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. INTRODUCTIONclinical phase I and II studies (4,26). Cell-based therapies are in clinical trials in, for example, Parkinson's disease (13,14), ischemic stroke (4,21), and spinal cord Emerging stem cell therapies aimed at treatment of different central nervous system (CNS) disorders show lesions (29). When comparing intra-arterial and intravenous transplantations in clinical trials following spinal great promise (7). Different stem cell lines have been transplanted in a wide spectrum of pathological condicord injuries patient outcome seems to favor an intraarterial approach (29). Evidence is gathering for both tions, both in preclinical animal models and in a few open surgical and different intravascular methods of stream, as the multiple sclerosis pharmaceutical monoclonal antibody drug Natalizumab that target it (28). With transplantation to the CNS (4...

Strategies for CNS repair following TBI

“…Lundberg and associates compared the cell engraftment of multiple cell lines (human MSC, human NPC, rat NPC) when given intra-arterially versus intravenously and found significantly higher rates of engraftment with IA administration of hMSC, but no evidence of human NPC migration to the site of injury via either administration method. The authors in this study determined that this was likely due to the lack of VCAM-1 to CD49d interaction in the latter cell population (Lundberg et al, 2012). Rodent stroke models have also been able to demonstrate higher rates of engraftment by IA administration of BM-MNC (Kamiya et al, 2008;Yang et al, 2013), MSC (Byun et al, 2013) and with NSC (Pendharkar et al, 2010) when compared to IV.…”

“…CD49d expression may be required for adequate cell engraftment as supported by absence of engraftment of hNPC with minimal CD49d expression (Lundberg et al, 2012). Alternatively, selection for CD49d positive neural stem cells have shown to enhance engraftment in a murine stroke model (Guzman et al, 2008).…”

Regenerative Medicine for Cerebral Infarction

“…Intravenous administration, on the other hand, is the least invasive, but most stem cells end up in the liver and lung , leaving a much smaller number of stem cells surviving in the area of the ischemic penumbra compared with the intraparenchymal transplantation method. This is why the quantity of stem cells administrated intravenously in animal experiments is roughly an order of magnitude larger than that used in other delivery methods (Li et al, 2008;Lundberg et al, 2011). Lappalainen et al detected an accumulation of graft cells which were intraarterially administrated in the ischemic brain, using SPECT/CT, but such cells were not observed when administrated intravenously (Lappalainen et al, 2008).…”

Stem cell therapy for acute cerebral injury

“…The production of neurotrophic factors could underlie this functional amelioration. [40,45-49] Limited evidence of a role for immortalized neural cell lines has been shown by transplanting NT2N human neuronal cells to improve cognitive outcome. [50]…”