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.
Highlights
The prevalence of neurodegenerative disease is increasing as the population ages
They report that LIF-nano-stroma, a prototype biodegradable poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle matrix (PLGA is FDA approved for therapeutic devices) loaded with leukaemia inhibitory factor (LIF; a proneural and reparative factor) provided fourfold increased survival when targeted to DA neurons maintained ex vivo
To overcome the problem of the rapid degradation of LIF and its excretion in vivo, we previously developed LIF formulated as PLGAnanoparticles (LIF-nano) and demonstrated that LIF-nano is superior to soluble LIF in being able to provide a stable source of low-dose LIF, mimicking paracrine delivery (Park et al, 2011), with activation of the STAT-3 signalling pathway (Anna Williams and S.M.M., unpublished observations)
Summary
The prevalence of neurodegenerative disease is increasing as the population ages. After Alzheimer’s disease, Parkinson’s disease (PD) is the second commonest neurodegenerative disorder of the central nervous system (CNS). The concept of replacing lost DA neurons with healthy cells of the same lineage underpins one major clinical approach that uses allografts of human fetal ventral mesencephalic (hfVM) tissue. This strategy has shown significant long-term benefits in some patients with PD (reviewed by Barker et al, 2013). As is the case for all cellular therapeutic approaches, two challenges arise: first, the need to deliver appropriate numbers of cells to the right site(s) and, second, to promote their survival long-term In this latter respect, therapeutic support of the transplanted cells is required, raising the question, can the delivery of neurogenic growth factors or small molecules improve the efficacy and efficiency of cell therapy? Many fetuses are required to graft a single individual, owing to the loss of harvested DA neurons denuded of their natural stromal microenvironment
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