title: Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: engraftment is dependent on cell type and adhesion molecule expression.
abstract: Stem cell transplantation procedures using intraparenchymal injections cause tissue injury in addition to associated surgical risks. Intravenous cell administration give engraftment in parenchymal lesions although the method has low efficacy and specificity. In pathological conditions  with inflammation, such as traumatic brain injury, there is a transient up-regulation of ICAM-1 and VCAM-1 which might provide environmental cues for migration of stem cells from blood to parenchyma. The aim of this study was to i) analyze the effect of intra-arterial administration on cellular  engraftment, ii) compare engraftment and side effects between three different stem cell systems, and iii) analyze gene expression in these three systems. We performed specific intra-arterial transplantations with human mesenchymal stem cells (hMSCs), human neural progenitor cells (hNPCs),  and rat neural progenitor cells (rNPCs) in a rat model of traumatic brain injury. These results were compared to the intravenous route for each cell type, respectively. Analysis of engraftment and recipient characterization was performed by immunohistochemistry. We further characterized the  different types of cells by microarray and RT-qPCR analysis. Specific intra-arterial transplantations produced significantly higher engraftment compared to intravenous transplantation with hMSCs and rNPCs. No engraftment was detected after intra-arterial or intravenous administration of hNPCs.  Characterization of integrin expression indicated that CD49dVCAM-1 and possibly ICAM-1 interactions through CD18 and CD11a, respectively, are important for engraftment after intravascular cell administration. No side effects, such as thromboembolic complications, were detected. When translating  stem cell therapies to clinical practice, the route of transplantation and the properties of the cell lines (homing, diapedesis, and migration) become important. This study supports the use of selective intra-arterial transplantation for improving engraftment after traumatic brain injury.  In addition, we conclude that careful analysis of cells intended for local, intra-arterial transplantation with respect to integrin expression is important.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundberg
authors.forename: Erik
authors.initials: E
authors.lastname: Södersten
authors.forename: Erik
authors.initials: E
authors.lastname: Sundström
authors.forename: Katarina
authors.initials: K
authors.lastname: Le Blanc
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
authors.forename: Staffan
authors.initials: S
authors.lastname: Holmin
mesh_terms: D000818:Animals; D001158:Arteries; D001921:Brain / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D001930:Brain Injuries / Q000601:surgery*; D040881:CD11a Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006085:Graft Survival; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation*; D009474:Neurons / Q000166:cytology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014680:Veins
chemical_list: D040881:CD11a Antigen; D018821:CD18 Antigens; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1