Neural Stem Cells and Induced Neurons for Nerve Injury Repair

Download PDF

Published Date: March 24, 2015

Neural Stem Cells and Induced Neurons for Nerve Injury Repair

Yi Chao Hsu1, Su Liang Chen2, Tai Yu Hsu2,3 and Ing Ming Chiu2,3*

1Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan
2Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
3Graduate Program of Biotechnology in Medicine, Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan

*Corresponding author: Ing Ming Chiu, Institute of Cellular and System Medicine, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli 35053, Taiwan, Tel: 886-37-246-166 ext. 37501; Fax: 886-37-587-408; E-mail: ingming@nhri.org.tw

Citation: Hsu YC, Chen SL, Hsu TY, Chiu IM (2015) Neural Stem Cells and Induced Neurons for Nerve Injury Repair. J Stem Trans Bio 1(1): 102. Doi: http://dx.doi.org/10.19104/jstb.2015.102

 

Abstract 

 

Cell transplantation can relieve the symptoms of 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.

Keywords: Cell therapy; Neural stem cells; FGF1; Induced neurons; Peripheral nerve injury 

Top ↑

Fibroblast Growth Factor 1 for Nerve Injury Repair 

 

In 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 FGF-binding 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 Fgf1−/−Fgf2−/− mice 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 pressure could still be regulated [9]. Interestingly, FGF1 has been shown to be crucial in the remodeling process of adipose tissues [10]. Fibroblast growth factor 1 is induced in the gonadal white adipose tissue of a high-fat-diet–fed animal model [10]. Furthermore, Fgf1−/− knockout mice developed a phenotype of profound diabetes when fed with a high-fat diet [10], suggesting the importance of FGF1, particularly when challenged with various nutritional conditions. A similar situation was also observed in collagen VI null mice that exhibited metabolic dysregulation and adipose tissue fibrosis only when fed with a high-fat diet [11,12]. 

The therapeutic potential of FGF1 has been demonstrated for cardiovascular disorders. Phase I trials have revealed that the intramyocardial injection of FGF1 during coronary artery bypass graft surgery improves collateral artery growth and capillary proliferation [13]. The beneficial effects of FGF1 on the peripheral circulation have also been shown. Injecting a plasmid encoding FGF1 into the leg improved the perfusion of end-stage lower-extremity ischemia in a Phase I trial [14] and reduced amputations in patients with critical limb ischemia by 2-fold in a recent Phase II study [15]. Interestingly, the distal blood and oxygen pressure were similar after the injection of FGF1 plasmid or a placebo [16], and the mechanism of FGF1 action might not have been primarily angiogenic. 

FGF1, which can repair nerve injuries, enabled the functional regeneration of transected spinal cords in rats [17] and restored some motor functions in the paralyzed limbs of six months old boy with brachial plexus avulsion [18]. In addition, it benefited patients with chronic transverse myelitis [19]. Administering FGF1 and a combination of nerve grafts with FGF1 treatment partly restored ambulation in a paraplegic [20]. A combination of peripheral nerve grafts and FGF1 restored hind limb locomotor function in spinal cord-transected rats [17,21,22]. The expression of arginase I, the macrophage M2 marker, and the recruitment of M2 macrophages were observed in the repaired site [23]. Furthermore, FGF1 and nerve grafts induced IL-4 and NGF/BDNF expression in the repaired site, respectively. Therefore, developers of an ideal repair strategy should consider the beneficial effects of both FGF1 and nerve grafts [23]. We have previously demonstrated that a combination of FGF1, neural stem cells (NSCs), and micropatterned poly(D,L-lactide) conduits facilitated nerve repair and functional recovery in rats [24,25], and we are continually analyzing the efficacy of combinations of various growth factors and adult NSCs in peripheral nerve regeneration [26]. 

Top ↑

Neural Stem Cells for Peripheral Nerve Injury Repair

 

Sources of neural stem cells for clinical applications 
Cell transplantation is expected to relieve symptoms of or even reverse the progression of various neural diseases. The efficacy of mesenchymal, embryonic, or brain stem cells was evaluated in various animal models, such as those of Parkinson, Huntington, and Alzheimer disease, as well as in those with multiple sclerosis and cerebral ischemia [27]. In addition to involving direct cell transplantation, ideal therapeutic approaches should stimulate endogenous stem cells and induce the expression of active molecules in situ simultaneously. Several key concerns should be considered: (1) the source of cells should be autologous, (2) consistent methods and protocols for cell isolation should be used, (3) the approaches 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 [26].

Patient-derived cells are ideal NSC sources for autologous cell transplantation because they can prevent immune rejection. Potential cell sources for treating neural diseases include brain tissue-derived NSCs [28,29], blood- or bone marrow-derived mesenchymal stem cells [30-32], skin- or blood-derived induced pluripotent stem cells (iPSCs) [33-36], skin- or urine-derived induced neural stem cells (iNSCs) [37-43], and skin-derived induced neurons (iNs) [44-53].


Isolation and characterization of neural stem cells
Flow cytometry and fluorescence-activated cell sorting have been applied extensively in stem cell biology, such as in stem and progenitor cell isolation from the hematopoietic and nervous systems. Neural stem cells have been isolated from brain tissues according to the NSC-specific cell surface marker CD133 and NSC-specific genes, such as Sox1, Sox2, nestin, and FGF1 [54,55]. Thus, NSCs can be isolated using such approaches and then cultured to form neurospheres, which are indicators of self-renewal. For determining the multipotency, EGF and FGF2 were withdrawn from the culture, or other inducing factors were added [56]. 

The human FGF1 gene was first cloned in our laboratory [57]. Fibroblast growth factor 1 is expressed in neurons in various regions, including the ventral cochlear nucleus, olfactory bulbs, and hippocampus [58]. The FGF-1B promoter is brain-specific [59,60]. Interestingly, FGF-1B mRNA is elevated in the hippocampal neurogenic region for supporting NSCs during exercise-induced neurogenesis [61]. Furthermore, the FGF-1B promoter-driven GFP reporter (F1B-GFP) (USA patent No. 6984 518; 7045 678; and 7745 214) was used to isolate NSCs from human [55] and mouse brains [54,55]. The F1B-GFP–selected NSCs exhibited significant repair efficacy in the damaged sciatic nerves of paraplegic rats. A combination of nerve conduits, NSCs, and FGF1 repaired peripheral nerve injuries in animals [25,62]. Our laborarory has also demonstrated applying ultrananocrystalline diamond, a novel material, as a biomaterial for NSC transplantation in peripheral nerve injuries [63,64]. Recently, we demonstrated that F1B-GFP–selected NSCs with nerve conduits significantly improved the functional recovery of sciatic nerve injuries in mice (Figure 1) through the secretion of a cytokine (unpublished data). As a proof of concept, the direct combination of this cytokine with F1B-GFP NSCs in nerve conduits improved motor function recovery, promoted nerve regeneration, and increased the diameter of newly regenerated nerves by as much as 4.5-fold. Our data suggested a reduced likelihood of the administration of an immune factor in clinical settings for sciatic nerve injury repair.

Figure 1: Combination of neural stem cells and nerve conduit in a mouse model of sciatic nerve injury. (A) Before nerve transection, the sciatic nerve was fixed on the gluteus maximus by using 6-0 nylon microsutures, with a 5 mm distance between the proximal and distal fixed sites. A 3 mm nerve segment was transected in the medial site. A 5 mm conduit with or without neural stem cells (NSCs) and/or growth factors was interposed into the 3 mm nerve defect. The proximal and distal ends of the severed nerve were anchored to the conduit with 1 mm of residual nerve. The proximal and distal ends of the implanted conduit were tied using 6-0 nylon microsutures. After nerve conduit implantation, the muscle was sutured using 6-0 insoluble microsutures, and the skin was sutured using 6-0 nylon microsutures. (B) To investigate whether NSCs could facilitate the repair process after sciatic nerve injury, we injected 20 μL of PBS with or without suspended NSCs into the adjacent muscle of the transected sciatic nerve. The sciatic nerve was one-cut severed in the medial site, without damaging the epineurium and connective tissue, which connected to the muscle. (C) Three weeks after the nerve injury, the NSC-injected mouse could extend the toes, which indicated functional recovery after the nerve injury. Compared with the NSC-injected mouse, the PBS-injected mouse failed to extend the toes, indicating a dysfunction of the sciatic nerve after transection. 

