title: Modelling of a targeted nanotherapeutic 'stroma' to deliver the cytokine LIF, or XAV939, a potent inhibitor of Wnt-β-catenin signalling, for use in human fetal dopaminergic grafts in Parkinson's disease.
abstract: The endogenous reparative capacity of the adult human brain is low, and chronic neurodegenerative disorders of the central nervous system represent one of the greatest areas of unmet clinical need in the developing world. Novel therapeutic strategies to treat them include: (i) growth factor delivery to boost endogenous repair and (ii) replacement cell therapy, including replacing dopaminergic neurons to treat Parkinson's disease (PD). However, these approaches are restricted not only by rapid degradation of growth factors, but also by the limited availability of cells for transplant and the poor survival of implanted cells that lack the necessary stromal support. We therefore hypothesised that provision of a transient artificial stroma for paracrine delivery of pro-survival factors could overcome both of these issues. Using leukaemia inhibitory factor (LIF) - a proneural, reparative cytokine - formulated as target-specific poly(lactic-co-glycolic acid) (PLGA) nano-particles (LIF-nano-stroma), we discovered that attachment of LIF-nano-stroma to freshly isolated fetal dopaminergic cells improved their survival fourfold: furthermore, in vivo, the number of surviving human fetal dopaminergic cells tended to be higher at 3 months after grafting into the striatum of nude rats, compared with controls treated with empty nanoparticles. In addition, we also analysed the effect of a novel nano-stroma incorporating XAV939 (XAV), a potent inhibitor of the developmentally important Wnt-β-catenin signalling pathway, to investigate whether it could also promote the survival and differentiation of human fetal dopaminergic precursors; we found that the numbers of both tyrosine-hydroxylase-positive neurons (a marker of dopaminergic neurons) and total neurons were increased. This is the first demonstration that LIF-nano-stroma and XAV-nano-stroma each have pro-survival effects on human dopaminergic neurons, with potential value for target-specific modulation of neurogenic fate in cell-based therapies for PD.
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Zhao
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Dyson
authors.affiliation: Department of Biomedical Engineering, Yale University, Malone Engineering Center, 55 Prospect Street, New Haven, CT 06511, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Kriegel
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK.
authors.forename: Pam
authors.initials: P
authors.lastname: Tyers
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Biomedical Engineering, Yale University, Malone Engineering Center, 55 Prospect Street, New Haven, CT 06511, USA.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK. smm1001@cam.ac.uk.
authors.forename: Su M
authors.initials: SM
authors.lastname: Metcalfe
authors.affiliation: John van Geest Centre for Brain Repair, Addenbrookes Hospital, University of Cambridge, Cambridge, CB2 0PY, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
mesh_terms: D004298:Dopamine / Q000008:administration & dosage; D004337:Drug Carriers; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage*; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D010300:Parkinson Disease / Q000628:therapy*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; D006575:Heterocyclic Compounds, 3-Ring; D053605:Leukemia Inhibitory Factor; D051153:Wnt Proteins; C544261:XAV939; D051176:beta Catenin; D004298:Dopamine
keywords: LIF; Nanotherapy; Parkinson’s disease; XAV939
references.citation: Am J Physiol Endocrinol Metab. 2012 Feb 15;302(4):E458-67
references.pmid: 22146310
references.citation: Biomaterials. 2012 Oct;33(28):6634-43
references.pmid: 22749449
references.citation: Nat Biotechnol. 2005 Jan;23(1):47-55
references.pmid: 15637621
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92
references.pmid: 20133810
references.citation: J Control Release. 2012 Jul 20;161(2):505-22
references.pmid: 22353619
references.citation: J Neurosci. 2005 Apr 20;25(16):4091-8
references.pmid: 15843611
references.citation: Curr Opin Neurobiol. 2000 Jun;10(3):392-9
references.pmid: 10851180
references.citation: Nat Commun. 2013;4:2403
references.pmid: 23985566
references.citation: Exp Neurol. 1998 Feb;149(2):411-23
references.pmid: 9500954
references.citation: Immunity. 2011 Aug 26;35(2):273-84
references.pmid: 21835648
references.citation: Restor Neurol Neurosci. 2013;31(5):579-95
references.pmid: 23777636
references.citation: Nature. 1991 Mar 21;350(6315):230-2
references.pmid: 2005978
references.citation: Development. 2013 Apr;140(8):1684-92
references.pmid: 23487312
references.citation: Mol Pharm. 2011 Feb 7;8(1):143-52
references.pmid: 20977190
references.citation: Nature. 2009 Oct 1;461(7264):614-20
references.pmid: 19759537
references.citation: Exp Neurol. 2000 Apr;162(2):350-60
references.pmid: 10739641
references.citation: PLoS One. 2012;7(12):e50265
references.pmid: 23227162
references.citation: Chem Eng Sci. 2012 May 28;74:114-123
references.pmid: 22485051
references.citation: Cell Cycle. 2009 May 1;8(9):1444-50
references.pmid: 19342884
references.citation: J Clin Invest. 2013 Jun;123(6):2364-5
references.pmid: 23728166
references.citation: J Neurosci. 2012 Feb 8;32(6):2100-9
references.pmid: 22323722
references.citation: Nat Biotechnol. 2001 Oct;19(10):934-9
references.pmid: 11581658
references.citation: Neuroscience. 1993 Feb;52(4):855-66
references.pmid: 8095710
references.citation: Nat Commun. 2013;4:2597
references.pmid: 24169527
references.citation: Curr Protoc Stem Cell Biol. 2009 Dec;Chapter 2:Unit 2D.5
references.pmid: 19960452
references.citation: Genes Dev. 2011 Sep 1;25(17):1783-95
references.pmid: 21856776
references.citation: Mol Ther. 2008 Apr;16(4):765-72
references.pmid: 18334990
references.citation: Science. 2002 May 31;296(5573):1644-6
references.pmid: 12040179