The traditional dogma that no new neurons are made in the adult brain has been challenged. With the widespread study of stem cells and the characterization of the neurogenic niches in the brain, it is now clear that new neurons are indeed generated, either by way of transplanted stem or progenitor cells, or via endogenous neural stem cells. This is true under basal conditions as well as in injury. Importantly, not only are new neurons being made, but functional improvements have been realized in animals in a number of disease models including stroke, Parkinson's disease and ALS. For any of these experimental therapies to achieve clinical feasibility, it will be critical to develop non-invasive methods for detecting cell migration, differentiation and function. For cell transplant procedures, non-invasive detection of cells has been accomplished with the use of magnetic resonance imaging (MRI)-based cell tracking. However, while research into the manipulation of endogenous cells with trophic factors is accelerating, there are unmet needs in non-invasive detection and quantification of endogenous cells in the brain.
The aim of this proposal is to develop MRI methods for longitudinal detection and quantification of endogenous cell migration in intact organisms. First, in vivo cell labeling protocols will be optimized with concurrent optimization of MRI parameters and image analysis. Then, these protocols will be validated in a known model of neurogenic enhancement. Lastly, these protocols will be used to investigate a potentially novel method of boosting the native neurogenic response to stroke. Classically, neurogenesis studies have relied on microscopic analysis of histological sections of brain tissues. While highly informative, this approach cannot be translated into the clinic and provides limited information on cell migration rates and trajectories due to the large number of animals needed and inter-animal variability. The approach taken in this proposal of imaging neurogenesis in the living animal is very different and innovative. This work will develop a robust protocol for using MRI based cell tracking to monitor the migration of native neuroblasts at the single cell level, both under basal conditions and in response to stroke. The ability to study the same animal repeatedly will allow neurogenesis to be studied in four dimensions, integrating cellular migration rates, 3D migration trajectories and overall cell numbers. Never before, in any cell tracking imaging experiment, has cell number been quantified down to individual cells. MRI based data will be validated through correlation with conventional microscopic analyses. Furthermore, these methods will be applicable for a broad range of disease models employing neuron-reconstitution, as well as furthering research into basal neurogenesis and the participation of neuroblasts in learning and plasticity. It is anticipated that the high degree of corroboration of the data modalities will indeed demonstrate the robustness of the proposed MRI methods and provide the motivation to move these techniques into the regime of clinical research.

Public Health Relevance

Non-invasive imaging technologies will play a critical role in translating may cell based therapies from bench to bedside. This research detailed in this proposal aims to develop magnetic resonance imaging technologies to enable visualization and quantification of neural precursor cell migration, both under basal conditions and in response to injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS065297-02
Application #
7775015
Study Section
Neurotechnology Study Section (NT)
Program Officer
Owens, David F
Project Start
2009-03-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$179,205
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Granot, Dorit; Nkansah, Michael K; Bennewitz, Margaret F et al. (2014) Clinically viable magnetic poly(lactide-co-glycolide) particles for MRI-based cell tracking. Magn Reson Med 71:1238-50
Granot, Dorit; Shapiro, Erik M (2014) Accumulation of micron sized iron oxide particles in endothelin-1 induced focal cortical ischemia in rats is independent of cell migration. Magn Reson Med 71:1568-74
Tang, Kevin S; Hashmi, Sarah M; Shapiro, Erik M (2013) The effect of cryoprotection on the use of PLGA encapsulated iron oxide nanoparticles for magnetic cell labeling. Nanotechnology 24:125101
Granot, Dorit; Scheinost, Dustin; Markakis, Eleni A et al. (2011) Serial monitoring of endogenous neuroblast migration by cellular MRI. Neuroimage 57:817-24
Tang, Kevin S; Shapiro, Erik M (2011) Enhanced magnetic cell labeling efficiency using -NH2 coated MPIOs. Magn Reson Med 65:1564-9
Tang, Kevin S; Hann, Bradley; Shapiro, Erik M (2011) On the use of micron-sized iron oxide particles (MPIOS) to label resting monocytes in bone marrow. Mol Imaging Biol 13:819-24