Top ↑

Cellular Reprogramming for Induced Neurons and Induced Neural Stem Cells

 

Promising cellular sources for regenerative medicine should be personalized. Ideal sources are the somatic cells of patients, such as skin fibroblasts or peripheral blood cells. These personalized sources were reprogrammed into iPSCs [65]. Although the generation of iPSCs by patients with amyotrophic lateral sclerosis demonstrates the accessibility of patient-derived iPSCs [66], iPSCs have also been shown to have sizeable genetic and epigenetic abnormalities [67]. A recent direct reprogramming approach provides a straightforward, rapid, and reliable platform for producing various functional cells. Reports on the cellular reprogramming of myocytes [68], macrophages [69], cardiomyocytes [70], and hepatocytes [71] are summarized in Table 1. For example, a combination of miRNA124, Brn2, and Myt1l has been used to reprogram human fibroblasts into functional neurons [49,72]. Notably, these functional cells expressed various mature neuronal markers and could fire action potentials. Recent reports on the cellular reprogramming of neurons are summarized in Table 2. Recently, we showed that a signaling adaptor protein, SH2B1, enhanced the neurite outgrowth of iNs. These enhanced iNs expressed mature neuronal markers, such as NeuN, synapsin, GABA, vGluT2, and tyrosine hydroxylase. Notably, these SH2B1-enhanced iNs exhibited accelerated reprogramming (Figure 2) [48]. Our results will facilitate applying iNs in the disease modeling and treatment of neural diseases. Most recently, NSC-specific transcription factors, particularly SOX2, have been reported to reprogram mouse and human fibroblasts into multipotent iNSCs with a self-renewing ability [37-41]. Future studies are required for adapting this iNSC protocol and eventually substituting viral NSC factors using nonintegrating delivery modes such as Sendai viruses [73,74] or small molecules. We anticipate that iNSCs can provide a safe and robust cellular platform for generating patient-specific neural cells for nerve injury repair. Recent reports on iNSCs are summarized in Table 3.

Figure 2: Human foreskin fibroblasts were infected with 3 factors (IBM; upper panels) or 3 factors plus SH2B1 (S-IBM; lower panels). Traces of spontaneous (left panels) and evoked (right panels) action potentials were recorded in the current-clamp configuration. To measure evoked action potential firing in the current clamp, membrane potentials were held at 260 mV. Membrane potential in response to five current steps (in 10-pA increments) from the holding membrane potential was recorded. To measure evoked firing, cells were recorded at 260 mV, and then, a +50-pA current was injected to elicit spikes. To measure spontaneous firing, the cell membrane potential was held at 250 or 260 mV without current stimulation. Data was collected from three independent experiments at day 14 after cellular reprogramming. Abbreviations: IBM, microRNA miR124 and transcription factors BRN2 and MYT1L; SH2B1, SH2B adaptor protein 1β; S-IBM, SH2B1-enhanced IBM iNs

Top ↑

Future Prospects

 

Combination of biomaterials, growth factors, induced neural stem cells/induced neurons for peripheral nerve injury repair, natural polymers, including gelatin, collagen, chitosan, or chitin, and synthetic biodegradable polymers, such as poly(D,L-lactide) or poly(D,L-lactic-coglycolic acid), are commonly used for nerve regeneration because of their neurocompatible properties [75]. However, nondegradable materials should not be used for long-term neural repair to prevent nerve damage and chronic inflammation. Therefore, biodegradable materials are more acceptable for neural repair [76]. When used as the material for nerve conduits [77], poly(glycerol sebacate) exhibited surface-erodible and elastomeric properties. Notably, neurotrophic factors were linked to nerve conduits by using new techniques such as electrospinning or polymer blending [78], thus increasing the neural compatibility of the conduit surfaces [79]. 

