Growth Factor Treatment and Genetic Manipulation Stimulate Neurogenesis and Oligodendrogenesis by Endogenous Neural Progenitors in the Injured Adult Spinal Cord

Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2006; 26(46):11948-60. DOI: 10.1523/JNEUROSCI.3127-06.2006
Source: PubMed


Neurons and oligodendrocytes are highly vulnerable to various insults, and their spontaneous replacement occurs to only a limited extent after damage in the adult spinal cord. The environment of injured tissue is thus thought to restrict the regenerative capacity of endogenous neural stem/progenitor cells; strategies for overcoming such restrictions remain to be developed. Here, we combined growth factor treatment and genetic manipulation to stimulate neurogenesis and oligodendrogenesis by endogenous progenitors in vivo. The recombinant retrovirus pMXIG, which was designed to coexpress green fluorescent proteins (GFPs) and a neurogenic/gliogenic transcription factor, was directly injected into the injured spinal cord parenchyma to manipulate proliferative cells in situ. We found that cells expressing Olig2, Nkx2.2, and NG2 were enriched among virus-infected, GFP-positive (GFP+) cells. Moreover, a fraction of GFP+ cells formed neurospheres and differentiated into neurons, astrocytes, and oligodendrocytes in vitro, demonstrating that GFP retroviruses indeed infected endogenous neural progenitors in vivo. Neuronal differentiation of control virus-infected cells did not occur at a detectable level in the injured spinal cord. We found, however, that direct administration of fibroblast growth factor 2 and epidermal growth factor into lesioned tissue could induce a significant fraction of GFP-labeled cells to express immature neuronal markers. Moreover, retrovirus-mediated overexpression of the basic helix-loop-helix transcription factors Neurogenin2 and Mash1, together with growth factor treatment, enhanced the production and maturation of new neurons and oligodendrocytes, respectively. These results demonstrate that endogenous neural progenitors can be manipulated to replace neurons and oligodendrocytes lost to insults in the injured spinal cord.

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    • "The majority of the obtained cells expressed Sox2, nestin and Sox9, but neither glial fibrillary acidic protein (GFAP) nor oligodendrocyte transcription factor 2 (Olig2) (Fig. 3a and b). Several types of cells, oligodendrocyte precursors, astrocytes and ependymal cells, have been reported to be NSPs in the spinal cord21222526. Sox2, as well as nestin, is a common marker for those NSPs. GFAP is a marker for astrocytes. "
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    ABSTRACT: Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.
    Scientific Reports 05/2014; 4:4972. DOI:10.1038/srep04972 · 5.58 Impact Factor
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    • "Adult OPCs, typically identified by nerve/glial antigen 2 expression, are thought to be a heterogeneous cell population, only a portion of which function as OPC and is involved in the remyelination process (Nishiyama et al., 2009; Sellers et al., 2009; Trotter et al., 2010; Richardson et al., 2011). To enhance the differentiation of adult nerve/glial antigen 2-glia into mature oligodendrocytes, researchers have identified the effective function for several molecules, such as EGFR signaling, neurogenic/gliogenic transcription factor and growth factors (Ohori et al., 2006; Aguirre et al., 2007; Whittaker et al., 2012), which can enhance oligodendrocyte generation and axonal myelination after SCI. Besides, recent strategies have used transplantation of pluripotent/glial restricted cells to improve remyelination after SCI. "
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    ABSTRACT: Spinal cord injury is a major cause of disability with devastating neurological outcomes and limited therapeutic opportunities, even though there are thousands of publications on spinal cord injury annually. There are two major types of spinal cord injury, transaction of the spinal cord and spinal cord contusion. Both can theoretically be treated, but there is no well documented treatment in human being. As for spinal cord contusion, we have developed an operation with fabulous result.
    Neural Regeneration Research 04/2014; 9(8):789-94. DOI:10.4103/1673-5374.131591 · 0.22 Impact Factor
    • "The Olig family has been shown to regulate different types of neurons in the developing central nervous system, but its exact role in central nervous system injury has not been clearly elucidated. Many transcription factors (including the Olig family) show altered expression patterns after central nervous system injury and other acute/chronic diseases[6061]. Olig1 and Olig3 expression increases strongly with the BrdU state, while Olig2 is mainly expressed in neuronal precursors. It appears that the Olig family, and most importantly Olig2, is broadly engaged in neural repair process after central nervous system injury[5362]. "
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    ABSTRACT: Neural cell differentiation and maturation is a critical step during central nervous system development. The oligodendrocyte transcription family (Olig family) is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system development and related diseases.
    Neural Regeneration Research 02/2014; 9(3):329-36. DOI:10.4103/1673-5374.128232 · 0.22 Impact Factor
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