Stem Cell Properties and Requirements for Their Application in CRT for PD

As mentioned above, a major challenge in developing cell transplantation into a routine clinical practice for PD is the deficiency of fetal tissue supply, which implies the use of several fetal tissue to treat a single patient. For this reason, important research efforts have been carried out to find alternative sources of cells for

Table 5.1 Human stem cells used in clinical trials for treatment of Parkinson’s disease

Abbreviations: hMSCs human mesenchymal stem cells, hNSCs human neural stem cells

transplantation in PD. Several cell sources have been explored in order to generate DAn. The most promising cells found so far are stem cells.

Stem cells are undifferentiated cells characterized by their ability to proliferate and differentiate into more specialized types of cells. Stem cells can be classified according to how they were obtained or by their differentiation potential. Based on their ability to differentiate, stem cells are divided basically into two major categories: pluripotent stem cells (which can give rise to specialized cells of the three germ layers, i.e. endoderm, mesoderm and ectoderm) and multipotent stem cells (more specialized cells, that can generate specific cell lineages of a particular germ layer, although recently it has been shown that some multipotent cells possess the capacity to transdifferentiate into cells of more than one germ layer, such as MSCs) (Bongso et al. 2008; Zhan and Kilian 2013; Macias et al. 2010).

Overall it is assumed that in order to make the differentiation of DAn from stem cells a clinically competitive treatment option for PD, these cells need to be equivalent to those of human VM tissue in terms of their phenotype, as well as neurochemical and electrophysiological properties both in vitro and in vivo after grafting.

This means that transplanted cells must induce a substantial improvement of motor symptoms, without causing side effects (Lindvall et al. 2012; Martinez- Serrano and Liste 2010). To achieve this, grafted cells must survive, re-innervate the striatum, integrate into the neural circuitry of the host and exhibit the same characteristics of authentic nigral A9 DAn.

Also they have to satisfy a number of safety requirements such as not forming tumors, avoiding the development of dyskinesia, either by the presence of serotonergic neurons or inappropriate distribution of implants, and they should not induce immune rejection in the host. Furthermore, it must be possible to grow sufficient numbers of these cells in order to reach clinical relevance. As a result, only a reduced number of clinical trials are being conducted in which stem cells are applied.

In addition to CRT itself, stem cells can also be beneficial by providing a trophic support, by improving the survival of affected neurons (Lindvall and Kokaia 2009; Lunn et al. 2011) or acting as inflammation modulators. Not surprisingly, both epidemiological and genetic studies support an important role of neuro-inflammation in the pathophysiology of PD (Hirsch et al. 2012; More et al. 2013).