Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke

doi:10.1016/j.neuroscience.2007.01.020

Neuroscience

Volume 146, Issue 1, 25 April 2007, Pages 31-40

https://doi.org/10.1016/j.neuroscience.2007.01.020 Get rights and content

Abstract

Stroke patients suffer from severe impairments and significant effort is under way to develop therapies to improve functional recovery. Stem cells provide a promising form of therapy to replace neuronal circuits lost to injury. Indeed, previous studies have shown that a variety of stem cell types can provide some functional recovery in animal models of stroke. However, it is unlikely that replacement therapy alone will be sufficient to maximize recovery. The aim of the present study was to determine if rodent stem cell transplants combined with rehabilitation resulted in enhanced functional recovery after focal ischemia in rats. Middle cerebral artery occlusion was induced by injection of the vasoconstrictive peptide endothelin-1 adjacent to the middle cerebral artery. Seven days after stroke the rats received adult neural stem cell transplants isolated from mouse subventricular zone or vehicle injection and then subsequently were housed in enriched or standard conditions. The rats in the enriched housing also had access to running wheels once a week. Enriched housing and voluntary running exercise enhanced migration of transplanted stem cells toward the region of injury after stroke and there was a trend toward increased survival of stem cells. Enrichment also increased the number of endogenous progenitor cells in the subventricular zone of transplanted animals. Finally, functional recovery measured in the cylinder test was facilitated only when the stem cell transplants were combined with enrichment and running exercise 7 days after the transplant. These results suggest that the ability of transplanted stem cells in promoting recovery can be augmented by environmental factors such as rehabilitation.

Section snippets

Subjects

Eighty-two, male, Sprague–Dawley rats (Charles River, Montreal, Quebec, Canada) weighing 300–350 g at the time of middle cerebral artery occlusion (MCAo) were used in this study. Animals received food and water ad libitum and were housed either in pairs in standard Plexiglas cages or in groups of six in environmental enrichment cages (see below). Rats were maintained on a reverse 12-h light/dark cycle and all behavioral testing was performed during the dark phase. All procedures were in

Infarct volumes

ET-1 caused significant cortical and striatal damage as illustrated in Fig. 1A. Typically the sensory-motor cortex dorsal and ventral to the rhinal fissure and the dorsolateral striatum were infarcted. Except in the most severely injured rats, forelimb motor cortex was largely spared, as was the medial striatum. For the most part, the transplant sites were localized to areas of intact tissue or minimal injury in cortex and dorsal striatum (Fig. 1B). As expected, there was no difference in

Discussion

In this study exposing ischemic animals to an EE and running exercise (a form of rehabilitation) resulted in a tendency for greater survival of SVZ stem cell transplants and significantly greater migration toward the region of infarction. In addition, the combination of this rehabilitation and SVZ stem cell transplants facilitated functional recovery after MCAo. Interestingly, EE alone did not facilitate behavioral recovery which may be due to the reduced sensitivity of the cylinder test to EE

Conclusions

It appears there are several factors that work in concert in the post-ischemic brain to attract and support progenitor/stem cell survival and migration. Our data indicate that one important factor that can augment the restorative effects of stem cell transplants may be the activation of endogenous neuroplasticity mechanisms induced by rehabilitation-like experience such as environmental enrichment. The nature of the mechanisms underlying these beneficial interactions is currently under

Acknowledgments

This research was supported by grants from the Canadian Stroke Network (S.W. and D.C.) and CIHR (D.C.). D.C. holds a Canada Research Chair in Stroke and Neuroplasticity. The authors thank Rozina Hassam, Kathy McKay, Jared Clarke, Suzanne Evans and Shirley Granter-Button for valuable technical assistance.

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Behavioural neuroscienceEnriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke

Abstract

Section snippets

Subjects

Infarct volumes

Discussion

Conclusions

Acknowledgments

Brain Res

NeuroRx

Neuroscience

Prog Neurobiol

Neurosci Lett

Behav Brain Res

Brain Res

Neuroscience

Trends Neurosci

Exp Neurol

Exp Neurol

Horm Behav

Prog Brain Res

Brain Res

Neuroscience

Neuroscience

Neuroscience

Neuroscience

Behav Brain Res

Neuroscience

Brain Res

Exp Neurol

Exp Neurol

Exp Neurol

Neuroscience

Neuronal replacement from endogenous precursors in the adult brain after stroke

Nat Med

Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury

J Neurosci

Behavioural neuroscience
Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke