Research ReportBilateral cortical hyperactivity detected by fMRI associates with improved motor function following intravenous infusion of mesenchymal stem cells in a rat stroke model
Highlights
► We infused mesenchymal stem cells (MSCs) in a rat stroke model. ► Two fMRI patterns were observed in the MSC infused animals. ► They are unilateral and bilateral activation of sensorimotor cortex. ► Bilateral activated pattern showed the greatest functional recovery. ► Bilateral activated pattern indicates functional outcome than lesion volume.
Introduction
There has been considerable effort using intravenously infused mesenchymal stem cells (MSCs) prepared from bone marrow to study potential therapeutic effects in rodent models of stroke (Honmou et al., 2012). Current thinking is that key therapeutic mechanisms of MSCs in various models of central nervous system (CNS) diseases are not primarily from neuronal or glial differentiation, but from secretion of neurotrophic factors which can provide for neuroprotection (Chen et al., 2002b, Parr et al., 2007, Honmou et al., 2012), induction of axonal sprouting (Shen et al., 2006), neovascularization (Onda et al., 2008) and immunomodulation (Ohtaki et al., 2008, Bai et al., 2009). Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) have a critical role in activity-dependent modulation of synaptic plasticity in the brain (Johansson et al., 2011) and generate microenvironments within the injured brain that enhance neural plasticity and lead to improvement in neurological function after stroke (Chopp et al., 2009).
Functional recovery in the rat middle cerebral artery occlusion (MCAO) model as assessed using the treadmill stress test is not always directly correlated with the ischemic volume calculated from high intensity signals using T2-weighted image (T2WI) MRI. Komatsu et al. (2010) reported that although MRI analysis revealed that rats receiving MSCs 7 days after MCAO exhibited decreased ischemic volume whereas those receiving MSCs at 14 and 28 days did not, all of the MSC treated animals showed greater functional recovery as compared to sham control rats. Thus, the gross lesion volume was not a precise predictor of functional outcome. Conventional T2WI MRI represents static/anatomical images and not dynamic/functional images. Functional MRI (fMRI) could potentially be a better predictor of the recovery process after stroke. To address this issue lesion volume (T2WI) and functional activity (fMRI) after MCAO induction were compared to behavioral outcome in animals infused with medium or MSCs.
Section snippets
fMRI localization of forelimb representation area in primary somatosensory cortex in response to electrical stimulation in normal and MCAO rats without MSC infusion
T2⁎ weighted images of the rat brain in the resting state (Rest) and during electrical stimulation of the left forepaw (Task) are shown in Fig. 1A and B, respectively. A T2WI is shown in Fig. 1C. The subtraction of the T2⁎ weighted images (see Section 4) are superimposed on the T2WI in Fig. 1D. Note the area of increased blood-oxygen-level-dependent (BOLD) signal within the right somatosensory cortex elicited by the electrical stimulation. In normal rats the BOLD signal was exclusively on one
Discussion
This study demonstrates that following intravenous infusion of MSCs 6 h after MCAO, lesion volume and functional outcome were improved as compared to MCAO rats infused with medium alone. fMRI indicated that within the MSC infused rats two patterns of sensorimotor cortex activation from contra-regional forepaw stimulation were observed: unilateral and bilateral cortical activity. There was only a unilateral activated signal (contralateral to forepaw stimulation) in the medium infused group and
Preparation of mesenchymal stem cells from rat bone marrow
The use of animals in this study was approved by the animal care and use committee of Sapporo Medical University, and all procedures were carried out in accordance with institutional guidelines. Methodology of MSC culture and phenotype analysis of expanded MSCs were based upon our previous studies (Kim et al., 2006, Ukai et al., 2007). Briefly, bone marrow was obtained from femoral bone in adult Sprague–Dawley rats. Rats were anesthetized with ketamine (75 mg/kg) and xylazine (10 mg/kg)
Acknowledgments
This work was supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Coordination, Support and Training Program for Translational Research to O.H.; Grant-in Aid for Scientific Research (B) to O.H. (20390388); Grant-in Aid for Scientific Research to M.S. (Start-up; 24890181), R.O., (24592138), T.M. (22591593), M.W. (23592101)); the Medical and Rehabilitation and Development Research Services of Department of Veterans Affairs (VA); the VA
References (36)
- et al.
