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
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2014-10-01
|
| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/7/10/1193 |
| _version_ | 1819058602835443712 |
|---|---|
| author | Jing-Wei Zhao Sean C. Dyson Christina Kriegel Pam Tyers Xiaoling He Tarek M. Fahmy Su M. Metcalfe Roger A. Barker |
| author_facet | Jing-Wei Zhao Sean C. Dyson Christina Kriegel Pam Tyers Xiaoling He Tarek M. Fahmy Su M. Metcalfe Roger A. Barker |
| author_sort | Jing-Wei Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T13:57:49Z |
| format | Article |
| id | doaj.art-cd5c7eae99284186a78ab9fa4c49232b |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-21T13:57:49Z |
| publishDate | 2014-10-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-cd5c7eae99284186a78ab9fa4c49232b2022-12-21T19:01:29ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-10-017101193120310.1242/dmm.015859015859Modelling 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 diseaseJing-Wei ZhaoSean C. DysonChristina KriegelPam TyersXiaoling HeTarek M. FahmySu M. MetcalfeRoger A. BarkerThe 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.http://dmm.biologists.org/content/7/10/1193Parkinson’s diseaseNanotherapyLIFXAV939 |
| spellingShingle | Jing-Wei Zhao Sean C. Dyson Christina Kriegel Pam Tyers Xiaoling He Tarek M. Fahmy Su M. Metcalfe Roger A. Barker 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 Disease Models & Mechanisms Parkinson’s disease Nanotherapy LIF XAV939 |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Parkinson’s disease Nanotherapy LIF XAV939 |
| url | http://dmm.biologists.org/content/7/10/1193 |
| work_keys_str_mv | AT jingweizhao modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT seancdyson modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT christinakriegel modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT pamtyers modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT xiaolinghe modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT tarekmfahmy modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT summetcalfe modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease AT rogerabarker modellingofatargetednanotherapeuticstromatodeliverthecytokineliforxav939apotentinhibitorofwntbcateninsignallingforuseinhumanfetaldopaminergicgraftsinparkinsonsdisease |