Methods of reactivation and reprogramming of neural stem cells for neural repair

Research on the biology of adult neural stem cells (NSCs) and induced NSCs (iNSCs), as well as NSC-based therapies for diseases in central nervous system (CNS) has started to generate the expectation that these cells may be used for treatments in CNS injuries or disorders. Recent technological progresses in both NSCs themselves and their derivatives have brought us closer to therapeutic applications. Adult neurogenesis presents in particular regions in mammal brain, known as neurogenic niches such as the dental gyrus (DG) in hippocampus and the subventricular zone (SVZ), within which adult NSCs usually stay for long periods out of the cell cycle, in G0. The reactivation of quiescent adult NSCs needs orchestrated interactions between the extrinsic stimulis from niches and the intrinsic factors involving transcription factors (TFs), signaling pathway, epigenetics, and metabolism to start an intracellular regulatory program, which promotes the quiescent NSCs exit G0 and reenter cell cycle. Extrinsic and intrinsic mechanisms that regulate adult NSCs are interconnected and feedback on one another. Since endogenous neurogenesis only happens in restricted regions and steadily fails with disease advances, interest has evolved to apply the iNSCs converted from somatic cells to treat CNS disorders, as is also promising and preferable. To overcome the limitation of viral-based reprogramming of iNSCs, bioactive small molecules (SM) have been explored to enhance the efficiency of iNSC reprogramming or even replace TFs, making the iNSCs more amenable to clinical application. Despite intense research efforts to translate the studies of adult and induced NSCs from the bench to bedside, vital troubles remain at several steps in these processes. In this review, we examine the present status, advancement, pitfalls, and potential of the two types of NSC technologies, focusing on each aspects of reactivation of quiescent adult NSC and reprogramming of iNSC from somatic cells, as well as on progresses in cell-based regenerative strategies for neural repair and criteria for successful therapeutic applications.