Bilateral cortical hyperactivity detected by fMRI associates with improved motor function following intravenous infusion of mesenchymal stem cells in a rat stroke model

Suzuki, Junpei; Sasaki, Masanori; Harada, Kuniaki; Bando, Michio; Kataoka, Yuko; Onodera, Rie; Mikami, Takeshi; Wanibuchi, Masahiko; Mikuni, Nobuhiro; Kocsis, Jeffery D.; Honmou, Osamu

doi:10.1016/j.brainres.2012.12.028

Cited by 33 publications

(30 citation statements)

References 36 publications

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“…Parameters such as the animal model, dosage, and therapeutic window have been shown to highly influence infarct volume reduction and functional recovery3943838487.…”

Section: Discussionmentioning

confidence: 99%

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

Argibay

Trekker

Himmelreich

et al. 2017

Sci Rep

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Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke.

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“…Parameters such as the animal model, dosage, and therapeutic window have been shown to highly influence infarct volume reduction and functional recovery3943838487.…”

Section: Discussionmentioning

confidence: 99%

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

Argibay

Trekker

Himmelreich

et al. 2017

Sci Rep

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“…Intravenous transplantation of MSCs led to motor function improvement as assessed by fMRI (Suzuki et al, 2013). In a previous study, we have shown that post-stroke G-CSF treatment of aged animals improved survival and had a beneficial effect on functional outcome in somatosensory, motor, learning, and memory tests.…”

Section: Discussionmentioning

confidence: 99%

Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone

Bălșeanu

Buga

Cãtãlin

et al. 2014

Front. Aging Neurosci.

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Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (106 cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration.” However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.

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“…The use of animals in this study was approved by the animal care and use committee at Sapporo Medical University (#12–030), and all procedures were carried out in accordance with institutional guidelines. Methodology of MSC culture was based upon our previous studies [17]. Briefly, bone marrow was obtained from femoral bones in adult Sprague–Dawley rats (male, 200–250 g), 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 (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% CO 2 , 37°C).…”

Section: Methodsmentioning

confidence: 99%

Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury

Takayanagi

Sasaki

Kataoka‐Sasaki

et al. 2015

The Journal of Sexual Medicine

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Introduction We evaluated the potential preventive effects and mechanisms of intravenously preloaded mesenchymal stem cells (MSCs) for erectile dysfunction (ED) in a cavernous nerve (CN) injury model. Methods Male Sprague–Dawley (SD) rats were used for this study. Rats were randomized into two groups. One group was intravenously preloaded with MSCs (1.0 × 106 cells in 1 mL total fluid volume) and the other was infused with medium alone (1 mL Dulbecco's modified Eagle's medium [DMEM]) for sham control, respectively. Crushed CN injury was induced immediately after infusion. The surgeon was blind to the experimental conditions (MSC or medium). Main Outcome Measures To assess erectile function, we measured the intracavernous pressure (ICP) and arterial pressure (AP) at 1 hour and 2 weeks after CN injury. After measuring the initial ICP/AP of pre-injury (normal) male SD rats, they were randomized into the two groups and infused with MSCs or medium. PKH26-labelled MSCs were used for tracking. To investigate the mRNA expression levels of neurotrophins in the major pelvic ganglia (MPG), we performed real-time quantitative real-time polymerase chain reaction. Results The reduction of ICP/AP and area under the curve of ICP (ICP-AUC) in the MSC group was significantly lower than in the DMEM group (P < 0.05; P < 0.05) at 1 hour. The ICP/AP and ICP-AUC at 2 weeks post-injury in the MSC group was significantly higher than in the DMEM group (P < 0.01; P < 0.05). The preloaded PKH26-labelled MSCs were detected in the MPG and CN using confocal microscopy indicating homing of the cells to the injured nerve and ganglia. Glia cell-derived neurotrophic factor (GDNF) and neurturin, which are important neurotrophic factors for erection, had expression levels in MPG significantly higher in the MSC group than in the DMEM group (P < 0.01, 0.05). Conclusion Intravenous preload of MSCs before a CN injury may prevent or reduce experimental ED.

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Bilateral cortical hyperactivity detected by fMRI associates with improved motor function following intravenous infusion of mesenchymal stem cells in a rat stroke model

Cited by 33 publications

References 36 publications

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone

Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury

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