Background and Purpose
Intravascular injection of mesenchymal stem cells (MSCs) has been found to cause considerable vascular obstructions which may lead to serious outcomes, particularly after intra-arterial injection. However, the underlying mechanisms have been poorly understood.
In this study, we fractionated MSCs that had been cultured in monolayer for six passages into small (average diameter = 17.9 μm) and large (average diameter 30.4 μm) populations according to their sizes, and examined their vascular obstructions after intra-internal carotid artery injection in rats and mice in comparison with MSCs derived from 3D spheroids which were uniformly smaller in size (average diameter 12.6 μm).
We found that 3D MSCs did not cause detectable infarct in the brain as evidenced by MRI scan and TTC stain, 2D MSCs in small size caused a microinfarct in one of five animals, which was co-localized to the area of entrapped MSCs (labeled with DiI), while 2D MSCs in large size caused much larger infarcts in all five animals, and substantial amounts of DiI-positive MSCs were found in the infarct. Meanwhile, corresponding neurological defects were observed in the animals with stroke. In consistence, injection of 2D MSCs (average diameter 26.5) caused a marked loss of cortical neurons and their axons in Thy1-GFP transgenic mice and the activation of microglia in CX3CR1-GFP transgenic mice in the area with MSC entrapment.
Our results suggest that the size of MSCs is a significant cause of MSC caused vascular obstructions and stroke.
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This work was supported by grants from Natural Science Foundation of China (No. 30871273, 31371404, U1032003) and Shenzhen Science and Technology Innovation Committee (JC201005280597A, GJHZ20120614194251967 and JCYJ20130402145002397) to Y Wu.
Conflict of interest
The authors have declared that no conflict of interest exists.
Jianfeng Ge and Ling Guo contributed equally to this work
Electronic supplementary material
Trafficking of MSCs. Prior to the injection of MSCs, FITC-Dextran was injected into the tail vein of wild type Balb/C mice to illuminate the vasculature. DiI-labeled MSCs were injected into the carotid artery. The trafficking of DiI-MSCs was recorded by a video camera under fluorescence microscope. MSCs derived from 3D spheroids moved fast and smoothly in the blood vessels, while MSCs derived from monolayers moved much slower and some stopped moving in the blood vessels. (MP4 4095 kb)
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Ge, J., Guo, L., Wang, S. et al. The Size of Mesenchymal Stem Cells is a Significant Cause of Vascular Obstructions and Stroke. Stem Cell Rev and Rep 10, 295–303 (2014). https://doi.org/10.1007/s12015-013-9492-x
- Mesenchymal stem cells
- Vascular obstruction
- Cell size