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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

Zhao, Jing-Wei; Dyson, Sean C; Kriegel, Christina; Tyers, Pam; He, Xiaoling; Fahmy, Tarek M; Metcalfe, Su M and Barker, Roger A LU (2014) In DMM Disease Models and Mechanisms 7(10). p.1193-1203
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Dopamine, Drug Carriers, Heterocyclic Compounds, 3-Ring, Humans, Leukemia Inhibitory Factor, Microscopy, Electron, Scanning, Nanoparticles, Parkinson Disease, Signal Transduction, Wnt Proteins, beta Catenin, Journal Article, Research Support, Non-U.S. Gov't
in
DMM Disease Models and Mechanisms
volume
7
issue
10
pages
11 pages
publisher
The Company of Biologists Ltd
external identifiers
  • scopus:84907527767
ISSN
1754-8411
DOI
10.1242/dmm.015859
language
English
LU publication?
no
id
6359a8f5-4d04-4629-98e7-7b08f219f221
date added to LUP
2016-11-24 15:03:11
date last changed
2017-09-03 05:15:24
@article{6359a8f5-4d04-4629-98e7-7b08f219f221,
  abstract     = {<p>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.</p>},
  author       = {Zhao, Jing-Wei and Dyson, Sean C and Kriegel, Christina and Tyers, Pam and He, Xiaoling and Fahmy, Tarek M and Metcalfe, Su M and Barker, Roger A},
  issn         = {1754-8411},
  keyword      = {Dopamine,Drug Carriers,Heterocyclic Compounds, 3-Ring,Humans,Leukemia Inhibitory Factor,Microscopy, Electron, Scanning,Nanoparticles,Parkinson Disease,Signal Transduction,Wnt Proteins,beta Catenin,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {10},
  pages        = {1193--1203},
  publisher    = {The Company of Biologists Ltd},
  series       = {DMM Disease Models and Mechanisms},
  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},
  url          = {http://dx.doi.org/10.1242/dmm.015859},
  volume       = {7},
  year         = {2014},
}