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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    • "The main differences between germinal-layer-derived and parenchymal neurogenesis are listed in Table 2. It has been proposed that some parenchymal newborn neurons have a transient existence (Gould et al. 2001; Luzzati et al. 2011), and their fate and role remain unknown (Arvidsson et al. 2002; Chen et al. 2004; Liu et al. 2009; Ohira et al. 2010; Bonfanti and Peretto 2011; Luzzati et al. 2011). Among the unsolved issues of parenchymal neurogenesis are the numerous reports that have not been confirmed by further studies performed by the same or other laboratories (Gould et al. 1999; Magavi et al. 2000; Nakatomi et al. 2002; Zhao et al. 2003; Rivers et al. 2008; Guo et al. 2010), along with a series of findings that have been denied in studies trying to reproduce the same results (Kornack and Rakic 2001; Frielingsdorf et al. 2004; Richardson et al. 2011). "
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    ABSTRACT: Two decades after the discovery that neural stem cells (NSCs) populate some regions of the mammalian central nervous system (CNS), deep knowledge has been accumulated on their capacity to generate new neurons in the adult brain. This constitutive adult neurogenesis occurs throughout life primarily within remnants of the embryonic germinal layers known as "neurogenic sites." Nevertheless, some processes of neurogliogenesis also occur in the CNS parenchyma commonly considered as "nonneurogenic." This "noncanonical" cell genesis has been the object of many claims, some of which turned out to be not true. Indeed, it is often an "incomplete" process as to its final outcome, heterogeneous by several measures, including regional location, progenitor identity, and fate of the progeny. These aspects also strictly depend on the animal species, suggesting that persistent neurogenic processes have uniquely adapted to the brain anatomy of different mammals. Whereas some examples of noncanonical neurogenesis are strictly parenchymal, others also show stem cell niche-like features and a strong link with the ventricular cavities. This work will review results obtained in a research field that expanded from classic neurogenesis studies involving a variety of areas of the CNS outside of the subventricular zone (SVZ) and subgranular zone (SGZ). It will be highlighted how knowledge concerning noncanonical neurogenic areas is still incomplete owing to its regional and species-specific heterogeneity, and to objective difficulties still hampering its full identification and characterization.
    Cold Spring Harbor perspectives in biology 09/2015; 7(10). DOI:10.1101/cshperspect.a018846 · 8.68 Impact Factor
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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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