In order to develop stem and progenitor cell therapies for treating CNS diseases, it is important to be able to determine the fate of transplanted cells non-invasively over time, including the location, survival, and status of downstream cell differentiation. We propose to use two complementary modalities, magnetic resonance imaging (MRI) and bioluminescence imaging (BLI), to follow the fate (sites of injection, movements, survival, and differentiation) of transplanted cells in two complementary models of motor neuron disease (MND), i.e., a ricin-induced model as a localized, monophasic and a neurotropic Sindbis virus (NSV)-induced as a global, inflammatory disease model. Magnetically labeled and dual luciferase (Luc-BLI)-transducted glial restrictor precursors (GRPs) or embryonic stem cell-derived motor neurons (ESC-MNs) will be transplanted in the spinal cord of rats following the induction of MND disease. We hypothesize that ESC-MNs can improve functional recovery through formation of new motor neurons, while GRPs can neuroprotect host MNs and/or support transplanted ESC-MNs. In order to assess functional recovery, we will perform behavioral analyses, electrophysiologic measurements (motor-evoked potentials), and muscle mass measures, and will determine whether intraparenchymal or intrathecal injections are the optimal route of transplantation. We will use MRI to monitor the accuracy of cell injections, the extent of cell migration and intraparenchymal tissue distribution (white vs. gray matter), whereas dual luciferase reporter BLI will be used to report on the survival and enhancer (HB9) or promoter (GFAP)-driven lineage differentiation of transplanted cells. We hypothesize that accurate cell injections, extended migration distances, and the relative ratio of cell survival and downstream cell differentiation will correlate with the measured behavioral scores, electrophysiologic readouts, and total skeletal muscle mass segmentation measurements. In addition, we will test the feasibility of our novel artificial MRI reporter, lysine-rich protein (LRP) or its improved derivatives, to interrogate the fate of cells in a similar fashion as using the luciferase gene.

Public Health Relevance

We will use magnetic resonance imaging and bioluminescence imaging as non-invasive imaging techniques to monitor the distribution, survival, and fate of transplanted stem or progenitor cells in pre-clinical animal models of motor neuron disease that resemble Lou Gehrig's disease, a devastating disease for which there is no cure. The ultimate goal is to develop ways of reporting on successful cell transplantation without removing any tissue, and to provide neurologists with a means to evaluate stem cell treatment in their patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Owens, David F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Srivastava, Amit K; Bulte, Jeff W M (2014) Seeing stem cells at work in vivo. Stem Cell Rev 10:127-44
Bar-Shir, Amnon; Liu, Guanshu; Chan, Kannie W Y et al. (2014) Human protamine-1 as an MRI reporter gene based on chemical exchange. ACS Chem Biol 9:134-8
Bulte, Jeff W M (2013) Science to practice: can stem cells be labeled inside the body instead of outside? Radiology 269:1-3
Barczewska, Monika; Wojtkiewicz, Joanna; Habich, Aleksandra et al. (2013) MR monitoring of minimally invasive delivery of mesenchymal stem cells into the porcine intervertebral disc. PLoS One 8:e74658
Bar-Shir, Amnon; Liu, Guanshu; Liang, Yajie et al. (2013) Transforming thymidine into a magnetic resonance imaging probe for monitoring gene expression. J Am Chem Soc 135:1617-24
Janowski, Miroslaw; Lyczek, Agatha; Engels, Charla et al. (2013) Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation. J Cereb Blood Flow Metab 33:921-7
Aarntzen, Erik H J G; Srinivas, Mangala; Bonetto, Fernando et al. (2013) Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells. Clin Cancer Res 19:1525-33
Ahrens, Eric T; Bulte, Jeff W M (2013) Tracking immune cells in vivo using magnetic resonance imaging. Nat Rev Immunol 13:755-63
Cromer Berman, Stacey M; Kshitiz; Wang, C Joanne et al. (2013) Cell motility of neural stem cells is reduced after SPIO-labeling, which is mitigated after exocytosis. Magn Reson Med 69:255-62
Bar-Shir, Amnon; Liu, Guanshu; Greenberg, Marc M et al. (2013) Synthesis of a probe for monitoring HSV1-tk reporter gene expression using chemical exchange saturation transfer MRI. Nat Protoc 8:2380-91

Showing the most recent 10 out of 64 publications