title: Oscillatory protein expression dynamics endows stem cells with robust differentiation potential.
abstract: The lack of understanding of stem cell differentiation and proliferation is a fundamental problem in developmental biology. Although gene regulatory networks (GRNs) for stem cell differentiation have been partially identified, the nature of differentiation dynamics and their regulation leading to robust development remain unclear. Herein, using a dynamical system modeling cell approach, we performed simulations of the developmental process using all possible GRNs with a few genes, and screened GRNs that could generate cell type diversity through cell-cell interactions. We found that model stem cells that both proliferated and differentiated always exhibited oscillatory expression dynamics, and the differentiation frequency of such stem cells was regulated, resulting in a robust number distribution. Moreover, we uncovered the common regulatory motifs for stem cell differentiation, in which a combination of regulatory motifs that generated oscillatory expression dynamics and stabilized distinct cellular states played an essential role. These findings may explain the recently observed heterogeneity and dynamic equilibrium in cellular states of stem cells, and can be used to predict regulatory networks responsible for differentiation in stem cell systems.
authors.affiliation: Department of Basic Science and Research Center for Complex Systems Biology, University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: Narito
authors.initials: N
authors.lastname: Suzuki
authors.forename: Chikara
authors.initials: C
authors.lastname: Furusawa
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D002454:Cell Differentiation; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D011506:Proteins
references.citation: Nat Cell Biol. 2008 Mar;10(3):353-60
references.pmid: 18264089
references.citation: Cell Stem Cell. 2009 Oct 2;5(4):420-33
references.pmid: 19796622
references.citation: Mol Syst Biol. 2009;5:293
references.pmid: 19638974
references.citation: Nature. 2008 May 22;453(7194):544-7
references.pmid: 18497826
references.citation: Evol Dev. 2001 Mar-Apr;3(2):84-94
references.pmid: 11341677
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):71-86
references.pmid: 18371337
references.citation: Science. 2002 Oct 25;298(5594):824-7
references.pmid: 12399590
references.citation: Prog Neurobiol. 2002 Jan;66(1):1-18
references.pmid: 11897403
references.citation: Science. 2000 Feb 25;287(5457):1427-30
references.pmid: 10688781
references.citation: Phys Rev Lett. 2005 Apr 1;94(12):128701
references.pmid: 15903968
references.citation: J Theor Biol. 1991 Oct 21;152(4):429-53
references.pmid: 1758194
references.citation: J Theor Biol. 2008 Aug 21;253(4):779-87
references.pmid: 18541270
references.citation: Nat Rev Mol Cell Biol. 2009 Oct;10(10):672-81
references.pmid: 19738627
references.citation: J Theor Biol. 1973 Apr;39(1):103-29
references.pmid: 4741704
references.citation: Cell. 2005 Sep 23;122(6):947-56
references.pmid: 16153702
references.citation: Science. 2008 Jul 4;321(5885):126-9
references.pmid: 18599789
references.citation: Cell Stem Cell. 2008 Oct 9;3(4):391-401
references.pmid: 18940731
references.citation: Nature. 2000 Jan 20;403(6767):335-8
references.pmid: 10659856
references.citation: Nat Neurosci. 2008 Nov;11(11):1247-51
references.pmid: 18956012
references.citation: Development. 1990 Dec;110(4):1001-20
references.pmid: 2100251
references.citation: Phys Rev Lett. 1995 Jul 31;75(5):966-969
references.pmid: 10060163
references.citation: PLoS Biol. 2009 Jan 20;7(1):e15
references.pmid: 19166268
references.citation: J Biol. 2009 Sep 21;8(8):70
references.pmid: 19769787
references.citation: J Biosci. 2009 Oct;34(4):553-72
references.pmid: 19920341
references.citation: Bull Math Biol. 1997 Jan;59(1):139-96
references.pmid: 8980305
references.citation: Phys Rev Lett. 2007 Oct 5;99(14):148103
references.pmid: 17930726
references.citation: FASEB J. 2007 Jul;21(9):2020-32
references.pmid: 17356004
references.citation: Science. 2002 Aug 16;297(5584):1183-6
references.pmid: 12183631
references.citation: Nat Genet. 2006 Apr;38(4):431-40
references.pmid: 16518401
references.citation: Genes Dev. 2009 Aug 15;23(16):1870-5
references.pmid: 19684110
references.citation: Science. 2007 Jul 27;317(5837):526-9
references.pmid: 17569828
references.citation: Cell. 2008 Jun 13;133(6):1106-17
references.pmid: 18555785
references.citation: J Theor Biol. 2001 Apr 21;209(4):395-416
references.pmid: 11319890
references.citation: Science. 2002 Oct 25;298(5594):840-3
references.pmid: 12399594
references.citation: Phys Biol. 2009 Nov 12;6(4):046013
references.pmid: 19910671
references.citation: Bioessays. 2009 May;31(5):546-60
references.pmid: 19319911
references.citation: Oncogene. 2004 Sep 20;23(43):7188-98
references.pmid: 15378079
references.citation: Cell. 1997 Feb 7;88(3):287-98
references.pmid: 9039255
references.citation: FASEB J. 2006 Aug;20(10):1730-2
references.pmid: 16790525
references.citation: Nature. 2007 Dec 20;450(7173):1230-4
references.pmid: 18097409
references.citation: Biol Direct. 2009 May 15;4:17
references.pmid: 19445676
references.citation: Science. 2002 Oct 18;298(5593):597-600
references.pmid: 12228720
references.citation: Bull Math Biol. 1998 Jul;60(4):659-87
references.pmid: 9659010
references.citation: Development. 2008 Mar;135(5):909-18
references.pmid: 18263842
references.citation: J Theor Biol. 1969 Mar;22(3):437-67
references.pmid: 5803332
references.citation: Dev Growth Differ. 2010 Apr;52(3):253-62
references.pmid: 20298257