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
Liang, Yajie; Zhang, Jiangyang; Walczak, Piotr et al. (2018) Quantification of motor neuron loss and muscular atrophy in ricin-induced focal nerve injury. J Neurosci Methods 308:142-150
Kim, Taeho; Lee, Nohyun; Arifin, Dian R et al. (2017) In Vivo Micro-CT Imaging of Human Mesenchymal Stem Cells Labeled with Gold-Poly-L-Lysine Nanocomplexes. Adv Funct Mater 27:
Lyczek, Agatha; Arnold, Antje; Zhang, Jiangyang et al. (2017) Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin. Exp Neurol 291:74-86
Srivastava, Amit K; Gross, Sarah K; Almad, Akshata A et al. (2017) Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 289:96-102
Chehade, Moussa; Srivastava, Amit K; Bulte, Jeff W M (2016) Co-Registration of Bioluminescence Tomography, Computed Tomography, and Magnetic Resonance Imaging for Multimodal In Vivo Stem Cell Tracking. Tomography 2:159-165
Srivastava, Amit K; Bulte, Camille A; Shats, Irina et al. (2016) Co-transplantation of syngeneic mesenchymal stem cells improves survival of allogeneic glial-restricted precursors in mouse brain. Exp Neurol 275 Pt 1:154-61
Bar-Shir, Amnon; Liang, Yajie; Chan, Kannie W Y et al. (2015) Supercharged green fluorescent proteins as bimodal reporter genes for CEST MRI and optical imaging. Chem Commun (Camb) 51:4869-71
Srivastava, Amit K; Kadayakkara, Deepak K; Bar-Shir, Amnon et al. (2015) Advances in using MRI probes and sensors for in vivo cell tracking as applied to regenerative medicine. Dis Model Mech 8:323-36
Bar-Shir, Amnon; Bulte, Jeff W M; Gilad, Assaf A (2015) Molecular engineering of nonmetallic biosensors for CEST MRI. ACS Chem Biol 10:1160-70
Liang, Yajie; Bar-Shir, Amnon; Song, Xiaolei et al. (2015) Label-free imaging of gelatin-containing hydrogel scaffolds. Biomaterials 42:144-50

Showing the most recent 10 out of 92 publications