. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421-426 (2006).
9. Broxmeyer, H. E., Franklin, D. S., Cooper, S., Hangoc, G. & Mantel, C. Cyclin dependent kinase inhibitors differentially modulate synergistic cytokine responsiveness of hematopoietic progenitor cells. Stem Cells Dev. 21, 1597-1603 (2012).
10. Bowie, M. B., Kent, D. G., Copley, M. R. & Eaves, C. J. Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells. Blood 109, 5043-5048 (2007).
11. Sirin, O., Lukov, G. L., Mao, R., Conneely, O. M. & Goodell, M. A. The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat. Cell. Biol. 12, 1213-1219 (2010).
12. Walkley, C. R., Fero, M. L., Chien, W. M., Purton, L. E. & McArthur, G. A. Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nat. Cell. Biol. 7, 172-178 (2005).
13. Cheng, T., Rodrigues, N., Dombkowski, D., Stier, S. & Scadden, D. T. Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nature Med. 6, 1235-1240 (2000).
14. Takano, H., Ema, H., Sudo, K. & Nakauchi, H. Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs. J. Exp. Med. 199, 295-302 (2004).
15. Ema, H., Takano, H., Sudo, K. & Nakauchi, H. In vitro self-renewal division of hematopoietic stem cells. J. Exp. Med. 192, 1281-1288 (2000).
16. Mossadegh-Keller, N. et al. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497, 239-243 (2013).
17. Chen, J. Z., Wang, J. & Xie, X. Q. GPCR structure-based virtual screening approach for CB2 antagonist search. J. Chem. Inf. Model. 47, 1626-1637 (2007).
18. Xie, X. Q., Chen, J. Z. & Billings, E. M. 3D structural model of the G-proteincoupled cannabinoid CB2 receptor. Proteins 53, 307-319 (2003).
19. Venkataramani, R., Swaminathan, K. & Marmorstein, R. Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations. Nature Struct. Biol. 5, 74-81 (1998).
20. Jeffrey, P. D., Tong, L. & Pavletich, N. P. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dev. 14, 3115-3125 (2000).
21. Xie, X. Q. & Chen, J. Data-mining a small molecule drug screening representative subset from NIH PubChem database. J. Comput. Inf. Model. 48, 465-475 (2008).
22. Greenberger, J. S., Sakakeeny, M. & Parker, L. M. In vitro proliferation of hemopoietic stem cells in long-term marrow cultures: principles in mouse applied to man. Exp. Hematol. 7(Suppl 5), 135-148 (1979).
23. Song, Y. et al. Stem cell traits in long-term co-culture revealed by time-lapse imaging. Leukemia 24, 153-161 (2010).
24. Huynh, H. et al. IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood 118, 3236-3243 (2011).
25. Zhang, C. C., Kaba, M., Iizuka, S., Huynh, H. & Lodish, H. F. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 111, 3415-3423 (2008).
26. Zhang, Y., Li, W., Laurent, T. & Ding, S. Small molecules, big roles-the chemical manipulation of stem cell fate and somatic cell reprogramming. J. Cell. Sci. 125, 5609-5620 (2012).
27. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55-63 (2004).
28. Trowbridge, J. J., Xenocostas, A., Moon, R. T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Med. 12, 89-98 (2006).
29. Perry, J. M. et al. Cooperation between both Wnt/{beta}-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion. Genes Dev. 25, 1928-1942 (2011).
30. Huang, J., Nguyen-McCarty, M., Hexner, E. O., Danet-Desnoyers, G. & Klein, P. S. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nature Med. 18, 1778-1785 (2012).
31. Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345-1348 (2010).
32. Fares, I. et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509-1512 (2014).
33. Li, Y. et al. An opposite effect of the CDK inhibitor, p18(INK4c) on embryonic stem cells compared with tumor and adult stem cells. PLoS ONE 7, e45212 (2012).
34. Yuan, Y. et al. Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18(INK4C)-null reconstituted mice. Cancer Res. 66, 343-351 (2006).
35. Cheng, H., Liang, P. H. & Cheng, T. Mouse hematopoietic stem cell transplantation. Methods Mol. Biol. 976, 25-35 (2013).
36. Shen, H., Boyer, M. & Cheng, T. Flow cytometry-based cell cycle measurement of mouse hematopoietic stem and progenitor cells. Methods Mol. Biol. 430, 77-86 (2008).
37. Venkataramani, R. N., MacLachlan, T. K., Chai, X., El-Deiry, W. S. & Marmorstein, R. Structure-based design of p18INK4c proteins with increased thermodynamic stability and cell cycle inhibitory activity. J. Biol. Chem. 277, 48827-48833 (2002).