Allogeneic adipose-derived mesenchymal stem cell sheet that produces neurological improvement with angiogenesis and neurogenesis in a rat stroke model

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OBJECTIVE

Stem cell therapy is a promising strategy for the treatment of severe cerebral ischemia. However, targeting sufficient grafted cells to the affected area remains challenging. Choosing an adequate transplantation method for the CNS appears crucial for this therapy to become a clinical reality. The authors used a scaffold-free cell sheet as a translational intervention. This method involves the use of cell sheet layers and allows the transplantation of a large number of cells, locally and noninvasively. The authors evaluated the effectiveness of allogeneic adipose tissue–derived mesenchymal stem cell sheets in a rat model of stroke.

METHODS

The animals, subjected to middle cerebral artery occlusion, were randomly divided in two groups: one in which a cell sheet was transplanted and the other in which a vehicle was used (n = 10/group). Over a period of 14 days after transplantation, the animals’ behavior was evaluated, after which brain tissue samples were removed and fixed, and the extent of angiogenesis and infarct areas was evaluated histologically.

RESULTS

Compared to the vehicle group, in the cell sheet group functional angiogenesis and neurogenesis were significantly increased, which resulted in behavioral improvement. Transplanted cells were identified within newly formed perivascular walls as pericytes, a proportion of which were functional. Newly formed blood vessels were found within the cell sheet that had anastomosed to the cerebral blood vessels in the host.

CONCLUSIONS

The transplantation approach described here is expected to provide not only a paracrine effect but also a direct cell effect resulting in cell replacement that protects the damaged neurovascular unit. The behavioral improvement seen with this transplantation approach provides the basis for further research on cell sheet–based regenerative treatment as a translational treatment for patients with stroke.

ABBREVIATIONS AMSC = adipose-derived mesenchymal stem cell; AMSCS = AMSC sheet; CS = cell sheet; GFP = green fluorescent protein; MCAO = middle cerebral artery occlusion; MSC = mesenchymal stem cell; NG2 = anti–chondroitin sulfate proteoglycan; NVU = neurovascular unit; qRT-PCR = quantitative real-time polymerase chain reaction; VE = vehicle.

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Contributor Notes

Correspondence Hidekazu Sekine: Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan. sekine.hidekazu@twmu.ac.jp.INCLUDE WHEN CITING Published online February 22, 2019; DOI: 10.3171/2018.11.JNS182331.Disclosures Dr. Shimizu reports direct stocker ownership in and receiving research funding from CellSeed Inc., for which he is also on the scientific advisory board. Dr. E. Kobayashi is a medical adviser for Sysmex and Regience Ltd.Tokyo Women’s Medical University received research funds from CellSeed Inc.
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