Original ArticleTransplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model
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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2020, Brain Research BulletinCitation Excerpt :These studies are limited to evaluate the diagnostic applications of these cells in psychiatric disorders by investigating the number of stem cells in circulation or factors that direct their trafficking (Adamiak et al., 2015; Borkowska et al., 2014, 2016; Karapetyan et al., 2013; Ratajczak and Suszynska, 2016). To support this last notion, it has been shown that in response to systemic or local inflammation due to tissue or organ injuries, stem cells could be mobilized into peripheral blood from bone marrow and other tissue-specific niches as well (Bryukhovetskiy and Bryukhovetskiy, 2015; Cambria et al., 2016; Carvalho et al., 2015; Kasahara et al., 2016; Liu and Ratajczak, 2012). These circulating stem cells potentially would home to the damaged tissues and attempt to contribute to regeneration (Quesenberry et al., 2007; Shyu et al., 2006).
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2019, Journal of Clinical NeuroscienceCitation Excerpt :In pre-clinical AIS models, IA-administered stem cells reduce inflammation, increase trophic factors and replace damaged cells, resulting in improved sensorimotor and functional outcomes and reduced final infarct volumes [23–25]. IA administration has been shown to increase the risk of microemboli and cellular accumulation, however, with these complications occurring more commonly with larger stem cells (i.e., mesenchymal stem cells vs. neural stem cells) and with higher infused doses and faster injection velocities [21,22,26,27]. Both systemic and local hypothermia demonstrate neuroprotective properties in AIS by diminishing excitotoxicity and inflammation, suppressing free-radical formation, and preventing BBB breakdown [28–31].
Adipose-derived stem cell therapy inhibits the deterioration of cerebral infarction by altering macrophage kinetics
2019, Brain ResearchCitation Excerpt :Quantification was conducted by investigators who were blinded to the experimental protocol and the samples. This procedure has been described previously (Kasahara et al., 2016). Briefly, mice at 7–9 weeks post-MCAO were euthanized with sodium pentobarbital and perfused transcardially with saline followed by 4% paraformaldehyde.