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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.

Byun JS, Kwak BK, Kim JK, Jung J, Ha BC, Park S - J Korean Neurosurg Soc (2013)

Bottom Line: 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.In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Chung-Ang University College of Medicine, Seoul, Korea.

ABSTRACT

Objective: This 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.

Methods: Male 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.

Results: Grafted 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.

Conclusion: In 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.

No MeSH data available.


Related in: MedlinePlus

Aggregated MSCs at arterial lumen in IA rat model on combined Anti-mitochondrial antibody-Prussian blue staining. Note aggregated cells (arrows) which are positive on Anti-mitochondrial antibody (brown color) and Prussian blue staining (blue color).
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Figure 8: Aggregated MSCs at arterial lumen in IA rat model on combined Anti-mitochondrial antibody-Prussian blue staining. Note aggregated cells (arrows) which are positive on Anti-mitochondrial antibody (brown color) and Prussian blue staining (blue color).

Mentions: Functional recovery may be achieved through various routes of MSC administration, including intracerebral, IA, and IV13,15,18,26,34,55,59). Intracerebral and intravascular administration provide the best chance to engraft MSCs to the brain. Intravascular delivery is less invasive than intracerebral stereotactic delivery. In the field of experimental endovascular transplantation, IV infusion has been tested more extensively than IA administration. However, recent studies have demonstrated an unfavorable distribution of cells after IV infusion38,42,48). One study using bioluminescence imaging (BLI) of neural stem cells after middle cerebral artery occlusion (MCAO) showed a BLI signal from the brain that was 12 times higher in IA-injected than in IV-injected animals. After IA injection, 69% of the total luciferase activity emerged from the brain early after transplantation and 93% at 1 week. After intravenous injection, 94% of the BLI signal was detected in the lungs followed by an overall signal loss of 94% at 1 week; thus the cells failed to survive outside the brain48). Another study using immunohistochemical analysis of engrafted MSCs transplanted after brain injury detected a significantly higher number of transplanted MSCs in the injured brain after IA as compared to IV administration at both 1 day and day 5 after transplantation42). Use of Prussian blue staining and MRI of labeled neural progenitor cells after MCAO showed significantly greater cell migration, wider distribution, and a larger number of transplanted neural progenitor cells in the target brain area following IA administration than by IV or intracisternal administration38). The majority of administered MSCs are initially trapped in the pulmonary capillaries and removed from circulation in the first passage effect22,47). The first passage effect in lung differs significantly between IA and IV administration. Cells administered by IA generate higher local concentrations, have shorter blood stream exposure, and suffer less mechanical stress before reaching the target site42). In agreement with the previous studies, we found significantly more stem cells residing in the brain after IA administration than with the IV route and higher total entrapment of cells in the lung after IV as compared to IA administration. However, more animals were assigned to the IA group than to the IV group, because carotid artery injection resulted in high mortality, possibly through distal embolization of intraluminal plaques38,59). Several rat treated by IA in the present study showed MSC aggregates in the arterial lumen on combined staining with anti-mitochondrial antibody and Prussian blue (Fig. 8). These findings suggested that intracarotid infusion may cause further ischemia or thrombosis in humans. In this respect, the intravenous infusion of MSCs may prove to be the safer and more feasible route for stem cell therapy in stroke patients6,31,36).


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.

Byun JS, Kwak BK, Kim JK, Jung J, Ha BC, Park S - J Korean Neurosurg Soc (2013)

Aggregated MSCs at arterial lumen in IA rat model on combined Anti-mitochondrial antibody-Prussian blue staining. Note aggregated cells (arrows) which are positive on Anti-mitochondrial antibody (brown color) and Prussian blue staining (blue color).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921273&req=5

Figure 8: Aggregated MSCs at arterial lumen in IA rat model on combined Anti-mitochondrial antibody-Prussian blue staining. Note aggregated cells (arrows) which are positive on Anti-mitochondrial antibody (brown color) and Prussian blue staining (blue color).
Mentions: Functional recovery may be achieved through various routes of MSC administration, including intracerebral, IA, and IV13,15,18,26,34,55,59). Intracerebral and intravascular administration provide the best chance to engraft MSCs to the brain. Intravascular delivery is less invasive than intracerebral stereotactic delivery. In the field of experimental endovascular transplantation, IV infusion has been tested more extensively than IA administration. However, recent studies have demonstrated an unfavorable distribution of cells after IV infusion38,42,48). One study using bioluminescence imaging (BLI) of neural stem cells after middle cerebral artery occlusion (MCAO) showed a BLI signal from the brain that was 12 times higher in IA-injected than in IV-injected animals. After IA injection, 69% of the total luciferase activity emerged from the brain early after transplantation and 93% at 1 week. After intravenous injection, 94% of the BLI signal was detected in the lungs followed by an overall signal loss of 94% at 1 week; thus the cells failed to survive outside the brain48). Another study using immunohistochemical analysis of engrafted MSCs transplanted after brain injury detected a significantly higher number of transplanted MSCs in the injured brain after IA as compared to IV administration at both 1 day and day 5 after transplantation42). Use of Prussian blue staining and MRI of labeled neural progenitor cells after MCAO showed significantly greater cell migration, wider distribution, and a larger number of transplanted neural progenitor cells in the target brain area following IA administration than by IV or intracisternal administration38). The majority of administered MSCs are initially trapped in the pulmonary capillaries and removed from circulation in the first passage effect22,47). The first passage effect in lung differs significantly between IA and IV administration. Cells administered by IA generate higher local concentrations, have shorter blood stream exposure, and suffer less mechanical stress before reaching the target site42). In agreement with the previous studies, we found significantly more stem cells residing in the brain after IA administration than with the IV route and higher total entrapment of cells in the lung after IV as compared to IA administration. However, more animals were assigned to the IA group than to the IV group, because carotid artery injection resulted in high mortality, possibly through distal embolization of intraluminal plaques38,59). Several rat treated by IA in the present study showed MSC aggregates in the arterial lumen on combined staining with anti-mitochondrial antibody and Prussian blue (Fig. 8). These findings suggested that intracarotid infusion may cause further ischemia or thrombosis in humans. In this respect, the intravenous infusion of MSCs may prove to be the safer and more feasible route for stem cell therapy in stroke patients6,31,36).

Bottom Line: 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.In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Chung-Ang University College of Medicine, Seoul, Korea.

ABSTRACT

Objective: This 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.

Methods: Male 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.

Results: Grafted 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.

Conclusion: In 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.

No MeSH data available.


Related in: MedlinePlus