MRI Tracking of Stem Cell Migration During Brain Injury

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DESCRIPTION (provided by applicant): A promising therapeutic approach for brain injury and many neurological diseases is to harness the endogenous neural stem cells (NSCs) to replenish damaged neurons and glia. To study the response of NSCs to brain injury in mouse models, we are developing micro-MRI methods to label and track cells originating in the subventricular zone (SVZ) of the lateral ventricles, a site of persistent neurogenesis in the neonatal to adult forebrain in which NSCs generate highly proliferative neuroblasts (NBs) that migrate long distances to the olfactory bulb in the normal brain, and to lesion sites during brain injury. Specifically, we will analyze NB migration after excitotoxic neuronal injury, which is highly relevant to many human neurological and neuro-degenerative diseases. By performing in vivo neuroimaging experiments at different developmental stages, these studies will provide critical new information on the stage-dependent differences in the potential of endogenous NSCs to mediate repair, which should have direct implications for the responsiveness of patients experiencing brain injury at different ages. All of the micro-MRI results will be validated with histology, including immunohistochemistry to determine the final fates of the NBs after migration into injury sites. We will also begin to analyze the effects of specific growth factors on NSC and NB behavior. The specific aims of the project are: 1) to establish the temporal and spatial characteristics of NB cell migration in the mouse RMS from neonatal to adult stages of development, using in situ magnetic cell labeling and in vivo micro-MRI; 2) to analyze stage-dependent changes in NB cell migration after brain injury, with and without administration of growth factors known to induce NSC proliferation; and 3) to determine the final distributions and fates of the magnetically labeled NBs after migration into the olfactory bulb and injury sites, using immunohistochemistry on histological sections taken after micro-MRI. The ability to perform the imaging studies in mice will enable important future studies of NSC behaviors in genetically-engineered mouse models of many human brain diseases, and to use this vast resource of mouse models for testing drugs designed to enhance the therapeutic effects of the endogenous NSCs. PUBLIC HEALTH RELEVANCE: We are developing magnetic resonance micro-imaging approaches to label endogenous neural stem cells (NSCs) in the mouse brain, and to track their migrations at different developmental stages, from neonatal to adult, as well as in mice with brain injury, with and without administration of growth factors to enhance the response of the NSCs. The excitotoxic neuronal injury model is highly relevant to stroke and many human neurodevelopmental and neurodegenerative diseases. The ability to perform the imaging studies in mice will enable important future studies of NSC behaviors in genetically- engineered mouse models of many human brain diseases, and to use this vast resource of mouse models for testing drugs designed to enhance the therapeutic effects of the endogenous NSCs.