Growth factors in situ play numerous crucial roles in regulating local neural and nonneural cells after an injury. Although endogenous growth factors secreted by neural cells in the distal nerve stump can support axonal regeneration, the supportive action may not be sustained indefinitely because of a decline in the cellular production of growth factors with time; hence, a continuous supply of growth factors is essential, mainly through the addition of exogenous growth factors. During tissue remodeling, growth factors can initiate signaling pathways involved in repair. In addition to stimulating endogenous neural stem/progenitor cells, some growth factors are also critical for their differentiation into various neural cells [80]. Nerve conduits used for nerve repair also provide a channel for growth factor diffusion [81]. A combination of liposomes and neurotrophic factor genes used in another approach effectively facilitated nerve injury repair [82,83]. Furthermore, the release of acidic products when poly(D,L-lactic-coglycolic acid) is used as microspheres for carrying growth factors may result in protein inactivation [84]. To control the delivery of growth factors, an electrospun nanofibrous scaffold is the ideal delivery vehicle because it can serve as a scaffold and provides optimal contact guidance [85].

Possible application in spinal cord and traumatic brain injury
To enhance the outcome of peripheral nerve regeneration by using scaffolds alone, efforts have been focused on optimally incorporating biochemical cues, including supporting cells, growth factors, and/or cytokines, within biomaterials. A combination of FGF1, biomaterials, and iNSCs/iNs has promising clinical applications. Notably, peripheral nerve grafts and FGF1 have not only repaired the hind limb of adult paraplegic rats [17,21] but also exerted therapeutic effects on patients with spinal cord injury (SCI) and common peroneal nerve lesions [86,87]. Thus, direct FGF1 treatment may benefit patients. Notably, Chen et al. developed an FGF1-based SCI repair strategy and designed a clinical trial to test the efficacy and safety of using FGF1 in combination with surgical intervention in human SCI. Through the clinical trial, they demonstrated that using FGF1 is safe and feasible for treating SCI [87]. Significant improvements were observed in American Spinal Injury Association motor and sensory scale scores, ASIA impairment scales, neurological levels, and the functional independence measure 24 mo after treatment [87]. Accumulating evidence suggests that FGF1 can be used to treat SCI and peripheral nerve injury. Future efforts for generating FGF1-expressing iNSCs or iNs can further the potential treatment of peripheral nerve injury and central nervous system diseases, such as SCI and traumatic brain injury.

Top ↑

References 

 

1. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004; 20(11): 563-9.

2. Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 2005; 16(2):107-37.

3. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009; 8(3):235-253. doi: 10.1038/nrd2792.

4. Johnson DE, Lu J, Chen H, Werner S, Williams LT. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol.1991; 11(9): 4627-34.

5. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol. 2000; 20(6): 2260-8.

6. Cuevas P, Carceller F, Ortega S, Zazo M, Giménez-Gallego G. Hypotensive activity of fibroblast growth factor. Science. 1991; 254(5035): 1208-10.

7. Cuevas P, Garcia-Calvo M, Carceller F, Reimers D, Zazo M, Cuevas B, et al. Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc Natl Acad Sci USA. 1996; 93(21): 11996-2001.

8. Zhou M, Sutliff RL, Paul RJ, Lorenz JN, Hoying JB, Haudenschild CC, et al. Fibroblast growth factor 2 control of vascular tone. Nat Med. 1998; 4(2): 201-7.

9. Dono R, Texido G, Dussel R, Ehmke H, Zeller R. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J. 1998; 17(15): 4213-25.

