Abstract
Millions of people suffer from these neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, and there is no known cure, therefore, new therapeutic strategies are needed. Stem cell-based regenerative medicine has become a promising approach and this review compares the two major stem cell types used for the treatment of these disorders: induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) comprehensively. Their various sources, differential activity, mode of action, pre-clinical data, clinical trial results, safety and translational issues are examined critically. Patient-specific autologous therapy, pluripotent differentiation potential to generate any neural cell type, unlimited expansion capacity for disease modeling and drug screening are the unique features of iPSCs. They do come with a number of drawbacks, however, such as teratoma formation due to the presence of leftover undifferentiated cells, genomic instability due to the reprogramming process, and the fact that their production cost is too great. Contrastingly, MSCs are easily accessible in various adult tissues, possess immune-privileged properties that allow for allogeneic transplantation without the need to immunosuppress, and release a large and diverse range of neurotrophic molecules, anti-inflammatory cytokines, and exosomes with neuroprotective functions, that pose no risk of teratoma development. They have limited inherent neural differentiation potential and significant differences in therapeutic efficacy between studies. When compared with MSCs, iPSCs have higher precision in disease modelling and have true cell replacement potential, but are at a significantly earlier stage in clinical translation, with less than 30 trials completed or ongoing. Most importantly, there is a lack of comparative studies of the direct head-to-head type. In conclusion, we believe that iPSCs and MSCs are optimally suited to different niches in the disease process: MSCs to paracrine-based neuroprotection and immunomodulation in early disease stages, and iPSCs to cell replacement strategies in later disease stages, although with potentially increased risk. The following directions for future development involve the manufacture of off-the-shelf iPSC-derived products, the engineering of MSC exosomes, the rational combination approach, and stringent comparative trials for clinical decision making