Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies

Abstract

Current approaches to cell replacement therapy in Parkinson's disease are strongly focused on the dopamine system, with the view that restoring dopaminergic inputs in a localized and physiologic manner will provide superior benefits in terms of effect and longevity compared with oral medication. Experience using transplants of fetal tissue containing dopaminergic cell precursors has provided valuable proof that the approach is feasible, and that engrafted cells can survive and function over many years. However, multiple drawbacks and procedural complications are recognized in using fetal cells. Recent strides in stem cell technology now make it possible to overcome some of the barriers associated with fetal tissue. In particular the generation of high numbers of specific cell types, such as dopaminergic neurons, from stem cells means that quality, consistency, activity, and safety can be more thoroughly determined prior to transplantation, thus providing hope for more robust outcomes. These cells are also predicted to provide benefit without leading to the graft-induced dyskinesia that led to morbidity in a subset of individuals who underwent fetal mesencephalic cell and tissue grafting in the 1990s. In thinking about developing such novel therapeutics, the choice of starting material has also expanded, with the availability of multiple human embryonic stem cell lines, as well as the possibilities for producing induced pluripotent cells, or neuronal cells from a patient's own tissue. In this article, we speculate on how rapidly expanding knowledge and technical possibilities may impact on stem cell-based therapies for cell replacement in Parkinson's disease over the next two decades.

Keywords: Dopamine neurons; Parkinson’s disease; stem cell therapy.

Fig.1

Stem cells today and in the future. When using fetal cells for transplantation (a), tissue is collected and transplanted without the possibility for banking or quality assessment of the cells prior to transplantation. In contrast, DA progenitors derived from hESCs (b) can be banked and stored, allowing for extensive pre-clinical safety and efficacy testing of the cells prior to transplantation. Pluripotent stem cells can be obtained from pre-implantation blastocyst (c) or via reprogramming from fibroblasts (d) and differentiated into DA progenitors that mature into fully functional DA neurons after transplantation. In the case of iPSCs, they can be reprogrammed from matched donors or from the patients themselves. In the future, directly converted cells (e) or cells reprogrammed by viral injection into the brain (f) are attractive alternatives.