Diffusion tensor imaging as a biomarker for assessing neuronal stem cell treatments affecting areas distal to the site of spinal cord injury.
OBJECTIVE The aims of this study were to determine if the morphological and functional changes induced by neural stem cell (NSC) grafts after transplantation into the rodent spinal cord can be detected using MR diffusion tensor imaging (DTI) and, furthermore, if the DTI-derived mean diffusivity (MD) metric could be a biomarker for cell transplantation in spinal cord injury (SCI). METHODS A spinal contusion was produced at the T-8 vertebral level in 40 Sprague Dawley rats that were separated into 4 groups, including a sham group (injury without NSC injection), NSC control group (injury with saline injection), co-injection control group (injury with Prograf), and the experimental group (injury with NSC and Prograf injection). The NSC injection was completed 1 week after injury into the site of injury and the rats in the experimental group were compared to the rats from the sham, NSC control, and co-injection groups. The DTI index, MD, was assessed in vivo at 2, 5, and 10 weeks and ex vivo at 10 weeks postinjury on a 9.4-T Bruker scanner using a spin-echo imaging sequence. DTI data of the cervical spinal cord from the sham surgery, injury with saline injection, injury with injection of Prograf only, and injury with C17.2 NSC and Prograf injection were examined to evaluate if cellular proliferation induced by intrathoracic C17.2 engraftment was detectable in a noninvasive manner. RESULTS At 5 weeks after injury, the average fractional anisotropy, longitudinal diffusion (LD) and radial diffusion (RD) coefficients, and MD of water (average of the RD and LD eigenvalues in the stem cell line-treated group) increased to an average of 1.44 × 10-3sec/mm2in the cervical segments, while the control groups averaged 0.98 × 10-3s/mm2. Post hoc Tukey's honest significant difference tests demonstrated that the transplanted stem cells had significantly higher MD values than the other groups (p = 0.032 at 5 weeks). In vivo and ex vivo findings at 10 weeks displayed similar results. This statistical difference between the stem cell line and the other groups was maintained at the 10-week postinjury in vivo and ex vivo time points. CONCLUSIONS These results indicate that the DTI-derived MD metric collected from noninvasive imaging techniques may provide useful biomarker indices for transplantation interventions that produce changes in the spinal cord structure and function. Though promising, the results demonstrated here suggest additional work is needed before implementation in a clinical setting.
Department of Biomedical Engineering, Marquette University.|Air Force Research Laboratory, 711th Human Performance Wing, Human Effectiveness Directorate, Bioeffects Division, Radio Frequency Bioeffects Branch, and.
Michael B
MB
Jirjis
National Research Council Research Associateship Program, Joint Base San Antonio, Fort Sam Houston, San Antonio, Texas.
Chris
C
Valdez
Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
Aditya
A
Vedantam
Department of Biomedical Engineering, Marquette University.
Brian D
BD
Schmit
Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
Shekar N
SN
Kurpad
D000818:Animals; D002460:Cell Line; D066193:Cervical Cord / Q000000981:diagnostic imaging / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D056324:Diffusion Tensor Imaging / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006358:Hot Temperature; D007150:Immunohistochemistry; D009043:Motor Activity / Q000502:physiology; D058953:Neural Stem Cells / Q000502:physiology / Q000637:transplantation*; D058748:Pain Perception / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods; D013904:Thoracic Vertebrae / Q000293:injuries; D013997:Time Factors; D016896:Treatment Outcome
BBB = Basso, Beattie, and Bresnahan; C17.2 neuronal stem cells; CGRP = calcitonin gene–related peptide; DAPI = 4,6′-diamino-2-phenylindole-dihydrochloride; DTI = diffusion tensor imaging; FA = fractional anisotropy; FOV = field of view; GAP43 = growth-associated peptide 43; LD = longitudinal diffusion; MD = mean diffusivity; NEX = number of excitations; NSC = neural stem cell; OD = optical density; PBS = phosphate-buffered saline; RD = radial diffusion; ROI = region of interest; SCI = spinal cord injury; diffusion tensor imaging; magnetic resonance imaging; spinal cord injury