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research-article
Author(s):
Jun Yan 1 ,
Leyan Xu 1 ,
Annie M Welsh 1 ,
Glen Hatfield 1 ,
Thomas Hazel 2 ,
Karl Johe 2 ,
Vassilis E Koliatsos 1 , 3 , 4 , 5 , *
Publication date (Electronic): 13 February 2007
Journal: PLoS Medicine
Publisher: Public Library of Science
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Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages. In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter. NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections. When neural stem cells from human fetal spinal cord were grafted into the lumbar cord of normal or injured adult nude rats, substantial neuronal differentiation was found. Every year, spinal cord injuries, many caused by road traffic accidents, paralyze about 11,000 people in the US. This paralysis occurs because the spinal cord is the main communication highway between the body and the brain. Information from the skin and other sensory organs is transmitted to the brain along the spinal cord by bundles of neurons, nervous system cells that transmit and receive messages. The brain then sends information back down the spinal cord to control movement, breathing, and other bodily functions. The bones of the spine normally protect the spinal cord but, if these are broken or dislocated, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord can paralyze the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause many other medical problems, including the loss of bowel and bladder control. Although the deleterious effects of spinal cord injuries can be minimized by quickly immobilizing the patient and using drugs to reduce inflammation, the damaged nerve fibers never regrow. Consequently, spinal cord injury is permanent. Scientists are currently searching for ways to reverse spinal cord damage. One potential approach is to replace the damaged neurons using neural stem cells (NSCs). These cells, which can be isolated from embryos and from some areas of the adult nervous system, are able to develop into all the specialized cells types of the nervous system. However, because most attempts to repair spinal cord damage with NSC transplants have been unsuccessful, many scientists believe that the environment of the spinal cord is unsuitable for nerve regeneration. In this study, the researchers have investigated what happens to NSCs derived from the spinal cord of a human fetus after transplantation into the spinal cord of adult rats. The researchers injected human NSCs that they had grown in dishes into the spinal cord of intact nude rats (animals that lack a functioning immune system and so do not destroy human cells) and into nude rats whose spinal cord had been damaged at the transplantation site. The survival and fate of the transplanted cells was assessed by staining thin slices of spinal cord with an antibody that binds to a human-specific protein and with antibodies that recognize proteins specific to NSCs, neurons, or other nervous system cells. The researchers report that the human cells survived well in the adult spinal cord of the injured and normal rats and migrated into the gray matter of the spinal cord (which contains neuronal cell bodies) and into the white matter (which contains the long extensions of nerve cells that carry nerve impulses). 75% and 60% of the human cells in the gray and white matter, respectively, contained a neuron-specific protein six months after transplantation but only 10% of those in the membrane surrounding the spinal cord became neurons; the rest developed into astrocytes (another nervous system cell type) or remained as stem cells. Finally, many of the human-derived neurons made the neurotransmitter GABA (one of the chemicals that transfers messages between neurons) and made contacts with host spinal cord neurons. These findings suggest that human NSC grafts can, after all, develop into neurons (predominantly GABA-producing neurons) in normal and injured adult spinal cord and integrate into the existing spinal cord if the conditions are right. Although these animal experiments suggest that NSC transplants might help people with spinal injuries, they have some important limitations. For example, the spinal cord lesions used here are mild and unlike those seen in human patients. This and the use of nude rats might have reduced the scarring in the damaged spinal cord that is often a major barrier to nerve regeneration. Furthermore, the researchers did not test whether NSC transplants provide functional improvements after spinal cord injury. However, since other researchers have also recently reported that NSCs can grow and develop into neurons in injured adult spinal cord, these new results further strengthen hopes it might eventually be possible to use human NSCs to repair damaged spinal cords. Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040039. The US National Institute of Neurological Disorders and Stroke provides information on spinal cord injury and current spinal cord research Spinal Research (a UK charity) offers information on spinal cord injury and repair The US National Spinal Cord Injury Association Web site contains factsheets on spinal cord injuries MedlinePlus encyclopedia has pages on spinal cord trauma and interactive tutorials on spinal cord injury The International Society for Stem Cell Research offers information on all sorts of stem cells including NSCs The US National Human Neural Stem Cell Resource provides information on human NSCs, including the current US government's stance on stem cell research Abstract
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Most cited references47
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A PCR primer bank for quantitative gene expression analysis.
X. Wang (2003)
Although gene expression profiling by microarray analysis is a useful tool for assessing global levels of transcriptional activity, variability associated with the data sets usually requires that observed differences be validated by some other method, such as real-time quantitative polymerase chain reaction (real-time PCR). However, non-specific amplification of non-target genes is frequently observed in the latter, confounding the analysis in approximately 40% of real-time PCR attempts when primer-specific labels are not used. Here we present an experimentally validated algorithm for the identification of transcript-specific PCR primers on a genomic scale that can be applied to real-time PCR with sequence-independent detection methods. An online database, PrimerBank, has been created for researchers to retrieve primer information for their genes of interest. PrimerBank currently contains 147 404 primers encompassing most known human and mouse genes. The primer design algorithm has been tested by conventional and real-time PCR for a subset of 112 primer pairs with a success rate of 98.2%.
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Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice.
Brian Cummings, Nobuko Uchida, Stanley Tamaki … (2005)
We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease.
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Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS.
Marie Filbin (2003)
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Author and article information
Contributors
: Role: Academic Editor
Journal
Journal ID (nlm-ta): PLoS Med
Journal ID (publisher-id): pmed
Title: PLoS Medicine
Publisher: Public Library of Science (San Francisco, USA )
ISSN (Print): 1549-1277
ISSN (Electronic): 1549-1676
Publication date (Print): February 2007
Publication date (Electronic): 13 February 2007
Volume: 4
Issue: 2
Electronic Location Identifier: e39
Affiliations
[1 ] Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
[3 ] Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
[4 ] Department of Neuroscience, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
Author notes
* To whom correspondence should be addressed. E-mail: koliat@ 123456jhmi.edu
Article
Publisher ID: 05-PLME-RA-0454R4 Serial Item and Contribution ID: plme-04-02-08
DOI: 10.1371/journal.pmed.0040039
PMC ID: 1796906
PubMed ID: 17298165
SO-VID: d96ee101-1397-4508-af6b-e7ef99b725a6
Copyright © Copyright: © 2007 Yan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date received : 30 August 2005
Date accepted : 18 December 2006
Related
Making Human Neurons from Stem Cells after Spinal Cord Injury
Page count
Pages: 15
Categories
Subject: Research Article
Subject: Developmental Biology
Subject: Neurological Disorders
Subject: Neurological Disorders
Subject: Neuroscience
Subject: Neuroscience
Subject: Neurology
Subject: Spinal Cord Injury
Custom metadata
citation Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, et al. (2007) Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med 4(2): e39. doi: 10.1371/journal.pmed.0040039
ScienceOpen disciplines: Medicine
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ScienceOpen disciplines: Medicine
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