title: Sparse feature selection methods identify unexpected global cellular response to strontium-containing materials.
abstract: Despite the increasing sophistication of biomaterials design and functional characterization studies, little is known regarding cells' global response to biomaterials. Here, we combined nontargeted holistic biological and physical science techniques to evaluate how simple strontium ion incorporation within the well-described biomaterial 45S5 bioactive glass (BG) influences the global response of human mesenchymal stem cells. Our objective analyses of whole gene-expression profiles, confirmed by standard molecular biology techniques, revealed that strontium-substituted BG up-regulated the isoprenoid pathway, suggesting an influence on both sterol metabolite synthesis and protein prenylation processes. This up-regulation was accompanied by increases in cellular and membrane cholesterol and lipid raft contents as determined by Raman spectroscopy mapping and total internal reflection fluorescence microscopy analyses and by an increase in cellular content of phosphorylated myosin II light chain. Our unexpected findings of this strong metabolic pathway regulation as a response to biomaterial composition highlight the benefits of discovery-driven nonreductionist approaches to gain a deeper understanding of global cell-material interactions and suggest alternative research routes for evaluating biomaterials to improve their design.
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Hélène
authors.initials: H
authors.lastname: Autefage
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom; Craniofacial Development and Stem Cell Biology, King's College London, London SE1 9RT, United Kingdom;
authors.forename: Eileen
authors.identifier: http://orcid.org/0000-0003-0447-5137
authors.initials: E
authors.lastname: Gentleman
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Elena
authors.initials: E
authors.lastname: Littmann
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom; Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, DK-5230 Odense, Denmark;
authors.forename: Martin A B
authors.initials: MA
authors.lastname: Hedegaard
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Von Erlach
authors.affiliation: Departments of Materials and.
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Donnell
authors.affiliation: Cell Biology Group, Biomedical Manufacturing Program, CSIRO Manufacturing Flagship, Clayton 3168, VIC, Australia;
authors.forename: Frank R
authors.initials: FR
authors.lastname: Burden
authors.affiliation: Cell Biology Group, Biomedical Manufacturing Program, CSIRO Manufacturing Flagship, Clayton 3168, VIC, Australia; Monash Institute of Pharmaceutical Sciences, Parkville 3052, VIC, Australia; and Latrobe Institute of Molecular Science, Latrobe University, Bundoora 3086, VIC, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Winkler
authors.affiliation: Departments of Materials and Bioengineering and Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom; m.stevens@imperial.ac.uk.
authors.forename: Molly M
authors.initials: MM
authors.lastname: Stevens
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry*; D001861:Bone Regeneration; D018786:Bone Substitutes / Q000737:chemistry*; D002516:Ceramics / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D017077:Culture Media, Conditioned / Q000737:chemistry; D005898:Glass / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008422:Materials Testing; D021962:Membrane Microdomains; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008798:Mevalonic Acid / Q000737:chemistry; D046228:Microarray Analysis; D009218:Myosins / Q000737:chemistry; D010766:Phosphorylation; D011506:Proteins / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D013059:Spectrum Analysis, Raman; D013324:Strontium / Q000737:chemistry*; D015854:Up-Regulation
chemical_list: D001672:Biocompatible Materials; D018786:Bone Substitutes; D017077:Culture Media, Conditioned; D008055:Lipids; D011506:Proteins; D012333:RNA, Messenger; C425330:bioactive glass 45S5; D002784:Cholesterol; D009218:Myosins; D008798:Mevalonic Acid; D013324:Strontium
