Effect of Single and Double Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Focal Cerebral Ischemia in Rats

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Abstract

Stem cell therapies are administered during the acute phase of stroke to preserve the penumbral tissues from ischemic injury. However, the effect of repeated cell therapy during the acute phase remains unclear. In this study, we investigated and compared the functional outcome of single (two days post-injury) and repeated (two and nine days post-injury) treatment with human umbilical cord derived mesenchymal stem cells (hUCB-MSCs) after middle cerebral artery occlusion (MCAO). The rotarod and limb placement tests were utilized to investigate functional outcomes, while infarct volume and tissue damage were measured by immunofluorescent staining for neovascularization, neurogenesis, apoptosis, and inflammation in the penumbral zones. We observed notable motor dysfunction and a significant decrease in infarcted brain volume, as well as increases in neurons and vessels in both single and repeated hUCB-MSC treatments compared to the control group. Interestingly, repeated administration of hUCB-MSCs was not found to elicit additional or synergistic improvements over monotherapy. This study suggests that a clearer understanding of the therapeutic window after stroke will facilitate the development of more efficient treatment protocols in the clinical application of stem cell therapy.

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A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

Jin Soo Lee, Ji Hong, Gyeong Joon Moon … (2010)

We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients.

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Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic.

Zheng Zhang, Michael Chopp (2009)

Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

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The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury.

R Hamm, B. Pike, D O'Dell … (1994)

The purpose of the present experiment was to examine the effectiveness of a modified rotarod test in detecting motor deficits following mild and moderate central fluid percussion brain injury. In addition, this investigation compared the performance of the rotarod task with two other commonly used measures of motor function after brain injury (beam-balance and beam-walking latencies). Rats were either injured with a mild (n = 14) or moderate (n = 8) level of fluid percussion injury or were surgically prepared but not injured (n = 8). All rats were assessed on all tasks for 5 days following their respective treatments. Results revealed that both the mild and moderate injury levels produced significant deficits in the ability of the animals to perform the rotarod task. Performance on the beam-balance and beam-walking tasks were not significantly impaired at the mild injury level. It was only at the moderate injury level that the beam-balance and beam-walking tasks detected deficits in motor performance. This result demonstrated that the rotarod task was a sensitive index of injury-induced motor dysfunction following even mild fluid percussion injury. A power analysis of the three tasks indicated that statistically significant group differences could be obtained with the rotarod task with much smaller sample sizes than with the beam-balance and beam-walking tasks. Performance on the rotarod, beam-walk, and beam-balance tasks were compared and evaluated by a multivariate stepdown analysis (multiple analysis of variance followed by univariate analyses of covariance). This analysis indicated that the rotarod task measures aspects of motor impairment that are not assessed by either the beam-balance or beam-walking latency. These findings suggest that compared to the beam-balance and beam-walking tasks, the rotarod task is a more sensitive and efficient index for assessing motor impairment produced by brain injury.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Neurobiol

Journal ID (iso-abbrev): Exp Neurobiol

Journal ID (publisher-id): EN

Title: Experimental Neurobiology

Publisher: The Korean Society for Brain and Neural Science

ISSN (Print): 1226-2560

ISSN (Electronic): 2093-8144

Publication date (Print): February 2017

Publication date (Electronic): 23 February 2017

Volume: 26

Issue: 1

Pages: 55-65

Affiliations

[1 ]Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.

[2 ]Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.

[3 ]Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.

[4 ]Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 13494, Korea.

[5 ]Stem Cell & Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea.

[6 ]Department of Neurosurgery, Soonchunhyang University Hospital, Seoul 31151, Korea.

Author notes

To whom correspondence should be addressed. TEL: 82-2-2072-3993, FAX: 82-2-744-8459, paeksh@ 123456snu.ac.kr

Article

DOI: 10.5607/en.2017.26.1.55

PMC ID: 5326715

SO-VID: 648b4d2d-7208-4b5d-af75-0e94dda6693a

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 10 November 2016

Date revision received : 09 February 2017

Date accepted : 13 February 2017

Funding

Funded by: Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries, CrossRef http://dx.doi.org/10.13039/501100003668;

Award ID: 311011-05-3-SB020

Funded by: Ministry of Health and Welfare, CrossRef http://dx.doi.org/10.13039/501100003625;

Effect of Single and Double Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Focal Cerebral Ischemia in Rats

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Abstract

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Functional role of amyloid

Most cited references 27

A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic.

The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury.

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