In vivo stem cell tracking using scintigraphy in a canine model of DMD

Abstract

One of the main challenges in cell therapy for muscle diseases is to efficiently target the muscle. To address this issue and achieve better understanding of in vivo cell fate, we evaluated the relevance of a non-invasive cell tracking method in the Golden Retriever Muscular Dystrophy (GRMD) model, a wellrecognised model of Duchenne Muscular Dystrophy (DMD). Mesoangioblasts were directly labelled with 111 In-oxine, and injected through one of the femoral arteries. The scintigraphy images obtained provided the first quantitative mapping of the immediate biodistribution of mesoangioblasts in a large animal model of DMD. The results revealed that cells were trapped by the first capillary filters: the injected limb and the lung. During the days following injection, radioactivity was redistributed to the liver. In vitro studies, performed with the same cells prepared for injecting the animal, revealed prominent cell death and 111 In release. In vivo, cell death resulted in 111 In release into the vasculature that was taken up by the liver, resulting in a non-specific and non-cell-bound radioactive signal. Indirect labelling methods would be an attractive alternative to track cells on the mid-and long-term. Cell therapy intending to regenerate diseased tissue with healthy stem cells is envisioned for diverse pathological conditions. Several different tissues are currently being targeted in clinical trials using a wide range of cell types. This diversity of situations is, at least in part, responsible for the mixed success of stem cells trials. Some of these trials have yielded very encouraging results with obvious cell engraftment and contribution to the tissue regeneration 1,2 , others have shown functional improvement through paracrine effects rather than through stem cells engraftment 3,4 , and finally some other trials have shown disappointing results 5,6. In every case, and particularly when the cells are injected systemically, the question of biodistribution and survival of cells is crucial, not only for safety reasons but also to better understand cell behaviour and to optimise tissue targeting. To this purpose, cell tracking methods have been developed, relying on diverse in vivo imaging techniques 7,8. The most obvious way to visualise cells in vivo using non-invasive methods is to label cells directly before transplantation. This can be achieved using radionuclides, pharmacologically designed to be taken up by cells; examples of these radionuclides include 99 mTc-HMPAO, 111 In-oxine and 124 I-HIB for SPECT imaging, 64 Cu-PTSM and 18 F-FDG or FHB for PET imaging 9-13. Alternatively, direct labelling with SPIO, Gd-DTPA or 19 F allows for cell tracking using MRI/MRS 14-16. The main advantage of these direct labelling methods is that they are easy to perform and that they provide information on cell biodistribution shortly after transplantation 7,8,14. The disadvantages include the potential cytotoxicity of some labelling agents, as well as the limited period of cell tracking conditioned by the radioactive decay ...

Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review

“…Therefore, renal intraarterial MSC infusion limits off-target engraftment, leading to efficient MSC delivery to the kidneys. Similar results were found after selective intraarterial infusion into the superior mesenteric artery regarding the intestine distribution of MSCs [58], and the selective intraarterial limb infusion [59,60], with MSCs distributed in the target area and a small quantity of MSCs in the rest of the organs.…”

“…The use of radionuclides is a common technique which is useful to assess the distribution of previously marked cells in preclinical models. Some of the most common radionuclides include 99m Technetium-hexamethylpropyleneamine oxime ( 9m Tc-HMPAO) [21,83], or 111 Indium-Oxine ( 111 In-Oxine) [60,115]. After culture, these substances enter into the cells.…”

Higher Loading of Gold Nanoparticles in PAD Mesenchymal-like Stromal Cells Leads to a Decreased Exocytosis

“…As methods for tracking cells in the human body are very limited, imaging and contrast agents like nanoparticles have been developed to increase the visibility of the cells in vivo [ 2 , 3 , 4 ]. To date, cell tracking is often performed using either radionuclides for scintigraphy, PET (positron emission tomography), and SPECT (single photon emission computer tomography), or using superparamagnetic iron oxide nanoparticles for MRI (magnetic resonance imaging) [ 5 , 6 , 7 ]. Radionuclide imaging has the main advantage of high sensitivity and very small amounts of label can be detected.…”

MRI Tracking of Iron Oxide Labelled Canine Mesenchymal Stem Cells in Artificial Stifle Defects

“…Different methods have been used in the past including radiopharmaceutical labelling and labelling with iron oxide particles. [14][15][16] Labelling should be easy, efficient and nontoxic for the cells and the patient. 14,16 The objective of the present prospective ex vivo study was to evaluate ultrasmall superparamagnetic iron oxides (USPIO) (Endorem, Guerbet, Roissy, France) labelling of canine mesenchymal stem cells in combination with magnetic resonance imaging (MRI) to detect canine mesenchymal stem cells in a complex anatomical structure such as the canine stifle combined with small cartilage defects.…”

“…Different methods have been used in the past including radiopharmaceutical labelling and labelling with iron oxide particles. 14 15 16 Labelling should be easy, efficient and non-toxic for the cells and the patient. 14 16…”