Local and Remote Growth Factor Effects after Primate Spinal Cord Injury

Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2010; 30(29):9728-37. DOI: 10.1523/JNEUROSCI.1924-10.2010
Source: PubMed

ABSTRACT Primate models of spinal cord injury differ from rodent models in several respects, including the relative size and functional neuroanatomy of spinal projections. Fundamental differences in scale raise the possibility that retrograde injury signals, and treatments applied at the level of the spinal cord that exhibit efficacy in rodents, may fail to influence neurons at the far greater distances of primate systems. Thus, we examined both local and remote neuronal responses to neurotrophic factor-secreting cell grafts placed within sites of right C7 hemisection lesions in the rhesus macaque. Six months after gene delivery of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) into C7 lesion sites, we found both local effects of growth factors on axonal growth, and remote effects of growth factors reflected in significant reductions in axotomy-induced atrophy of large pyramidal neurons within the primary motor cortex. Additional examination in a rodent model suggested that BDNF, rather than NT-3, mediated remote protection of corticospinal neurons in the brain. Thus, injured neural systems retain the ability to respond to growth signals over the extended distances of the primate CNS, promoting local axonal growth and preventing lesion-induced neuronal degeneration at a distance. Remote cortical effects of spinally administered growth factors could "prime" the neuron to respond to experimental therapies that promote axonal plasticity or regeneration.

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Available from: Armin Blesch, Sep 26, 2015
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    ABSTRACT: Stem/progenitor cells (SPCs) demonstrate neuro-regenerative potential that is dependent upon their humoral activity by producing various trophic factors regulating cell migration, growth, and differentiation. Herein, we compared the expression of neurotrophins (NTs) and their receptors in specific umbilical cord blood (UCB) SPC populations, including lineage-negative, CD34(+), and CD133(+) cells, with that in unsorted, nucleated cells (NCs). The expression of NTs and their receptors was detected by QRT-PCR, western blotting, and immunofluorescent staining in UCB-derived SPC populations (i.e., NCs vs. lineage-negative, CD34(+), and CD133(+) cells). To better characterize, global gene expression profiles of SPCs were determined using genome-wide RNA microarray technology. Furthermore, the intracellular production of crucial neuro-regenerative NTs (i.e., BDNF and NT-3) was assessed in NCs and lineage-negative cells after incubation for 24, 48, and 72 h in both serum and serum-free conditions. We discovered significantly higher expression of NTs and NT receptors at both the mRNA and protein level in lineage-negative, CD34(+), and CD133(+) cells than in NCs. Global gene expression analysis revealed considerably higher expression of genes associated with the production and secretion of proteins, migration, proliferation, and differentiation in lineage-negative cells than in CD34(+) or CD133(+) cell populations. Notably, after short-term incubation under serum-free conditions, lineage-negative cells and NCs produced significantly higher amounts of BDNF and NT-3 than under steady-state conditions. Finally, conditioned medium (CM) from lineage-negative SPCs exerted a beneficial impact on neural cell survival and proliferation. Collectively, our findings demonstrate that UCB-derived SPCs highly express NTs and their relevant receptors under steady-state conditions, NT expression is greater under stress-related conditions and that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.
    PLoS ONE 12/2013; 8(12):e83833. DOI:10.1371/journal.pone.0083833 · 3.23 Impact Factor
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    • "In SCI-related research, neurotrophins secreted from fibroblasts have been shown, to some extent, to improve behavioral recovery after SCI in adult rats [169], cats [187] and primates [188] possibly by improving neuronal survival [188] [189] [190], encouraging elongation of injured axons [22; 191-194], or promoting sprouting of spared fibers onto partially denervated cells [20; 194; 195]. The AAV vector-mediated transgene delivery of neurotrophins (NT-3 and BDNF) was shown to partially reverse chronic pain after SCI [176], rescue atrophy of rubrospinal neurons [196] and motoneurons [197] and induce partial improvement of locomotor function in models of incomplete SCI [178; 198-200] and after complete transection of the spinal cord [186; 201]. "
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    ABSTRACT: Synaptic transmission through descending motor pathways to lumbar motoneurons and then to leg muscles is essential for walking in humans and rats. Spinal cord injury (SCI), even when incomplete, results in diminished transmission to motoneurons and very limited recovery of motor function. Neurotrophins have emerged as essential molecules known to promote cell survival and support anatomical reorganization in damaged spinal cord. This review will summarize the evidence implicating the role of neurotrophins in synaptic plasticity in both undamaged and damaged spinal cord, with special emphasis on the potential for neurotrophins to strengthen synaptic connections to motoneurons in support of the application of neurotrophins for recovery of locomotor function after SCI. An important consideration related to therapeutic use of neurotrophins is the successful delivery of these molecules. Prolonged delivery of neurotrophins to the spinal cord of adult mammals has recently become possible through advances in biotechnology. Fibroblasts engineered to secrete neurotrophins and gene transfer of neurotrophins via recombinant viral vectors are among the most promising therapeutic transgene delivery systems for safe and effective neurotrophin delivery. Administration of neurotrophins to the spinal cord using these delivery systems was found to enhance both anatomical and synaptic plasticity and improve functional recovery after SCI. The findings summarized here indicate that neurotrophins have translational research potential for SCI repair, most likely as an essential component of combination therapy.
    Current pharmaceutical design 01/2013; 19(24). DOI:10.2174/13816128113199990378 · 3.45 Impact Factor
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    • "While BDNF appears not to be required for the survival of mature neurons (Giehl et al., 2001; Li et al., 2008; Rauskolb et al., 2010), its therapeutic effect has been documented in different neuronal populations under various pathological conditions such as spinal cord injury, stroke and axotomy among others (Klocker et al., 2000; Schabitz et al., 2000; Shulga et al., 2008; Brock et al., 2010). "
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    ABSTRACT: Accumulating experimental evidence suggests that groups of neurons in the central nervous system might react to pathological insults by activating developmental-like programs for survival, regeneration and re-establishment of lost connections. For instance, in cell and animal models it was shown that after trauma mature central neurons become dependent on BDNF trophic support for survival. This event is preceded by a shift of postsynaptic GABA(A) receptor -mediated responses from hyperpolarisation to developmental-like depolarisation. These profound functional changes in GABA(A) receptor -mediated transmission and the requirement of injured neurons for BDNF trophic support are interdependent. Thyroid hormones play a crucial role in the development of the nervous system, having significant effects on dendritic branching, synaptogenesis and axonal growth to name a few. In the adult nervous system thyroid hormone thyroxin has been shown to have a neuroprotective effect and to promote regeneration in experimental trauma models. Interestingly, after trauma there is a qualitative change in the regulatory effect of thyroxin on BDNF expression as well as on GABAergic transmission. In this review we provide an overview of the post-traumatic changes in these signaling systems and discuss the potential significance of their interactions for the development of novel therapeutic strategies.
    Neuroscience 12/2012; 239. DOI:10.1016/j.neuroscience.2012.12.007 · 3.36 Impact Factor
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