Engraftment of Human Mesenchymal Stem Cells in a Rat Photothrombotic Cerebral Infarction Model : Comparison of Intra-Arterial and Intravenous Infusion Using MRI and Histological Analysis

Abstract

ObjectiveThis study aimed to evaluate the hypotheses that administration routes [intra-arterial (IA) vs. intravenous (IV)] affect the early stage migration of transplanted human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in acute brain infarction.MethodsMale Sprague-Dawley rats (n=40) were subjected to photothrombotic infarction. Three days after photothrombotic infarction, rats were randomly allocated to one of four experimental groups [IA group : n=12, IV group : n=12, superparamagnetic iron oxide (SPIO) group : n=8, control group : n=8]. All groups were subdivided into 1, 6, 24, and 48 hours groups according to time point of sacrifice. Magnetic resonance imaging (MRI) consisting of T2 weighted image (T2WI), T2* weighted image (T2*WI), susceptibility weighted image (SWI), and diffusion weighted image of rat brain were obtained prior to and at 1, 6, 24, and 48 hours post-implantation. After final MRI, rats were sacrificed and grafted cells were analyzed in brain and lung specimen using Prussian blue and immunohistochemical staining.ResultsGrafted cells appeared as dark signal intensity regions at the peri-lesional zone. In IA group, dark signals in peri-lesional zone were more prominent compared with IV group. SWI showed largest dark signal followed by T2*WI and T2WI in both IA and IV groups. On Prussian blue staining, IA administration showed substantially increased migration and a large number of transplanted hBM-MSCs in the target brain than IV administration. The Prussian blue-positive cells were not detected in SPIO and control groups.ConclusionIn a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration. MRI and histological analyses revealed the time course of cell migration, and the numbers and distribution of hBM-MSCs delivered into the brain.

Strategies for CNS repair following TBI

“…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. However, the effect of increased engraftment by IA administration remains unclear as currently available data varies.…”

Sensitivity of Susceptibility-Weighted Imaging in Detecting Superparamagnetic Iron Oxide-Labeled Mesenchymal Stem Cells: A Comparative Study

“…The dark regions occurred because of migration of SPIO-hMSCs through ICA into the surrounding infarction, i.e. engraftment ( 15 ). Engraftment was confirmed by Prussian blue staining in all six rats ( Figure 4 B ).…”

“…At 24 h after ICA infusion in six rats with photothrombotic cerebral infarction, engrafted SPIO-hMSCs were detected around the cerebral infarction (6/6, 100%) on MRI ( Figure 4 ). ICA infusion is very effective in delivering stem cells to the lesion, particularly in the early phase after infusion ( 15 , 19 , 20 ). T 2 WI did not detect SPIO-hMSCs observed as dark regions in other sequences.…”

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

“…and i.v. administration in animal models of ischemic stroke with different degrees of success in terms of outcome373839 and brain engraftment23404142, but only a few have established a relationship between them434445. In this study, we administered MSCs labeled with D-MNPs to address the relationship between cell allocation and animal recovery after stroke.…”