## 3 Application of Nanotechnology in Stem-Cell Therapy
### Nanomedicine for Modulation of Neural Stem-Cell Differentiation  
The application of biomaterials, including nanoparticles will be a benefit to the regenerative medicine over the use of existing media that facilitates cell growth and differentiation into specific lineages. Based on size-dependent cellular uptake rates, NPs in size range of 20-70 nm have shown the best efficiency for stem-cell differentiation [46; 54]. Using tissue engineering technology, stem cells have the potential to produce patient-specific tissues or cells without concern of immune rejection. The culture of stem cells along with the nanoparticle-including biomaterials aids in effectively differentiation of stem cells into a specific lineage of mature cells or tissues. They can also remain undifferentiated and maintain their self-renewal activity [55]. Development and design of self-assembling, biodegradable nanoparticles of poly (\(\beta\)-amino esters) for embedding plasmid DNA within the nanoparticles results in successful, high-efficiency transfection of hESCs (Human Embryonic Stem Cells). It has been demonstrated that hESCs transfected with this procedure maintain their viability, undifferentiated state, and pluripotency following transfection with nanoparticles [56].  
Linking tissue engineering technology and stem cell-based strategy can aid in producing regenerative medicine and facilitate therapeutic replacement of injured or damaged tissues. Some tissue-specific stem cells have the ability of mutual dedifferentiate, redifferentiate or also transdifferentiate of certain cell types in response to particular chemical or physical stimuli (Figure 4) [57].  
Figure 4: Differentiate and reparation of neural stem cells with therapeutic effects.  
Figure 3: Schematic representative of scaffold structure fabricated from graphene–nanofiber for differentiation of neural stem cells.  
In order to be successful in the therapeutic replacement of tissue, it is necessary to enhance the interaction of the cells and tissues by combination of a beneficial physical microenvironment and cellular biochemical signals.  
Superparamagnetic iron oxide nanoparticles (SPIONs), including the iron oxide core and magnetic coating, have specific properties such as high saturation magnetic moment, relatively stable chemical features and minimized potential toxicity [58]. Conjunction of nanomaterial compounds with SPIO co-covered with photonic ZnO can facilitate noncovalent binding of nanostructure and functional proteins which leads to enhancement in the catalytic function of key proteins in the stem-cell cycle and effectively improves the differentiation of stem cells. Modified core-shelled nanoparticles including an SPIOs have been developed for modulation of stem-cell expansion and transdifferentiation, in vitro and in vivo. Therefore, stem cells along with nanomaterials have a good potential for developing the regenerative medicine and controlled neurogenesis [55]. Loading of polymeric nanoparticles (dextran sulfate and polyethylenimine) with retinoic acid (NP-RA) is another safe and efficient method to restore the ischemic brain by preparing a proangiogenic environment which improves neurogenesis and neural recovery. This complex compound increased proliferation of endothelial cell and formation of tubule network and also provided a protective property against ischemia-related death. In an effort to examine the efficiency of NP-RA on improving neural stem-cell differentiation and survival, endothelial cell-conditioned media (EC-CM) were examined and the findings revealed that NP-RA can protect these cells from ischemic death. NP-RA compound also stimulated the release of proliferation-related factors and induced differentiation signals for neural stem cells. It has been determined that NP-RA have efficiently increased the hEPC proliferation 83-fold more than RA-alone. Therefore, the various complexes of NP-RA can be considered as powerful neurogenic agents for vascular diseases or neurodegenerative disorders incorporated with vasculature [59].