10. Jonker JW, Suh JM, Atkins AR, Ahmadian M, Li P, Whyte J, et al. A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature.2012; 485(7398): 391-4. doi: 10.1038/nature10998.

11. Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2009; 29(6): 1575-91.

12. Sun K, Scherer PE. The PPARgamma-FGF1 axis: an unexpected mediator of adipose tissue homeostasis. Cell Res.2012; 22(10): 1416-8. doi: 10.1038/cr.2012.94.

13. Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998; 97(7): 645-50.

14. Comerota AJ, Throm RC, Miller KA, Henry T, Chronos N, Laird J et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg. 2002; 35(5): 930-6.

15. Nikol S, Baumgartner I, Van Belle E, Diehm C, Visona A, Capogrossi MC, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther. 2008; 16(5): 972-8. doi: 10.1038/mt.2008.33.

16. Ruck A, Sylven C. Therapeutic angiogenesis gains a leg to stand on. Mol Ther. 2008; 16(5): 808-10. doi: 10.1038/mt.2008.65.

17. Cheng H, Cao Y, Olson L. Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science. 1996; 273(5274): 510-3.

18. Lin PH, Cheng H, Huang WC, Chuang TY. Spinal cord implantation with acidic fibroblast growth factor as a treatment for root avulsion in obstetric brachial plexus palsy. J Chin Med Assoc. 2005; 68(8): 392-6.

19. Lin PH, Chuang TY, Liao KK, Cheng H, Shih YS. Functional recovery of chronic complete idiopathic transverse myelitis after administration of neurotrophic factors. Spinal Cord. 2006; 44(4): 254-7.

20. Cheng H, Liao KK, Liao SF, Chuang TY, Shih YH. Spinal cord repair with acidic fibroblast growth factor as a treatment for a patient with chronic paraplegia. Spine. 2004; 29(14): 284-8.

21. Lee YS, Hsiao I, Lin VW. Peripheral nerve grafts and aFGF restore partial hindlimb function in adult paraplegic rats. J Neurotrauma. 2002; 19(10): 1203-16.

22. Tsai MC, Shen LF, Kuo HS, Cheng H, Chak KF. Involvement of acidic fibroblast growth factor in spinal cord injury repair processes revealed by a proteomics approach. Mol Cell Proteomics. 2008; 7(9): 1668-87. doi: 10.1074/mcp.M800076-MCP200.

23. Kuo HS, Tsai MJ, Huang MC, Chiu CW, Tsai CY, Lee MJ, et al. Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. J Neurosci. 2011; 31(11): 4137-47. doi: 10.1523/JNEUROSCI.2592-10.2011.

24. Ni HC, Tseng TC, Chen JR, Hsu SH, Chiu IM. Fabrication of bioactive conduits containing the fibroblast growth factor 1 and neural stem cells for peripheral nerve regeneration across a 15 mm critical gap. Biofabrication. 2013; 5(3): 035010. doi: 10.1088/1758-5082/5/3/035010.

25. Hsu SH, Su CH, Chiu IM. A novel approach to align adult neural stem cells on micropatterned conduits for peripheral nerve regeneration: a feasibility study. Artif Organs. 2009; 33(1): 26-35. doi: 10.1111/j.1525-1594.2008.00671.x.

26. Hsu YC, Chen SL, Wang DY, Chiu IM. Stem cell-based therapy in neural repair. Biomed J. 2013; 36(3): 98-105. doi: 10.4103/2319-4170.113226.

27. Gogel S, Gubernator M, Minger SL. Progress and prospects: stem cells and neurological diseases. Gene Ther. 2011; 18(1): 1-6. doi: 10.1038/gt.2010.

28. Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G, et al. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res. 2002; 69(6): 976-86.

29. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA. 2000; 97(26): 14720-5.

30. Gologorsky Y, Chi J. Mesenchymal stem cells and neuroprotection after nerve root injury. Neurosurgery. 2013; 73(6): 9-10. doi: 10.1227/01.neu.0000438325.65740.53.