keywords: human mesenchymal stem cells; mevalonate pathway; microarray analysis; sparse feature selection analysis; strontium-releasing biomaterials
references.citation: Science. 2000 Dec 1;290(5497):1721-6
references.pmid: 11099405
references.citation: Chem Phys Lipids. 2007 Mar;146(1):1-25
references.pmid: 17241621
references.citation: Nat Rev Mol Cell Biol. 2000 Oct;1(1):31-9
references.pmid: 11413487
references.citation: J Neurosci Res. 2002 Jul 15;69(2):227-32
references.pmid: 12111804
references.citation: J Biol Chem. 2002 Nov 8;277(45):43399-409
references.pmid: 12202484
references.citation: N Engl J Med. 2004 Jan 29;350(5):459-68
references.pmid: 14749454
references.citation: Science. 2004 Feb 6;303(5659):839-42
references.pmid: 14764880
references.citation: Dev Cell. 2004 Apr;6(4):483-95
references.pmid: 15068789
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: J Biol Chem. 1996 Aug 23;271(34):20246-9
references.pmid: 8702756
references.citation: Mol Biol Cell. 1999 Jul;10(7):2441-59
references.pmid: 10397775
references.citation: J Clin Endocrinol Metab. 2005 May;90(5):2816-22
references.pmid: 15728210
references.citation: FASEB J. 2005 Nov;19(13):1845-7
references.pmid: 16160062
references.citation: Cell Mol Life Sci. 2006 Feb;63(3):255-67
references.pmid: 16378247
references.citation: Stem Cells. 2006 May;24(5):1213-7
references.pmid: 16439616
references.citation: Cell. 2006 Aug 25;126(4):677-89
references.pmid: 16923388
references.citation: Biochem Soc Trans. 2007 Jun;35(Pt 3):544-9
references.pmid: 17511648
references.citation: J Biol Chem. 2007 Jun 29;282(26):18777-85
references.pmid: 17483544
references.citation: Immunol Cell Biol. 2007 Jul;85(5):378-82
references.pmid: 17325693
references.citation: Bone. 2008 Jan;42(1):129-38
references.pmid: 17945546
references.citation: J Cell Biochem. 2008 Jul 1;104(4):1427-38
references.pmid: 18348254
references.citation: Clin Genet. 2009 Jan;75(1):19-29
references.pmid: 19054015
references.citation: Nat Mater. 2009 Jun;8(6):457-70
references.pmid: 19458646
references.citation: Biomaterials. 2009 Jul;30(21):3542-50
references.pmid: 19339047
references.citation: Cell Mol Life Sci. 2009 Jul;66(14):2319-28
references.pmid: 19370312
references.citation: Nat Mater. 2009 Sep;8(9):763-70
references.pmid: 19633661
references.citation: Biomaterials. 2010 May;31(14):3949-56
references.pmid: 20170952
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4872-7
references.pmid: 20194780
references.citation: Acta Biomater. 2010 Jul;6(7):2843-51
references.pmid: 20085830
references.citation: J Biol Chem. 2010 Aug 13;285(33):25251-8
references.pmid: 20554534
references.citation: Mol Pharmacol. 2011 Feb;79(2):251-61
references.pmid: 21056967
references.citation: Biomaterials. 2011 Apr;32(11):2757-74
references.pmid: 21292319
references.citation: EMBO J. 2012 Feb 1;31(3):534-51
references.pmid: 22157745
references.citation: J Proteome Res. 2012 Feb 3;11(2):586-98
references.pmid: 22088210
references.citation: Biomaterials. 2012 Apr;33(11):3205-15
references.pmid: 22285104
references.citation: Pharmacol Ther. 2012 Nov;136(2):216-26
references.pmid: 22820094
references.citation: Sci Transl Med. 2012 Nov 14;4(160):160sr4
references.pmid: 23152328
references.citation: ACS Nano. 2012 Nov 27;6(11):10239-49
references.pmid: 23072705
references.citation: ASN Neuro. 2012;4(6):409-21
references.pmid: 23127255
references.citation: Biomaterials. 2013 Apr;34(13):3184-95
references.pmid: 23380352
references.citation: Nat Methods. 2013 Mar;10(3):259-64
references.pmid: 23396283
references.citation: Integr Biol (Camb). 2013 Jul 24;5(7):920-31
references.pmid: 23752904
references.citation: Trends Biotechnol. 2013 Oct;31(10):594-605
references.pmid: 24012308
references.citation: J Bone Miner Metab. 2013 Nov;31(6):606-12
references.pmid: 23925392
references.citation: Biochim Biophys Acta. 2014 Feb;1838(2):532-45
references.pmid: 23899502
references.citation: Cell Mol Life Sci. 2014 May;71(9):1703-21
references.pmid: 24276852
references.citation: Tissue Eng Part A. 2014 Jul;20(13-14):1850-7
references.pmid: 24471799
references.citation: J Biomed Mater Res. 2001 May;55(2):151-7
references.pmid: 11255166