Neural Stem Cells and Induced Neurons for Nerve Injury Repair

Abstract

Cell transplantation can relieve the symptoms of or even reverse neurodegenerative diseases and repair nerve injuries. Fibroblast growth factor 1 promotes neuronal survival and stimulates axonal growth. A combination of fibroblast growth factor 1 and cell-based therapy is promising for nerve repair. Developers of future cell-based treatment should consider several key concerns: (1) the source of cells should be autologous, (2) consistent methods and protocols for cell isolation should be used, (3) the treatment should be tested in suitable animal models, and (4) the microenvironment of cells implanted should be optimally characterized. In addition, developing high temporal and spatial resolution images for cell tracking is crucial for evaluating the efficacy of cell transplantation. In this paper, we summarize recent progress in cellular reprogramming, such as induced neural stem cells and induced neurons, and the development of future cell-based therapy for peripheral nerve and spinal cord injury that includes conduits and growth factors. Fibroblast Growth Factor 1 for Nerve Injury RepairIn total, 22 mammalian fibroblast growth factors (FGFs) exist, grouped into seven subfamilies on the basis of differences in sequence homology and phylogeny. Notably, FGF1 and FGF2 share sequential and structural similarities and belong to the FGF1 subfamily [1]. The FGF ligands execute diverse functions by binding and activating the FGF receptor (FGFR) family of tyrosine kinase receptors with heparan sulfate proteoglycans. In total, four FGFR genes (FGFR1-FGFR4) encode receptors consisting of three extracellular immunoglobulin domains (D1-D3), a single-pass transmembrane domain, and a cytoplasmic tyrosine kinase domain [2]. Several FGFR isoforms exist because of exon skipping that removes the D1 domain and/or the acid box in FGFR1-FGFR4 [3]. Alternative splicing in the second half of the D3 domain of FGFR1-FGFR3 yields b (FGFR1b-FGFR3b) and c (FGFR1c-FGFR3c) isoforms that have distinct FGFbinding specificities [4] and are predominantly present in epithelial and mesenchymal cells, respectively. Each FGF binds to epithelial or mesenchymal FGFRs, with the exception of FGF1, which activates both spliced isoforms [3].The involvement of FGF signaling in human diseases has been thoroughly documented. Deregulated FGF signaling can contribute to pathological conditions through gain-or loss-of-function mutations in the FGFRs. Because both Fgf1 −/− and Fgf1mice are fertile and apparently normal [5], the physiological roles of FGF1 and FGF2 remain to be explored. However, FGF1 and FGF2 likely play a physiological role in the maintenance of the vascular tone because FGF1 and FGF2 administration lowers the blood pressure in rats [6] and can restore the nitric oxide synthase activity in spontaneously hypertensive rats [7]. In addition, blood vessels isolated from Fgf2 −/− mice exhibit a reduced response to vasoconstrictors. Although Fgf2 −/− mice had hypotension caused by reduced smooth muscle contractility [8], their blood pressu...