Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen


Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Neural Stem Cells

Rigorously defined, adult CNS 'stem cells' exhibit three cardinal features: they are 'self-renewing', with the theoretically unlimited ability to produce progeny indistinguishable from themselves; they are proliferative, continuing to undergo mitosis; and they are multipotent, with the ability to differentiate into neuroectodermal lineages of the CNS.[55] These lineages include a multitude of different neuronal and glial cells subtypes. Multipotent progenitors of the adult brain are proliferative cells with only limited self-renewal that can differentiate into at least two different cell lineages (multipotency).[56–58] Lineage-specific precursors or progenitors cells are cells that are restricted to one distinct lineage (e.g., neuronal, astroglial or oligodendroglial). Together, CNS stem cells and all precursor/progenitor types are broadly defined as 'neural precursors cells'.[55] NSCs can be found in developing embryos or in the adult CNS in the subventricular zone or in the dentate gyrus in the hippocampus.[59] NSCs have been categorized as multipotent stem cells derived from the CNS with the capacity to regenerate and give rise to cells belonging to all three major cell lineages of the nervous system: neurons, astrocytes and oligodendrocytes.[60] Intuitively, NSCs can be seen as ideal cells for neuron generation, or more specifically for DA neuron generation, since they have the same embryonic origin as the desired DA neurons. For NSC-based CRT in PD, differentiation of these cells into phenotypically stable and functional DA neurons is needed. Fetal rodent and human NSCs have been successfully transplanted into animal models of PD, demonstrating that the implanted cells survive, differentiate and migrate in the host brain. These studies further established that implantation of precursor-derived DA neurons from rodents leads to histological, biochemical and functional recovery in PD animal models.[61–65] Moreover, after long-term expansion and DA differentiation of human midbrain NSCs, no tumor formation has been seen and only mild immunoreactions were observed. Transplantation of rat embryonic VM-derived NCSs differentiated into A9 DA phenotype cells through genetic manipulation and exposure to embryonic VM-tissue explants was able to produce partial striatal reinnervation and a significant restitution of motor function.[31] In regard to adult NSCs, DA neurons were generated by two different protocols. The first one include the DA neuron generation from the subventricular zone NSCs, using the known five-step protocol established in ESCs, and the second one involves the genetic manipulation of adult neural progenitors through Nurr1 ectopic insertion.[66,67] Forced expression of Nurr1, a transcriptional factor specific to midbrain DA neuron development, caused NSC acquisition of the DA neurotransmitter phenotype and sufficient differentiation toward morphologically, phenotypically and ultrastructurally mature DA neurons in adults. The Nurr1-induced DA neurons demonstrated in vitro presynaptic DA neuronal functionality, releasing DA neurotransmitter in response to depolarization stimuli and specific DA reuptake.[66,67] Furthermore, Nurr1-engineered adult subventricular zone NSCs survived, and became integrated and differentiated into DA neurons in vivo, reversing the behavioral deficit observed in parkinsonian rats.[67] Fetal mesencephalic NSCs and adult NSCs fulfill some important requirements for CRT in PD, such as high yield of functional DA neuron generation starting from a small number of cells, and a major advantage is the fact that they can only be differentiated into CNS cells by natural fate, restricting the cell diversification possibilities.[61,68] Although NSCs seem to be the ideal source for neuronal CRT, their residence deep within the human brain makes them an unlikely source for harvesting. Therefore, researchers looked towards other stem cell population, which are more readily available, with easy access harvesting methods in humans and with plastic functions to generate selective neural populations.[69]