31. Frattini F, Lopes FR, Almeida FM, Rodrigues RF, Boldrini LC et al. (2012) Mesenchymal stem cells in a polycaprolactone conduit promote sciatic nerve regeneration and sensory neuron survival after nerve injury. Tissue engineering Part A 18: 2030-2039.

32. Chen M, Xiang Z, Cai J. The anti-apoptotic and neuro-protective effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on acute optic nerve injury is transient. Brain Res. 2013; 1532: 63-75. doi: 10.1016/j.brainres.2013.07.037.

33. Payne NL, Sylvain A, O'Brien C, Herszfeld D, Sun G, Bernard CC. Application of human induced pluripotent stem cells for modeling and treating neurodegenerative diseases. N Biotechnol. 2015; 32(1):212-28. doi: 10.1016/j.nbt.2014.05.001.

34. Faiz M, Nagy A. Induced Pluripotent Stem Cells and Disorders of the Nervous System: Progress, Problems, and Prospects. Neuroscientist. 2013.

35. Saadai P, Wang A, Nout YS, Downing TL, Lofberg K, Beattie MS, et al. Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. J Pediatr Surg. 2013; 48(1): 158-63. doi: 10.1016/j.jpedsurg.2012.10.034.

36. Cramer AO, MacLaren RE. Translating induced pluripotent stem cells from bench to bedside: application to retinal diseases. Curr Gene Ther. 2013; 13(2): 139-51.

37. Ruggieri M, Riboldi G, Brajkovic S, Bucchia M, Bresolin N, Comi GP, et al. Induced neural stem cells: methods of reprogramming and potential therapeutic applications. Prog Neurobiol. 2014; 114: 15-24. doi: 10.1016/j.pneurobio.2013.11.001.

38. Maucksch C, Jones KS, Connor B. Concise review: the involvement of SOX2 in direct reprogramming of induced neural stem/precursor cells. Stem Cells Transl Med. 2013; 2(8): 579-83. doi: 10.5966/sctm.2012-0179.

39. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, et al. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell stem cell. 2012; 11(1): 100-9. doi: 10.1016/j.stem.2012.05.018.

40. Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Araúzo-Bravo MJ, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell stem cell. 2012; 10(4): 465-72. doi: 10.1016/j.stem.2012.02.021.

41. Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, et al. Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res. 2012; 318(13): 1528-41. doi: 10.1016/j.yexcr.2012.02.040.

42. Wang L, Wang L, Huang W, Su H, Xue Y, SU Z, et al. Generation of integration-free neural progenitor cells from cells in human urine. Nat Methods. 2013; 10(1): 84-9. doi: 10.1038/nmeth.2283.

43. Zou Q, Yan Q, Zhong J, Wang K, Sun H, Yi X, et al. Direct conversion of human fibroblasts into neuronal restricted progenitors. J Biol Chem. 2014; 289(8): 5250-60. doi: 10.1074/jbc.M113.516112.

44. Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S, Fuentes DR, et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell. 2013; 155(3): 621-35. doi: 10.1016/j.cell.2013.09.028.

45. Qiang L, Inoue K, Abeliovich A. Instant neurons: directed somatic cell reprogramming models of central nervous system disorders. Biol Psychiatry. 2014; 75(12): 945-951. doi: 10.1016/j.biopsych.2013.10.027.

46. Grealish S, Jakobsson J, Parmar M. Lineage reprogramming: a shortcut to generating functional neurons from fibroblasts. Cell cycle. 2011; 10(20): 3421-2. doi: 10.4161/cc.10.20.17691.

47. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, et al. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell stem cell. 2011; 9(2): 113-8. doi: 10.1016/j.stem.2011.07.002. 

48. Hsu YC, Chen SL, Wang YJ, Chen YH, Wang DY, Chen L, et al. Signaling adaptor protein SH2B1 enhances neurite outgrowth and accelerates the maturation of human induced neurons. Stem Cells Transl Med. 2014 ; 3(6): 713-22. doi: 10.5966/sctm.2013-0111.

49. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, et al.  Induction of human neuronal cells by defined transcription factors. Nature. 2011; 476(7359): 220-3. doi: 10.1038/nature10202.

50. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 2011; 476(7359): 228-31. doi: 10.1038/nature10323.

51. Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A. 2011; 108(25): 10343-8. doi: 10.1073/pnas.1105135108.

52. Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 2011; 476(7359): 224-7. doi: 10.1038/nature10284.

53. Falk A, Koch P, Kesavan J, Takashima Y, Ladewig J, Alexander M, et al. Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro production of human neurons. PLoS One. 2012; 7(1): e29597. doi: 10.1371/journal.pone.0029597.

54. Lee DC, Hsu YC, Chung YF, Hsiao CY, Chen SL, Chen MS, et al. Isolation of neural stem/progenitor cells by using EGF/FGF1 and FGF1B promoter-driven green fluorescence from embryonic and adult mouse brains. Mol Cell Neurosci. 2009; 41(3): 348-63. doi: 10.1016/j.mcn.2009.04.010.

55. Hsu YC, Lee DC, Chen SL, Liao WC, Lin JW, Chiu WT, et al. Brain-specific 1B promoter of FGF1 gene facilitates the isolation of neural stem/progenitor cells with self-renewal and multipotent capacities. Dev Dyn. 2009; 238(2): 302-14. doi: 10.1002/dvdy.21753.

56. Hsu YC, Lee DC, Chiu IM. Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant. 2007; 16(2): 133-50.

57. Wang WP, Lehtoma K, Varban ML, Krishnan I, Chiu IM. Cloning of the gene coding for human class 1 heparin-binding growth factor and its expression in fetal tissues. Mol Cell Biol. 9(6): 2387-95.

58. Alam KY, Frostholm A, Hackshaw KV, Evans JE, Rotter A, Chiu IM. Characterization of the 1B promoter of fibroblast growth factor 1 and its expression in the adult and developing mouse brain. J Biol Chem. 1996; 271(47): 30263-71.

59. Chiu IM, Touhalisky K, Liu Y, Yates A, Frostholm A. Tumorigenesis in transgenic mice in which the SV40 T antigen is driven by the brain-specific FGF1 promoter. Oncogene. 2000; 19(54): 6229-39.

60. Chiu IM, Touhalisky K, Baran C. Multiple controlling mechanisms of FGF1 gene expression through multiple tissue-specific promoters. Prog Nucleic Acid Res Mol Biol. 2001; 70: 155-74.

61. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009; 323(5917): 1074-7. doi: 10.1126/science.1166859.

62. Lin YL, Jen JC, Hsu SH, Chiu IM. Sciatic nerve repair by microgrooved nerve conduits made of chitosan-gold nanocomposites. Surg Neurol. 2008; 70 Suppl 1: 9-18. doi: 10.1016/j.surneu.2008.01.057.

63. Chen YC, Lee DC, Tsai TY, Hsiao CY, Liu JW, et al. Induction and regulation of differentiation in neural stem cells on ultra-nanocrystalline diamond films. Biomaterials. 2010; 31(21): 5575-87. doi: 10.1016/j.biomaterials.2010.03.061.

64. Chen YC, Lee DC, Hsiao CY, Chung YF, Chen HC, Thomas JP, et al. The effect of ultra-nanocrystalline diamond films on the proliferation and differentiation of neural stem cells. Biomaterials. 2009; 30(20): 3428-35. doi: 10.1016/j.biomaterials.2009.03.058.

65. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5): 861-72.

66. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008; 321(5893): 1218-21. doi: 10.1126/science.1158799.

67. Pera MF. Stem cells: The dark side of induced pluripotency. Nature. 2011; 471(7336): 46-7. doi: 10.1038/471046a.

68. Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987; 51(6): 987-1000.

69. Feng R, Desbordes SC, Xie H, Tillo ES, Pixley F, Stanley ER, et al. PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells. Proc Natl Acad Sci U S A. 2008; 105(16): 6057-62. doi: 10.1073/pnas.0711961105.

70. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; 142(3): 375-86. doi: 10.1016/j.cell.2010.07.002.

71. Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z, et al. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell stem cell. 2014; 14(3): 370-84. doi: 10.1016/j.stem.2014.01.003.

72. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010; 463(7284): 1035-41. doi: 10.1038/nature08797.

73. Castano J, Menendez P, Bruzos-Cidon C, Straccia M, Sousa A, Zabaleta L, et al. Fast and efficient neural conversion of human hematopoietic cells. Stem cell reports. 2014; 3(6): 1118-31. doi: 10.1016/j.stemcr.2014.10.008.

74. Wang T, Choi E, Monaco MC, Campanac E, Medynets M, Do T, et al. Derivation of neural stem cells from human adult peripheral CD34+ cells for an autologous model of neuroinflammation. PLoS One. 2013; 8(11): e81720. doi: 10.1371/journal.pone.0081720.

75. Verreck G, Chun I, Li Y, Kataria R, Zhang Q, Rosenblatt J, et al. Preparation and physicochemical characterization of biodegradable nerve guides containing the nerve growth agent sabeluzole. Biomaterials. 2005; 26(11): 1307-15.

76. Haile Y, Haastert K, Cesnulevicius K, Stummeyer K, Timmer M, Berski S, et al. Culturing of glial and neuronal cells on polysialic acid. Biomaterials. 2007; 28(6): 1163-73.

77. Sundback CA, Shyu JY, Wang Y, Faquin WC, Langer RS, Vacanti JP, et al. Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. Biomaterials. 2005; 26(27): 5454-64.

78. Chen PR, Chen MH, Lin FH, Su WY. Release characteristics and bioactivity of gelatin-tricalcium phosphate membranes covalently immobilized with nerve growth factors. Biomaterials. 2005; 26(33): 6579-87.

79. Subramanian A, Krishnan UM, Sethuraman S. Development of biomaterial scaffold for nerve tissue engineering: Biomaterial mediated neural regeneration. J Biomed Sci. 2009; 16: 108. doi: 10.1186/1423-0127-16-108.

80. Newman KD, McBurney MW. Poly(D,L lactic-co-glycolic acid) microspheres as biodegradable microcarriers for pluripotent stem cells. Biomaterials. 2004; 25(26): 5763-71.

81. Schmidt CE, Leach JB. Neural tissue engineering: strategies for repair and regeneration. Annu Rev Biomed Eng. 2003; 5: 293-347.

82. Whittlesey KJ, Shea LD. Nerve growth factor expression by PLG-mediated lipofection. Biomaterials. 2006; 27(11): 2477-86.

83. Salvay DM, Shea LD. Inductive tissue engineering with protein and DNA-releasing scaffolds. Mol Biosyst. 2006; 2(1): 36-48.

84. Xu X, Yu H, Gao S, Ma HQ, Leong KW, Wang S. Polyphosphoester microspheres for sustained release of biologically active nerve growth factor. Biomaterials. 2002; 23(17): 3765-72.

85. Cao H, Liu T, Chew SY. The application of nanofibrous scaffolds in neural tissue engineering. Adv Drug Deliv Rev. 2009; 61(12): 1055-64. doi: 10.1016/j.addr.2009.07.009.

86. Tsai PY, Cheng H, Huang WC, Huang MC, Chiu FY, Chang YC, et al. Outcomes of common peroneal nerve lesions after surgical repair with acidic fibroblast growth factor. J Trauma. 2009; 66(5): 1379-84. doi: 10.1097/TA.0b013e3181847a63.

87. Wu JC, Huang WC, Chen YC, Tu TH, Tsai YA, Huang SF, et al. Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial. J Neurosurg Spine. 2011; 15(3): 216-27. doi: 10.3171/2011.4.SPINE10404.

Top ↑

Copyright: © 2015 Yi Chao Hsu, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.