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The Size of Mesenchymal Stem Cells is a Significant Cause of Vascular Obstructions and Stroke

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Abstract

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.

Methods

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).

Results

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.

Conclusions

Our results suggest that the size of MSCs is a significant cause of MSC caused vascular obstructions and stroke.

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. School of Life Sciences, Tsinghua University, Beijing, China

    Jianfeng Ge, Shan Wang & Ting Cai

  2. The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, China

    Jianfeng Ge, Ling Guo, Shan Wang, Ting Cai & Yaojiong Wu

  3. Department of Orthopedics, The General Hospital of Chinese People’s Liberation Army, Beijing, China

    Yiling Zhang

  4. Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Beijing, China

    Robert C. H. Zhao

  5. L406A, Tsinghua Campus, The University Town, Shenzhen, China

    Yaojiong Wu

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  1. Jianfeng Ge
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  2. Ling Guo
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  3. Shan Wang
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  4. Yiling Zhang
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Corresponding author

Correspondence to Yaojiong Wu.

Additional information

Jianfeng Ge and Ling Guo contributed equally to this work

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Supplementary video 1

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

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