Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen

Disclosures

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

In This Article

Embryonic Stem Cells

Embryonic stem cells have many characteristics required for an optimal cell source for CRT. ESCs are undifferentiated, self-renewing cells and possess the potential to differentiate into all three germ layers.[70] ESCs taken from the inner mass of the preimplanted blastocyst can be differentiated into NSCs or neural precursor cells (NPCs), and subsequently to DA neurons.[32,71] The DA neurons generated from these cells show morphological, functional and electrophysiological properties of midbrain neurons;[37] however, poor cell survival and phenotypic stability has been observed after intrastriatal transplantation.[72] Undifferentiated ESC were injected into the striatum of 6-hydroxydopamine (6-OHDA) hemiparkinsonian rat model and 14–16 weeks later, 20% of the rats developed teratoma-like tumors, 24% showed no graft survival and 56% had graft-derived, functional, integrated DA neurons within the affected striatum, with behavioral improvements.[30] In order to obviate the potential undesirable side effects derived from contaminated non-DA cells or remaining undifferentiated human ESCs and obtain a homogeneous DA neuronal population, a strict and efficient differentiation protocol is required. Therefore, coaxing human ESCs efficiently into neural lineage is the first step of the DA differentiation procedure.[73] In 2001, three groups separately reported protocols to generate NPCs from human ESCs. The NPCs generated by these methods were able to be further differentiated into cell types of three neural lineages; neurons, astrocytes and oligodendrocytes, in which the NPC-derived neurons were shown to display similar characteristics of mature neurons.[74] Essentially, two main protocols have been established to generate DA neurons from human ESCs: coculture of ESCs with stromal feeder cells[71] and embryonic bodies (EB)-based multistage method.[75] Cultivated human ESCs on PA6 stromal feeder cells resulted in the appearance of TH+ cells in approximately 87% of the colonies. The generated cells coexpressed DA neuron markers, synthesized and released dopamine and formed a graft stably integrated in the striatum of 6-OHDA-lesioned rats.[40] Utilization of MS5 stromal feeder cells to induce neuronal differentiation, with subsequent treatment with specific factors, yielded a high number of TH+ cells (30–50% of the cells were neurons and 64–79% of the neurons were TH+).[76] On the other hand, the EB-based method has also been used by many laboratories for the differentiation of human ESCs into DA neurons. Recently, Cho et al. reported a highly efficient differentiation protocol in which they were able to produce high yield of functional TH+ cells after differentiation: 77% of the cells differentiated into neurons and 86% of the neurons were TH+ cells.[77] The most unique feature of this protocol is the generation of neurosphere-like structures, so-called 'spherical neural masses' (SNMs). The SNMs could be expanded for a long time, frozen and thawed freely on demand, and differentiated into DA neurons within 14 days.[77] These characteristics are highly beneficial, enabling the production of a large number of DA neurons within a short time for cell transplantation. Despite all of these promising results, the ESC usage for CRT faces several limitations owing to ethical limitations and their capacity to form teratomas. The problem of controlling cell growth and differentiation is still unsolved and tumor formation is commonly observed after ESC transplantation.[61] Therefore, several obstacles still prevent the use of ESCs to treat human patients.

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