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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EAfter an acute stroke, neurologic deficit can be limited and functional recovery can be improved with neurorestorative therapies, including stem cells and exosomes that enhance the spontaneous remodeling that occurs in the brain, spinal cord, and throughout the body. Neurorestoration complements traditional approaches to treating the brain lesion, such as with a tissue plasminogen activator and endovascular therapy.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Ebone marrow stromal cells\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eexosomes\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EmicroRNA\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Efunctional recovery\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eischemic stroke\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eneurologic deficit\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eneuroplasticity\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eneurorestoration\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Espontaneous remodeling\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etissue plasminogen activator\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003ETherapies designed to enhance endogenous neurorestorative processes within intact tissue have a greater potential to reduce neurologic deficit and improve functional recovery after an acute stroke compared with traditional neuroprotective treatments that focus on treating the lesion and containing the degree of damage, according to Michael Chopp, PhD, Henry Ford Hospital, Detroit, and Oakland University, Rochester, Michigan, USA.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003ENeurologic improvement is seen over time in the majority of patients who have had a stroke, but the biological substrate and multiple endogenous processes that are responsible for this improvement have not been fully investigated nor capitalized on to improve outcomes after stroke or neural injury. Dr Chopp reviewed the intrinsic restorative processes that are stimulated after a stroke, as well as preclinical work in his laboratory to amplify these processes.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EParallel forms of spontaneous motor and neurological recovery are found in preclinical animal models of ischemic stroke and in human stroke. In both animals and humans, a \u201csymphony of recovery\u201d is automatically activated after an injury. These restorative processes, which include neurogenesis, angiogenesis, and neurite remodeling, work in concert to greatly enhance recovery, said Dr Chopp.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThis spontaneous recovery occurs in many organs in the body by generating stem cells that replace the decaying system. After a stroke, there is a remarkable proliferation of stem cells that are generated ipsilateral to the lesion along the ventricles and migrate to the sites of the lesion, where they interact with newly formed vasculature angiogenic processes to facilitate rewiring. Rewiring of the axons and dendrites, and oligodendrogenesis within the neurorestorative microenvironment of the central nervous system, determines the degree of recovery after a stroke.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EIn an experimental study of mice with right middle cerebral artery occlusion (MCAo), there was a significant correlation between neuronal reorganization in the contralateral and ipsilateral hemispheres adjacent to the lesion. This was measured by the density of pyramidal neurons in the cortex after injection of pseudorabies virus into the stroke-impaired forelimb muscles, and the functional recovery was measured by the Foot-Fault test (\u003Cem\u003EP\u2009\u003C\/em\u003E\u0026lt;\u003Cem\u003E\u2009\u003C\/em\u003E.01; \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Liu Z et al. \u003Cem\u003EStroke\u003C\/em\u003E. 2009].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Poststroke Functional Recovery Correlated With Cerebral Neuronal ReorganizationPRV, pseudorabies virus.Reprinted from Liu Z et al. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. Stroke. 2009;40:2546-2551. With permission from American Heart Association, Inc.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-782317660\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Poststroke Functional Recovery Correlated With Cerebral Neuronal ReorganizationPRV, pseudorabies virus.Reprinted from Liu Z et al. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. \u0026amp;lt;em\u0026amp;gt;Stroke.\u0026amp;lt;\/em\u0026amp;gt; 2009;40:2546-2551. With permission from American Heart Association, Inc.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15262\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003EPoststroke Functional Recovery Correlated With Cerebral Neuronal Reorganization\u003C\/p\u003E\n               \u003Cp id=\u0022p-8\u0022\u003EPRV, pseudorabies virus.\u003C\/p\u003E\n               \u003Cp id=\u0022p-9\u0022\u003EReprinted from Liu Z et al. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. \u003Cem\u003EStroke.\u003C\/em\u003E 2009;40:2546-2551. With permission from American Heart Association, Inc.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe ability of neurorestorative therapies to amplify the spontaneous rewiring after a stroke was shown by this group in a rat model of stroke injected with bone marrow stromal cells (BMSCs) [Liu Z et al. \u003Cem\u003EJ Cereb Blood Flow Metab\u003C\/em\u003E. 2010].The density of transcallosal axons in the contralateral cortex was significantly increased in rats subjected to MCAo compared with normal rats at day 28 after stroke, and this natural reorganization after a stroke was further increased with BMSC restorative treatment (\u003Cem\u003EP\u2009\u003C\/em\u003E\u0026lt;\u003Cem\u003E\u2009\u003C\/em\u003E.001). Additionally, neurological recovery after 28 days was correlated with contralateral cortical axonal sprouting and ipsilateral neuronal reorganization. Thus, the entire brain undergoes spontaneous remodeling, which contributes to improvement in neurologic deficits, stated Dr Chopp.