Promoting axonal rewiring to improve outcome after stroke
Neurobiol. Dis.
(2010) - et al.
Mesenchymal stem cells: therapeutic outlook for stroke
Trends Mol. Med.
(2012) - et al.
A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats
Brain Res.
(2004) - et al.
Neural differentiation potential of peripheral blood- and bone-marrow-derived precursor cells
Brain Res.
(2006) - et al.
Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia
Brain Res.
(2010) - et al.
Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome
Brain Res.
(2010) - et al.
Intracarotid transplantation of bone marrow stromal cells increases axon–myelin remodeling after stroke
Neuroscience
(2006) - et al.
Functional MRI at 4.7 T of the rat brain during electric stimulation of forepaw, hindpaw, or tail in single- and multislice experiments
Exp. Neurol.
(2000) - et al.
Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia
Brain Res.
(2010) - et al.
Transplanted neurally modified bone marrow-derived mesenchymal stem cells promote tissue protection and locomotor recovery in spinal cord injured rats
Neurorehabil. Neural Repair
(2011)
Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain
Brain
Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis
Glia
Autologous mesenchymal stem cell transplantation in stroke patients
Ann. Neurol.
Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult
J. Neurosci.
Inosine induces axonal rewiring and improves behavioral outcome after stroke
Proc. Natl. Acad. Sci. USA
Ischemic rat brain extracts induce human marrow stromal cell growth factor production
Neuropathology
Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies
Stroke
Extensive cortical rewiring after brain injury
J. Neurosci.
Cited by (28)
Intravenous infusion of auto-serum-expanded autologous mesenchymal stem cells into chronic severe brain injury patients
2024, Interdisciplinary Neurosurgery: Advanced Techniques and Case ManagementIntravenous infusion of mesenchymal stem cells improves impaired cognitive function in a cerebral small vessel disease model
2019, NeuroscienceCitation Excerpt :Infused MSCs reduce the infarcted volume and improve the functional outcome in experimental stroke models, such as occlusion of large cerebral arteries, including the middle cerebral artery. Several putative therapeutic mechanisms of infused MSCs, including neuroprotection (Sasaki et al., 2009), neovascularization (Onda et al., 2008), regeneration (Liu et al., 2006), and neuroplasticity, have been suggested (Suzuki et al., 2013). Importantly, intravenous infusion of MSCs inhibits the deterioration of BBB function and improves the functional outcome in a middle cerebral artery occlusion (MCAO) model (Nakazaki et al., 2017).
Preservation of interhemispheric cortical connections through corpus callosum following intravenous infusion of mesenchymal stem cells in a rat model of cerebral infarction
2018, Brain ResearchCitation Excerpt :First, we have shown that a greater number of neural fibers detected with DTI tractography was observed in the MSC treated animals compared to the vehicle group. Thus, we hypothesized preservation of interhemispheric cortical connections through the corpus callosum projecting from the infarcted cortex through the corpus callosum (Suzuki et al., 2013). Transcallosal axonal sprouting after cortical infarction has been reported (Carmichael and Chesselet, 2002).
Cell-based and pharmacological neurorestorative therapies for ischemic stroke
2018, NeuropharmacologyIntravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury
2016, NeuroscienceCitation Excerpt :All methods and data were reported in accordance with guidelines provided by Animals in Research: Reporting in Vivo Experiments (ARRIVE) and Minimum Information about a Spinal Cord Injury Experiment (MIASCI) (Kilkenny et al., 2010; Lemmon et al., 2014). MSC culture preparation was based on our previous studies (Kim et al., 2006; Ukai et al., 2007; Suzuki et al., 2013; Takayanagi et al., 2015). Briefly, bone marrow was obtained from the femoral bones of eight adult wild type and two GFP-expressing Sprague–Dawley rats (W-Tg (CAG-GFP)184Ys), diluted to 25 ml with Dulbecco’s modified Eagle’s medium (DMEM) (SIGMA, St. Louis, MO, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Thermo Fisher Scientific Inc., Waltham, MA, USA), 2 mM l-glutamine (SIGMA), 100 U/ml penicillin, 0.1 mg/ml streptomycin (Thermo Fisher Scientific Inc.) and incubated for 3 days (5% CO2, 37 °C).
Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury
2015, Journal of Sexual Medicine