Transplantation of Marrow Stromal Cells Restores Cerebral Blood Flow and Reduces Cerebral Atrophy in Rats with Traumatic Brain Injury: In vivo MRI Study

Abstract

Cell therapy promotes brain remodeling and improves functional recovery after various central nervous system disorders, including traumatic brain injury (TBI). We tested the hypothesis that treatment of TBI with intravenous administration of human marrow stromal cells (hMSCs) provides therapeutic benefit in modifying hemodynamic and structural abnormalities, which are detectable by in vivo MRI. hMSCs were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Male Wistar rats (300-350 g, n = 18) subjected to controlled cortical impact TBI were intravenously injected with 1 mL of saline (n = 9) or hMSCs in suspension (n = 9, approximately 3 · 10 6 SPIO-labeled hMSCs) 5 days post-TBI. In vivo MRI measurements consisting of cerebral blood flow (CBF), T2-weighted imaging, and 3D gradient echo imaging were performed for all animals 2 days post-TBI and weekly for 6 weeks. Functional outcome was evaluated with modified neurological severity score and Morris water maze test. Cell engraftment was detected in vivo by 3D MRI and confirmed by double staining. Ventricle and lesion volumetric alterations were measured using T2 maps, and hemodynamic abnormality was tracked by MRI CBF measurements. Our data demonstrate that treatment with hMSCs following TBI diminishes hemodynamic abnormalities by early restoration and preservation of CBF in the brain regions adjacent to and remote from the impact site, and reduces generalized cerebral atrophy, all of which may contribute to the observed improvement of functional outcome.

Diffusion-Derived Magnetic Resonance Imaging Measures of Longitudinal Microstructural Remodeling Induced by Marrow Stromal Cell Therapy after Traumatic Brain Injury

“…As described previously, 14,50 our TBI model induced severe brain injury, which affected both the cortical and underlying subcortical regions. Damage to the corpus callosum, the principal and largest bundle of nerve fibers in the brain, and its reorganization afterwards, led to readily detected MRI signal change (Fig.…”

“…49,50 Briefly, male Wistar rats (300-350 g, n = 30) were anesthetized with chloral hydrate (350 mg/kg, i.p.) and their rectal temperature was maintained at 37°C with a feedback-regulated water-heating pad.…”

“…To investigate how cell therapy benefits structural remodeling and whether acute cell engraftment advances the therapeutic effect compared with delayed intervention, strategies previously proven efficient in improvement of neurological function, including cell type, dose, and treatment time point, 49,50 had been used. MSCs are a mixed cell population, including stem and progenitor cells.…”

“…1D). To track the structural remodeling and compare the treatment effect (6 h cell or 1 week cell vs. saline) in this specific boundary region, the lesion was identified on a T2 map using a threshold value 49,50 provided by pre-injury scan. An ROI, encompassing the boundary region with apparent signal increase on FA and entropy map, was created by expanding the outline of the lesion 6 pixels outward in the cortex area (Fig.…”

“…In addition, the timing of cell transplantation, one of key issues regarding optimization of basic transplantation techniques, remains to be addressed. Although acute intravenous cell intervention (within 24 h) after TBI provides therapeutic benefit above that of delayed cell administration (*1 week) in retarding cerebral atrophy and reducing functional deficits, 49,50 how these treatment strategies affect structural plasticity is unclear. The objective of the present study was to investigate the capacity and sensitivity of FA and entropy to: 1) longitudinally identify structural reorganization in an experimental animal model of TBI, and 2) dynamically detect the therapeutic effect of human bone marrow stromal cells (hMSCs), engrafted at 6 h or 1 week post-TBI, on structural remodeling in the injured brain.…”