Neurogenesis of corticospinal motor neuron extending spinal projections in adult mice

Department of Neurosurgery and Program in Neuroscience, Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2004; 101(46):16357-62. DOI: 10.1073/pnas.0406795101
Source: PubMed


The adult mammalian CNS shows a very limited capacity to regenerate after injury. However, endogenous precursors, or stem cells, provide a potential source of new neurons in the adult brain. Here, we induce the birth of new corticospinal motor neurons (CSMN), the CNS neurons that die in motor neuron degenerative diseases, including amyotrophic lateral sclerosis, and that cause loss of motor function in spinal cord injury. We induced synchronous apoptotic degeneration of CSMN and examined the fates of newborn cells arising from endogenous precursors, using markers for DNA replication, neuroblast migration, and progressive neuronal differentiation, combined with retrograde labeling from the spinal cord. We observed neuroblasts entering the neocortex and progressively differentiating into mature pyramidal neurons in cortical layer V. We found 20-30 new neurons per mm(3) in experimental mice vs. 0 in controls. A subset of these newborn neurons projected axons into the spinal cord and survived >56 weeks. These results demonstrate that endogenous precursors can differentiate into even highly complex long-projection CSMN in the adult mammalian brain and send new projections to spinal cord targets, suggesting that molecular manipulation of endogenous neural precursors in situ may offer future therapeutic possibilities for motor neuron degenerative disease and spinal cord injury.

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Available from: Jeffrey Macklis, Oct 04, 2015
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    • "As additional data emerge from clinical trials, it will be important to evaluate what subsets of patients might specifically benefit from cell therapy. The integrity of critical white matter tracts, such as corticospinal tracts, may dictate maximal recovery potential, providing a better predictor of outcome than baseline neurological exam after stroke (Chen et al., 2004; Stinear and Byblow, 2014). The role of physical rehabilitation in accelerating this recovery, or potentially even raising the ultimate predicted plateau remains under active investigation . "
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    ABSTRACT: Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.041 · 2.53 Impact Factor
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    • " Silver , 2008 ; Hoehn et al . , 2005 ; Rasmussen et al . , 2011 ; Sofroniew , 2009 ) . However , both positive and negative effects on neurogenesis and repair have been reported ( Ekdahl et al . , 2009 ) . Neurogenesis and survival of new neurons is increased following apoptotic neuronal ablation that does not result in an inflammatory response ( Chen et al . , 2004 ; Magavi et al . , 2000 ) . In contrast , microglial accumulation following stroke can promote neurogenesis and subsequent neuronal survival ( Thored et al . , 2009 ) . A recent study in zebrafish suggests that the inflammatory response is required to initiate neuro - genic proliferation in the adult VZ through pathways that are distinc"
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    ABSTRACT: Zebrafish maintain a greater capacity than mammals for central nervous system repair after injury. Understanding differences in regenerative responses between different vertebrate species may shed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has been used to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected into the adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblast migration to injury. However, most new neurons fail to survive and lesion repair is minimal. We used quinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also used conditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integration of neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extent vehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhanced neurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injection than after vehicle injection. Fate mapping of her4-expressing radial glia showed injury-induced expansion of radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks and formed long-distance projections that crossed the anterior commissure and synapsed in the contralateral hemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adult neural stem cells to produce robust regeneration with long-distance integration of new neurons. This model should prove useful for elucidating reparative mechanisms that can be applied to restorative therapies for mammalian brain injury. GLIA 2014
    Glia 12/2014; 62(12). DOI:10.1002/glia.22726 · 6.03 Impact Factor
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    • "Nonetheless, these cells often show differentiated morphologies. It is noteworthy that an elevated death rate of newly generated neurons is a common feature in different studies of striatal and cortical neurogenesis, in both normal and pathologic conditions (Arvidsson et al., 2002; Chen et al., 2004; Gould et al., 2001; Luzzati et al., 2006, 2011a). The death of new striatal and cortical neurons has often been attributed to a strong selection exerted by a non-permissive environment (Kernie and Parent, 2010). "
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    ABSTRACT: In the adult brain, active stem cells are a subset of astrocytes residing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Whether quiescent neuronal progenitors occur in other brain regions is unclear. Here, we describe a novel neurogenic system in the external capsule and lateral striatum (EC-LS) of the juvenile guinea pig that is quiescent at birth but becomes active around weaning. Activation of neurogenesis in this region was accompanied by the emergence of a neurogenic-like niche in the ventral EC characterized by chains of neuroblasts, intermediate-like progenitors and glial cells expressing markers of immature astrocytes. Like neurogenic astrocytes of the SVZ and DG, these latter cells showed a slow rate of proliferation and retained BrdU labeling for up to 65 days, suggesting that they are the primary progenitors of the EC-LS neurogenic system. Injections of GFP-tagged lentiviral vectors into the SVZ and the EC-LS of newborn animals confirmed that new LS neuroblasts originate from the activation of local progenitors and further supported their astroglial nature. Newborn EC-LS neurons existed transiently and did not contribute to neuronal addition or replacement. Nevertheless, they expressed Sp8 and showed strong tropism for white matter tracts, wherein they acquired complex morphologies. For these reasons, we propose that EC-LS neuroblasts represent a novel striatal cell type, possibly related to those populations of transient interneurons that regulate the development of fiber tracts during embryonic life.
    Development 11/2014; 141(21). DOI:10.1242/dev.107987 · 6.46 Impact Factor
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