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003ESpontaneous remodeling also occurs in the spinal cord. After the intravenous injection of BMSCs into rats with a right MCAo, there was a profound increase in neurite outgrowth from the right to the left cord, which also correlated with a significant improvement (\u003Cem\u003EP\u2009\u003C\/em\u003E\u0026lt;\u003Cem\u003E\u2009\u003C\/em\u003E.01) in neurologic function [Liu Z et al. \u003Cem\u003EBrain Res\u003C\/em\u003E. 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EIn addition to the neuroplasticity that occurs in the ipsilateral and contralateral hemispheres of the brain and in the spinal cord, there is a response to stroke throughout the entire body. For example, in a rat model of stroke, the expression of restorative genes in the bone marrow was significantly increased (\u003Cem\u003EP\u2009\u003C\/em\u003E\u0026lt;\u003Cem\u003E\u2009\u003C\/em\u003E.05) [Zacharek A et al. \u003Cem\u003EStroke.\u003C\/em\u003E 2010], showing that the entire body is responding to the brain lesion, stated Dr Chopp.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003ESignificant improvement (\u003Cem\u003EP\u2009\u003C\/em\u003E\u0026lt;\u003Cem\u003E\u2009\u003C\/em\u003E.05) in neurologic function was obtained with a cell-based therapy that was injected 1 day [Chen J et al. \u003Cem\u003EStroke\u003C\/em\u003E. 2001], 1 week [Li Y et al. \u003Cem\u003EGlia.\u003C\/em\u003E 2005], or 1 month [Shen LH et al. \u003Cem\u003EJ Cereb Blood Flow Metab.\u003C\/em\u003E 2007] after a malignant stroke was induced in a rat model. This work showed that the endogenous restorative processes can be amplified by a cell-based therapy that promotes neurovascular remodeling, well after the onset of stroke.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003ERestorative therapies, such as cell-based therapies for stroke, enhance neurovascular remodeling and promote neurological recovery. However, the mechanisms by which the restorative therapy accomplishes this remodeling have not been elucidated.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EChopp and his colleagues recently discovered that mesenchymal stromal cells (MSCs) mediate neurological recovery poststroke by emitting biological lipid nanoparticles (30 to 100 nm), referred to as exosomes. These exosomes contain proteins, messenger RNAs (mRNAs), and microRNAs. MicroRNAs, which are short, noncoding RNAs, act as \u201cmaster molecular switches\u201d and provide cellular instructions to simultaneously regulate hundreds of genes and their translation. Restorative therapies, such as cell-based therapy, work by releasing exosomes that contain protein and genetic instructions and information (microRNAs, mRNAs, and proteins), which then infect astrocytes, endothelial cells, and neurons, thereby dictating to the parenchymal cells what to do to restore neurologic function (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Exosomes Package and Transfer Information Between CellsmiRNA, microRNA; mRNA, messenger RNA; MSC, mesenchymal stromal cell.Adapted from Li Y et al. The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia. 2014;62:1-16. With permission from Wiley Periodicals, Inc.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-782317660\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Exosomes Package and Transfer Information Between CellsmiRNA, microRNA; mRNA, messenger RNA; MSC, mesenchymal stromal cell.Adapted from Li Y et al. The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. \u0026amp;lt;em\u0026amp;gt;Glia.\u0026amp;lt;\/em\u0026amp;gt; 2014;62:1-16. With permission from Wiley Periodicals, Inc.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/2\/2\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15263\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-16\u0022 class=\u0022first-child\u0022\u003EExosomes Package and Transfer Information Between Cells\u003C\/p\u003E\n               \u003Cp id=\u0022p-17\u0022\u003EmiRNA, microRNA; mRNA, messenger RNA; MSC, mesenchymal stromal cell.\u003C\/p\u003E\n               \u003Cp id=\u0022p-18\u0022\u003EAdapted from Li Y et al. The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. \u003Cem\u003EGlia.\u003C\/em\u003E 2014;62:1-16. With permission from Wiley Periodicals, Inc.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EExosomes play a vital role in physiology and biology. Exosomes act as biological \u201cexchange\u201d particles that communicate information throughout the body. Thus, the presence of a lesion in the brain is communicated throughout the entire body, which activates the endogenous restorative processes.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EChopp and colleagues then showed that the direct administration of exosomes, derived from MSCs, into rats 24 hours after a stroke resulted in robust neurological recovery [Zhang Y et al. \u003Cem\u003EJ Neurosurg.\u003C\/em\u003E 2015; Xin H et al. \u003Cem\u003EJ Cereb Blood Flow Metab\u003C\/em\u003E. 2013]. Notably, the content of the exosomes can also be tailored by selecting specific microRNAs to turn on or off different processes, which is one of the ways that will lead to innovative restorative treatments.\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EIn closing, greater functional recovery can be achieved with neurorestorative therapies that enhance the natural spontaneous plasticity that occurs after a stroke, neural injury, or neurodegenerative disease.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/15\/2\/2.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzlqk4\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlqk4\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}