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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045062-09
Application #
8231391
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Owens, David F
Project Start
2002-12-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$416,280
Indirect Cost
$162,451
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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; 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
Liang, Yajie; Bar-Shir, Amnon; Song, Xiaolei et al. (2015) Label-free imaging of gelatin-containing hydrogel scaffolds. Biomaterials 42:144-50
Andrzejewska, Anna; Nowakowski, Adam; Janowski, Miroslaw et al. (2015) Pre- and postmortem imaging of transplanted cells. Int J Nanomedicine 10:5543-59
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
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
Tang, Yaohui; Zhang, Chunfu; Wang, Jixian et al. (2015) MRI/SPECT/Fluorescent Tri-Modal Probe for Evaluating the Homing and Therapeutic Efficacy of Transplanted Mesenchymal Stem Cells in a Rat Ischemic Stroke Model. Adv Funct Mater 25:1024-1034
Bulte, Jeff W M (2014) Science to Practice: Highly shifted proton MR imaging--a shift toward better cell tracking? Radiology 272:615-7
Janowski, M; Engels, C; Gorelik, M et al. (2014) Survival of neural progenitors allografted into the CNS of immunocompetent recipients is highly dependent on transplantation site. Cell Transplant 23:253-62

Showing the most recent 10 out of 85 publications