Consequences of central nervous system (CNS) physical injuries and neurodegenerative diseases are severe because the CNS has limited capacity to replace neurons lost through injuries or diseases. Neural stem cells (NSCs) are the most versatile and promising cell source for the regeneration of injured and diseased CNS. However, cell therapy faces many problems related to cell survival, control of cell fate and proper cell engraftment after transplantation. Cell survival is one of the most challenging technical issues as only a small percentage of implanted cells can survive after transplantation. These cells often die in the first few days after transplantation due to acute inflammation/immune response, trophic factor withdrawal, oxidative stress, excitotoxicity, hypoxia, or anoikis. To use appropriate size of cell aggregates, such as neurospheres, rather than individual cell suspension, may prevent anoikis and improve viability. Cells in aggregates or groups can form a community to provide paracrine signaling or trophic support for neighboring transplanted cells to be able to survive in the community manner. One important parameter in the neurosphere structure is the size or diameter. If the sphere size is too big, the nutrient and oxygen support for the cells in the core of the neurosphere will be limited or insufficient. If the sphere size is too small, the beneficial impact of the multicellular community may be limited. To this end, we hypothesize that the survival of transplanted NSCs may be improved with the transplantation of multicellular neurospheres as compared to the transplantation of individual cells in suspension, and there is an optimal range of the sphere size to get the highest viability for the transplanted neural cells. Another major factor is the immune response to the transplanted neural cells. Even with immunosuppressant used, host immune response can still jeopardize the viability of the transplanted cells. Mesenchymal stem cells (MSCs) have been demonstrated to possess immunosuppressive and neuroprotective properties. We further hypothesize that the viability of transplanted neural cells may be further improved in neurospheres coated with layers of MSCs on the surface of neurospheres by suppressing the host immune response at the transplantation site.
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