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Mesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in pre-clinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The ability of MSCs to modulate immune responses has been proposed as one of the mechanisms by which these cells provide therapeutic benefits, irrespective of whether they are sourced from bone marrow, adipose tissue or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the percentage, distribution and phenotype of neutrophils, monocytes and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 h, we observed a sharp increase in neutrophils, and pro-inflammatory monocytes and macrophages. Moreover, these immune cells localised in the vicinity of the MSCs suggesting an active role in their clearance. By 24 h, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 h later.
Mesenchymal stromal cells (MSCs) injected intravenously are trapped in the capillaries of the lungs and die within the first 24 h. Studying the biodistribution and fate of labelled therapeutic cells in the 3D pulmonary context is important to understand their function in this organ and gain insights into their mechanisms of action. Optical tissue clearing enables volumetric cell tracking at single-cell resolution. Thus, we compared three optical tissue-clearing protocols (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC), modified stabilised 3D imaging of solvent-cleared organs (s-DISCO) and ethyl cinnamate (ECi)) to evaluate their potential to track the biodistribution of human umbilical cord MSCs expressing the tdTomato fluorescence reporter and investigate how they interact with host cells in the mouse lung. The results showed that although CUBIC clearing is the only method that enables direct imaging of fluorescently labelled MSCs, combining s-DISCO or ECi with immunofluorescence or dye labelling allows the interaction of MSCs with endothelial and immune cells to be studied. Overall, this comparative study offers guidance on selecting an optical tissue-clearing method for cell tracking applications.
Tracking the fate of therapeutic cell types is important for assessing their safety and efficacy. Bioluminescence imaging (BLI) is an effective cell tracking technique, but poor spatial resolution means it has limited ability to precisely map cells in vivo in 3D. This can be overcome by using a bimodal imaging approach that combines BLI with a technique capable of generating high‐resolution images. Here we compared the effectiveness of combining either multispectral optoacoustic tomography (MSOT) or micro‐computed tomography (micro‐CT) with BLI for tracking the fate of luciferase+ human mesenchymal stromal cells (MSCs) labelled with gold nanorods. Following subcutaneous administration in mice, the MSCs could be readily detected with MSOT but not with micro‐CT. We conclude that MSOT is more sensitive than micro‐CT for tracking gold nanorod‐labelled cells in vivo and depending on the route of administration, can be used effectively with BLI to track MSC fate in mice.
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