In vivo tracking of ¹¹¹In-labeled bone marrow mesenchymal stem cells in acute brain trauma model

Abstract

Introduction

This study was to evaluate the in vivo distribution of intravenously transplanted bone marrow-derived mesenchymal stem cells (BMSCs) in an acute brain trauma model by ¹¹¹In-tropolone labeling.

Methods

Rat BMSCs were labeled with 37 MBq ¹¹¹In-tropolone. Their labeling efficiency and in vitro retention rate were measured. The viability and proliferation of labeled BMSCs were evaluated for 14 days after labeling. The biodistribution of ¹¹¹In-labeled BMSCs in trauma models was compared with those of sham-operated rats and normal rats on gamma camera images. The migration of ¹¹¹In-BMSCs to the traumatic brain was evaluated using confocal microscope.

Results

The labeling efficiency of ¹¹¹In-BMSCs was 66±5%, and their retention rate was 85.3% at 1 h after labeling. There was no difference in the number of viable cells between ¹¹¹In-BMSCs and controls at 48 h after labeling. However, the proliferation of ¹¹¹In-BMSCs was inhibited after the third day of labeling, and it did not reach confluency. On gamma camera images, most of the ¹¹¹In-BMSCs uptake was observed in the liver and spleen at the second day of injection. The brain uptake of ¹¹¹In-BMSCs was detected prominently in trauma models (1.4%) than in sham-operated (0.5%) or normal rats (0.3%). Radiolabeled BMSCs were observed at the traumatic brain on the confocal microscope as they have a homing capacity, although its proliferation capacity was suppressed.

Conclusion

Although growth inhibition by ¹¹¹In-labeling need to be evaluated further prior to use in humans, ¹¹¹In-labeled BMSCs are useful for the tracking of intravenously transplanted mesenchymal stem cells in brain disease models.

Introduction

Recent studies have demonstrated that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) reduced the size of infarction and increased functional recovery in animal models of brain disease [1], [2]. Moreover, it was reported that intravascularly injected, ex vivo-cultured, autologous BMSCs induce functional recovery in patients with stroke [3] and multiple system atrophy (MSA) [4]. Bone marrow-derived mesenchymal stem cells are multipotent and capable of differentiating into mesodermal lineages, such as bone, fat, cartilage and muscle and even into ectodermal lineages, including neurons and astrocytes, both in vitro and in vivo [5], [6], [7], [8], [9]. Bone marrow-derived mesenchymal stem cells can also differentiate into tumor cells [10], [11], [12], and thus, their migration and proliferation should be monitored carefully after transplantation.

Of the various techniques associated with in vivo cell tracking, nuclear medicine imaging is the most clinically friendly method. Nuclear medicine imaging has been widely used to label various types of blood cells, such as leukocytes, platelets and neutrophils [13], [14], [15]. Moreover, it can provide the quantitative measurement of transplanted cells in each organ as a percentage of the injected dose of a radioisotope [16], [17], [18]. Indium-111 (¹¹¹In) oxine/tropolone is a well-known cell-labeling agent that has been used to localize infections in the form of labeled leukocytes since the 1970s [13]. Moreover, ¹¹¹In was recently used to evaluate the migration and transplantation of therapeutic endothelial progenitor cells and mesenchymal stem cells following myocardial infarction [18], [19], [20], [21]. However, ¹¹¹In has not been used to track grafted mesenchymal stem cells in animal models of brain disease.

We, therefore, investigated whether gamma camera images of ¹¹¹In-BMSCs could be used to monitor intravenously injected rat BMSCs in an animal model of brain trauma and to evaluate their in vitro stability, viability and proliferation capacity. We also performed a histological evaluation using confocal microscope to confirm the results of gamma camera images.