A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons.
Sirtuin 1 (SIRT1) is known to suppress differentiation of pluripotent/multipotent cells and neural progenitor cells into neurons by blocking activation of transcription factors critical for neurogenesis. EX-527 is a highly selective and potent inhibitor against SIRT1 and has been used as a chemical probe that modulates SIRT1-associated biological processes. However, the effect of EX-527 on neuronal differentiation in pluripotent cells has not been well elucidated. Here, we report an examination of EX-527 effects on neurogenesis of pluripotent P19 cells. The results showed that EX-527 greatly accelerated differentiation of P19 cells into neurons without generation of cardiac cells and astrocytes. Importantly, neurons derived from P19 cells treated with EX-527 generated voltage-dependent sodium currents and depolarization-induced action potentials. The findings indicate that the differentiated cells have electrophysiological properties. The present study suggests that the selective SIRT1 inhibitor could have the potential of being employed as a chemical inducer to generate functionally active neurons.
National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 03722, Korea.
Beom Seok
BS
Kim
National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 03722, Korea.
Chang-Hee
CH
Lee
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Gyeong-Eon
GE
Chang
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Eunji
E
Cheong
National Creative Research Initiative Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 03722, Korea.
Injae
I
Shin
Nature. 2000 Feb 17;403(6771):795-800
10693811
Nature. 2001 Mar 8;410(6825):227-30
11242085
J Biol Chem. 2001 Oct 19;276(42):38837-43
11483616
Cell. 2001 Oct 19;107(2):137-48
11672522
Cell. 2001 Oct 19;107(2):149-59
11672523
Biochem Biophys Res Commun. 2003 Jan 31;301(1):250-7
12535671
Genome Biol. 2003;4(3):207
12620097
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7632-7
12794184
Science. 1992 Oct 23;258(5082):597-603
1329206
Cancer Cell. 2004 Jan;5(1):91-102
14749129
Exp Mol Med. 2004 Dec 31;36(6):515-23
15665584
J Biol Chem. 2005 Apr 29;280(17):17187-95
15749705
Cell. 2005 Nov 4;123(3):437-48
16269335
J Med Chem. 2005 Dec 1;48(24):7789-95
16302818
Angew Chem Int Ed Engl. 2006 Jan 16;45(4):591-3
16323231
Mol Cell Biol. 2006 Jan;26(1):28-38
16354677
Cell Prolif. 2006 Aug;39(4):281-300
16872363
Cell. 2006 Jul 28;126(2):257-68
16873059
Genes Dev. 2006 Nov 1;20(21):2913-21
17079682
Nat Cell Biol. 2007 Jun;9(6):625-35
17515932
J Am Chem Soc. 2007 Aug 1;129(30):9258-9
17622149
Nat Cell Biol. 2008 Apr;10(4):385-94
18344989
Dev Cell. 2008 May;14(5):661-73
18477450
Nat Chem Biol. 2008 Jul;4(7):408-10
18552832
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15599-604
18829436
Nat Neurosci. 2008 Dec;11(12):1383-91
18997789
Nat Biotechnol. 2009 Mar;27(3):275-80
19252484
Nat Chem Biol. 2009 Apr;5(4):217-9
19252499
Cell. 2009 Apr 17;137(2):216-33
19379690
Nature. 2009 Jul 30;460(7255):587-91
19641587
Biochim Biophys Acta. 2010 Aug;1804(8):1666-75
19879981
Nucleic Acids Res. 2010 Jan;38(3):822-31
19934264
Annu Rev Pathol. 2010;5:253-95
20078221
Mol Cancer Ther. 2010 Apr;9(4):844-55
20371709
Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13736-41
20631301
Physiol Rev. 2010 Jul;90(3):905-81
20664076
Mol Biol Cell. 2011 Feb 15;22(4):503-12
21169561
Aging (Albany NY). 2011 Feb;3(2):162-7
21307403
Annu Rev Biomed Eng. 2011 Aug 15;13:73-90
21513460
Blood. 2012 Feb 23;119(8):1856-60
22219225
Biochim Biophys Acta. 2013 Feb;1830(2):2435-48
22982587
J Neurosci Res. 2013 May;91(5):642-59
23404532
J Cell Sci. 2012 Dec 1;125(Pt 23):5609-20
23420199
Genes Cancer. 2013 Mar;4(3-4):105-11
24020001
Neuroreport. 2013 Dec 18;24(18):1041-6
24257250
J Cell Physiol. 2014 Sep;229(9):1224-35
24435709
Blood. 2014 Jul 3;124(1):121-33
24855208
Angew Chem Int Ed Engl. 2014 Aug 25;53(35):9271-4
25044422
Dev Growth Differ. 2014 Aug;56(6):460-8
25131500
Br J Clin Pharmacol. 2015 Mar;79(3):477-91
25223836
ACS Chem Neurosci. 2014 Dec 17;5(12):1164-77
25250644
Mol Neurobiol. 2016 Jul;53(5):2815-2825
25850787
Cell Stem Cell. 2015 Aug 6;17(2):195-203
26253201
Cell Stem Cell. 2015 Aug 6;17(2):204-12
26253202
Chem Biol. 2015 Nov 19;22(11):1512-1520
26590637
Mol Cell Biol. 1983 Dec;3(12):2280-6
6656767
Dev Biol. 1982 Feb;89(2):503-8
7056443
J Cell Biol. 1982 Aug;94(2):253-62
7107698
Brain Res. 1994 Aug 1;652(2):216-24
7953733
Genes Dev. 1995 Dec 15;9(24):3136-48
8543157
J Neurosci. 1996 Feb 1;16(3):1056-65
8558234