Elsevier

Translational Research

Volume 176, October 2016, Pages 69-80
Translational Research

Original Article
Transplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model

https://doi.org/10.1016/j.trsl.2016.04.003Get rights and content

Based on results of hematopoietic stem cell transplantation in animal models of stroke, clinical trials with hematopoietic stem cells administered intra-arterially or intravenously have been initiated in patients. Although intra-arterial injection is expected to deliver transplanted cells more directly to the ischemic tissue, the optimal route for enhancing clinical outcomes has not been identified in the setting of stroke. In this study, we compared the therapeutic potential of intra-arterial versus intravenous injection of bone marrow derived–mononuclear cells (BM-MNCs) and CD133-positive (CD133+) cells in a murine stroke model. We have found that intra-arterial injection of BM-MNCs exaggerates inflammation with accompanying loss of microvascular structures in poststroke brain and no improvement in cortical function. In contrast, intravenous injection of BM-MNCs did not similarly enhance inflammation and improved cortical function. Our results indicate that the optimal route of cell transplantation can vary with different cell populations and highlight possible issues that might arise with intra-arterial cell administration for acute ischemic cerebrovascular disease.

Introduction

Hematopoietic stem cells have been shown to contribute critically to angiogenesis in embryos1 and adults.2 These stem cells have also emerged as potential tools for treating ischemic disorders. The major sources of hematopoietic stem cells for treating ischemic diseases are relatively purified homogenous hematopoietic stem cell popultions, such as CD34-positive (CD34+) or CD133-positive (CD133+) cells, and mixtures of heterogeneous cells, such as bone marrow–derived mononuclear cells (BM-MNCs). Cell surface markers, CD34 and CD133 antigens, are commonly used for separating hematopoietic stem cells. CD133 is specifically expressed on an immature subset of CD34+ cells and a subset of CD34-negative stem cells.3 In addition to CD34+ cells,4, 5 clinical studies have been performed using CD133+ cells in patients with cardiovascular diseases.6, 7, 8 The purity of CD133+ cells in clinical use has been shown to be about 90%,9 in part because the percentage of CD133+ cells in bone marrow is only about 0.2% before purification.10 BM-MNCs, obtained by density gradient centrifugation, contain varied cell populations, including hematopoietic stem cells and immature inflammatory cells. Transplanted BM-MNCs have been shown to enhance angiogenesis in animal ischemia models,11 leading to clinical trials in patients with cardiovascular diseases.12

In the setting of cerebrovascular disease, intravenous transplantation (ie, cell transfer) of hematopoietic stem cells improves stroke outcomes in animal models.13, 14 Clinical trials of intravenous15, 16 and intra-arterial17, 18 hematopoietic stem cell transplantation have been initiated in stroke. However, the advantages/disadvantages of intra-arterial injection versus intravenous injection have not been carefully studied in experimental stroke models.19, 20 Although it is clear that intra-arterial injection delivers more transplanted cells to the site of cerebral ischemia, compared with intravenous administration,18, 21, 22 the impact on stroke recovery and other parameters of the host response has not been delineated. Mesenchymal stem cell transplantation has also been initiated as an experimental treatment for patients with stroke. Both advantages and disadvantages of intra-arterial injection of mesenchymal stem cells have been reported in experimental stroke model.23, 24, 25

In this study, we have compared intra-arterial versus intravenous administration of BM-MNCs and CD133+ cells in a murine stroke model and evaluated the impact on inflammatory cell infiltration, microvascular structures, brain atrophy, and functional recovery.

Section snippets

Materials and Methods

The following study was approved by the Animal Care and Use Committee of Institute of Biomedical Research and Innovation (Kobe, Hyogo, Japan) and complies with the Guide for the Care and Use of Animals published by the Ministry of Education, Culture, Sports, Science and Technology in Japan. Experiments and results are reported according to the Animal Research: Reporting of In Vivo Experimental guidelines.

Intra-arterial administration of BM-MNCs: effect on cerebral atrophy and cortical function/behavior

In a murine stroke model, we have previously reported that intravenous administration of BM-MNCs cells after stroke reduces ischemic brain damage and appears to enhance repair.30, 31 In contrast, injection of granulocyte colony-stimulating factor (G-CSF) enhanced brain atrophy and exaggerated inflammation at the site of ischemia.28 To investigate the effects of intra-arterial administration of BM-MNCs cells after stroke, 5 × 103, 1 × 104, or 1 × 105 human BM-MNCs were infused into the left CCA

Discussion

Our results, summarized in Table I, indicate that intra-arterial administration of BM-MNCs (104 cells) after stroke has a mild impact on stroke outcome, whereas a larger number of cells (105) administered by the same route has the potential to exaggerate inflammation with narrowing and breakdown of microvasculature in poststroke brain. The latter were not associated with suppression of brain atrophy or improvement in cortical function. In contrast, intravenous administration of the same number

Conclusions

In this study, we have demonstrated that higher doses of intra-arterially administered BM-MNCs 2 days after stroke enhanced the inflammatory response and breakdown of microvasculature. The latter was associated with less effective functional recovery in murine stroke model, compared with the beneficial effects of intravenous injection of BM-MNCs. Our results indicate intra-arterial transplantation of “therapeutic cell populations” is not always superior to intravenous cell injection for the

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest. There are no relationships with industry pertaining to this work.

The authors received no editorial support in preparation of the article.

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