Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats

Sasaki, Yuichi; Sasaki, Masanori; Kataoka‐Sasaki, Yuko; Nakazaki, Masahito; Nagahama, Hiroshi; Suzuki, Junpei; Tateyama, Daiki; Oka, Shinichi; Namioka, Takahiro; Namioka, Ai; Onodera, Rie; Mikami, Takeshi; Wanibuchi, Masahiko; Kakizawa, Masafumi; Ishiai, Sumio; Kocsis, Jeffery D.; Honmou, Osamu

doi:10.2522/ptj.20150504

Cited by 58 publications

(60 citation statements)

References 38 publications

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“…35 Intravenous infusion of MSCs in the acute phase of stroke has been shown to have therapeutic efficacy in animal studies. 13,17,18,27,30 However, although there are pathophysiological differences between acute and chronic cerebral ischemia, only a limited number of studies have examined the therapeutic efficacy of MSCs during the chronic phase of stroke. Developing approaches to provide therapeutic efficacy in chronic ischemia represents an important area of investigation.…”

Section: Intravenous Infusion Of Mesenchymal Stem Cells Promotes Funcmentioning

confidence: 99%

“…The MSC culture was prepared according to the methodology used in our previous studies. 16,17,27 Briefly, bone marrow was obtained from the femoral bones of adult rats (n = 16). The marrow was then diluted to 20 ml with Dulbecco's modified Eagle medium (DMEM; Sigma) and supplemented with 10% heat-inactivated fetal bovine serum (FBS; Thermo Fisher Scientific), 2 mM l-glutamine (Sigma), 100 U/ml penicillin, and 0.1 mg/ml streptomycin (Thermo Fisher Scientific) and incubated for 3 days (5% CO 2 , 37°C).…”

Section: Preparation Of Mscs From Rat Bone Marrowmentioning

confidence: 99%

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Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction

Namioka

Sasaki

et al. 2019

Journal of Neurosurgery

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OBJECTIVEIntravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.METHODSEight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.RESULTSMotor recovery was better in the MSC-treated group than in the vehicle-treated group, with rapid improvement (evident at 1 week post-infusion). In MSC-treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.CONCLUSIONSThese results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB.

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Section: Intravenous Infusion Of Mesenchymal Stem Cells Promotes Funcmentioning

confidence: 99%

Section: Preparation Of Mscs From Rat Bone Marrowmentioning

confidence: 99%

Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction

Namioka

Sasaki

et al. 2019

Journal of Neurosurgery

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“…In the present study, we showed that there is accumulation of intravenously administered MSCs in the injured region in CNS diseases, including stroke, which is consistent with previous studies. 4,16,30,34 It could be possible that infused MSCs migrated into the injured CNS tissue and provide beneficial effects. A hypothetical sequence of potential therapeutic mechanisms in a cell-based therapeutic approach for acute CNS insult is that beneficial effects may be provided from neuromodulators by MSC release, such as brain-derived neurotrophic factor 15,23 at early post-MSC infusion times (days).…”

Section: Discussionmentioning

confidence: 99%

“…The initial stroke volume evaluated with DWI was standardized at 220-370 mm 3 and excluded animals outside this range to assess the efficacy of MSCs following rtPA for a large ischemic injury. 30 We used a suture occlusion/reperfusion model in this study to investigate the effects of rtPA and MSCs following complete reperfusion. Physiological parameters (rectal temperature, blood pH, partial pressure of oxygen, partial pressure of carbon dioxide, and blood pressure) were maintained within normal ranges during surgery and transplantation procedures for all animals and did not significantly differ among the experimental groups.…”

Section: Cerebral Ischemic Modelmentioning

confidence: 99%

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Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats

Nakazaki

Sasaki

Kataoka‐Sasaki

et al. 2017

Journal of Neurosurgery

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OBJECTIVE Reperfusion therapy with intravenous recombinant tissue plasminogen activator (rtPA) is the standard of care for acute ischemic stroke. However, hemorrhagic complications can result. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA therapy in the acute phase of transient middle cerebral artery occlusion (tMCAO) in rats. METHODS After induction of tMCAO, 4 groups were studied: 1) normal saline [NS]+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined. Matrix metalloproteinase-9 (MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion. RESULTS The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of MMP-9, but MSCs inhibited MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups. CONCLUSIONS Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy of infused MSCs after rtPA therapy facilitated early behavioral recovery.

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Mesenchymal Stem Cells for Neurological Disorders

et al. 2021

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Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell‐based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell‐based therapies.

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Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats

Cited by 58 publications

References 38 publications

Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction

Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction

Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats

Mesenchymal Stem Cells for Neurological Disorders

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