In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm.
| Title: | In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm. |
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| Authors: | Novakovsky G; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Sasaki S; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Fornes O; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Omur ME; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Huang H; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.; Bayly CL; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.; Zhang D; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.; Lim N; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; Department of Psychiatry, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Cherkasov A; Department of Urological Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Pavlidis P; Department of Psychiatry, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Mostafavi S; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Department of Statistics, University of British Columbia, Vancouver, BC, Canada; Department of Computer Science, University of Washington, Seattle, WA, USA.; Lynn FC; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada. Electronic address: francis.lynn@ubc.ca.; Wasserman WW; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: wyeth@cmmt.ubc.ca. |
| Source: | Stem cell reports [Stem Cell Reports] 2023 Mar 14; Vol. 18 (3), pp. 765-781. Date of Electronic Publication: 2023 Feb 16. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101611300 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-6711 (Electronic) Linking ISSN: 22136711 NLM ISO Abbreviation: Stem Cell Reports Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Cambridge, MA] : Cell Press, c 2013- |
| MeSH Terms: | Endoderm* ; Human Embryonic Stem Cells*; Cell Differentiation/physiology ; Humans |
| Abstract: | Improving methods for human embryonic stem cell differentiation represents a challenge in modern regenerative medicine research. Using drug repurposing approaches, we discover small molecules that regulate the formation of definitive endoderm. Among them are inhibitors of known processes involved in endoderm differentiation (mTOR, PI3K, and JNK pathways) and a new compound, with an unknown mechanism of action, capable of inducing endoderm formation in the absence of growth factors in the media. Optimization of the classical protocol by inclusion of this compound achieves the same differentiation efficiency with a 90% cost reduction. The presented in silico procedure for candidate molecule selection has broad potential for improving stem cell differentiation protocols.; (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Conflict of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| References: | Stem Cell Reports. 2013 Nov 07;1(5):425-36. (PMID: 24286030); Cell Stem Cell. 2014 Feb 6;14(2):237-52. (PMID: 24412311); Nat Methods. 2017 Nov;14(11):1083-1086. (PMID: 28991892); Nat Genet. 2019 Jun;51(6):999-1010. (PMID: 31110351); Nucleic Acids Res. 1999 Jan 1;27(1):29-34. (PMID: 9847135); J Biol Chem. 2014 May 23;289(21):14913-24. (PMID: 24719321); Genome Biol. 2016 Aug 17;17(1):173. (PMID: 27534536); Cell Stem Cell. 2019 May 2;24(5):812-820.e5. (PMID: 30880026); Nat Commun. 2019 Jul 3;10(1):2939. (PMID: 31270324); Front Cell Dev Biol. 2017 Oct 25;5:93. (PMID: 29119099); Ann Endocrinol (Paris). 2019 Apr;80(2):128-133. (PMID: 30833018); Stem Cells. 2012 Aug;30(8):1624-33. (PMID: 22696450); Gut. 2010 Aug;59(8):1101-10. (PMID: 20442202); Cell Stem Cell. 2017 Oct 5;21(4):502-516.e9. (PMID: 28965765); Blood. 2008 Feb 15;111(4):1876-84. (PMID: 18032708); Stem Cell Reports. 2021 Sep 14;16(9):2395-2409. (PMID: 34450037); J Cell Biochem. 2007 Jan 1;100(1):29-42. (PMID: 16888815); Nat Cell Biol. 2019 Dec;21(12):1518-1531. (PMID: 31792383); BMC Bioinformatics. 2009 Jul 31;10:236. (PMID: 19646231); Cell Stem Cell. 2017 Jan 5;20(1):70-86. (PMID: 27889317); Cell Stem Cell. 2009 Apr 3;4(4):348-58. (PMID: 19341624); Cell J. 2014 Feb 3;16(1):63-72. (PMID: 24518969); Dev Biol. 2005 Sep 1;285(1):156-68. (PMID: 16054124); Database (Oxford). 2015 Sep 30;2015:. (PMID: 26424082); PLoS One. 2015 May 06;10(5):e0126082. (PMID: 25946000); Pancreas. 2012 Jan;41(1):65-73. (PMID: 21792086); Stem Cell Rev Rep. 2014 Aug;10(4):480-93. (PMID: 24913278); Cell. 2017 Nov 30;171(6):1437-1452.e17. (PMID: 29195078); Nat Rev Drug Discov. 2019 Jan;18(1):41-58. (PMID: 30310233); PLoS One. 2014 Dec 04;9(12):e114275. (PMID: 25474420); Nat Biotechnol. 2020 Sep;38(9):1061-1072. (PMID: 32341565); Mol Cell Biol. 1991 Feb;11(2):1009-16. (PMID: 1990262); Cold Spring Harb Perspect Med. 2013 Dec 01;3(12):a014381. (PMID: 24296349); Development. 2015 Jun 15;142(12):2121-35. (PMID: 26015544); Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021); Genes Dev. 2011 Feb 1;25(3):238-50. (PMID: 21245162); Mol Metab. 2017 May 04;6(7):640-650. (PMID: 28702321); Development. 2016 Sep 1;143(17):3050-60. (PMID: 27578176); Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517); Cell. 2015 May 21;161(5):999-1011. (PMID: 26000480); Nucleic Acids Res. 2019 Jul 2;47(W1):W357-W364. (PMID: 31106366); Int J Mol Sci. 2020 Mar 30;21(7):. (PMID: 32235681); BMC Bioinformatics. 2013 Jan 16;14:7. (PMID: 23323831); J Exp Clin Cancer Res. 2019 Oct 28;38(1):428. (PMID: 31665064); Nat Rev Drug Discov. 2015 Jul;14(7):475-86. (PMID: 26091267); J Biol Chem. 2005 Mar 18;280(11):9769-72. (PMID: 15632201); Sci Rep. 2021 Sep 2;11(1):17624. (PMID: 34475469); Prion. 2007 Jan-Mar;1(1):53-60. (PMID: 19164900); Dev Biol. 2011 Apr 15;352(2):354-66. (PMID: 21185279); Dev Cell. 2004 Sep;7(3):331-45. (PMID: 15363409); Mol Pharm. 2018 Oct 1;15(10):4314-4325. (PMID: 30001141); Dev Cell. 2017 Apr 24;41(2):129-142.e6. (PMID: 28441528); Proc Natl Acad Sci U S A. 2009 May 12;106(19):7840-5. (PMID: 19416884); EMBO J. 1997 Sep 1;16(17):5353-62. (PMID: 9311995); Science. 2006 Sep 29;313(5795):1929-35. (PMID: 17008526); J Cell Physiol. 2018 Jun;233(6):4895-4906. (PMID: 29194609); Nat Cell Biol. 2019 Feb;21(2):263-274. (PMID: 30710150); Stem Cell Res. 2018 Apr;28:48-55. (PMID: 29427839) |
| Grant Information: | R01 MH111099 United States MH NIMH NIH HHS; PJT-156377 Canada CIHR; PJT-162120 Canada CIHR |
| Contributed Indexing: | Keywords: bioinformatics; definitive endoderm; differentiation; drug repurposing; growth factor; pathway analysis; stem cell; transcription |
| Entry Date(s): | Date Created: 20230221 Date Completed: 20230320 Latest Revision: 20250222 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10031281 |
| DOI: | 10.1016/j.stemcr.2023.01.008 |
| PMID: | 36801003 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural