Abstract
Mesenchymal stromal/stem cells (MSCs) are a fibroblast-like cell population with high regenerative potential that can be isolated from many different tissues. Several data suggest MSCs as a therapeutic tool capable of migrating to a site of injury and guide tissue regeneration mainly through their secretome. Pulmonary first-pass effect occurs during intravenous administration of MSCs, where 50 to 80% of the cells tend to localize in the lungs. This phenomenon has been exploited to study MSC potential therapeutic effects in several preclinical models of lung diseases. Data demonstrated that, regardless of the lung disease severity and the delivery route, MSCs were not able to survive longer than 24 h in the respiratory tract but still surprisingly determined a therapeutic effect. In this work, two different mouse bone marrow-derived mesenchymal stromal/stem cell (mBM-MSC) lines, stably transduced with a third-generation lentiviral vector expressing luciferase and green fluorescent protein reporter genes tracking MSCs in vivo biodistribution and persistency, have been generated. Cells within the engrafted lung were in vivo traced using the high-throughput bioluminescence imaging (BLI) technique, with no invasiveness on animal, minimizing biological variations and costs. In vivo BLI analysis allowed the detection and monitoring of the mBM-MSC clones up to 28 days after implantation independently from the delivery route. This longer persistency than previously observed (24 h) could have a strong impact in terms of pharmacokinetics and pharmacodynamics of MSCs as a therapeutic tool.
Highlights
At the beginning of their discovery, 1970s, mesenchymal stromal/stem cells (MSCs) were described as a bone marrow population of cells with fibroblastic and clonogenic properties; for these reasons, they were defined as “colony-forming unit fibroblasts” (Friedenstein et al, 1970, 1974, 1976)
Before attempting mouse Mesenchymal stromal/stem cells (MSCs) lung localization in vivo, two different clones (#2 and #11) of C57BL/6 mouse bone marrow-derived mesenchymal stromal/stem cells were stably transduced/transgenized with two different reporter genes to track their biodistribution in vivo
VSVg pseudotyped lentiviral vector particles were reconstituted in HEK293T cells and mouse bone marrow-derived mesenchymal stromal/stem cell (mBM-MSC) transduced with efficiency close to 100% of green fluorescent protein (GFP) expression, measured by flow cytometry analysis (Figure 1B)
Summary
At the beginning of their discovery, 1970s, mesenchymal stromal/stem cells (MSCs) were described as a bone marrow population of cells with fibroblastic and clonogenic properties; for these reasons, they were defined as “colony-forming unit fibroblasts” (Friedenstein et al, 1970, 1974, 1976). Mesenchymal stromal/stem cells have been shown to exert therapeutic potential through their secretome (comprehensive complex array of components ranging from soluble secreted factors to mBM-MSCs in the Lung factors encapsulated in extracellular vesicles with antiinflammatory as well as growth properties) and through the capability of migrating to the site of tissue injury, a characteristic that involves a contact-dependent mechanism of action (Harrell et al, 2019a,b). It has been observed in a sepsis model that heat-inactivated and secretome-deficient MSCs were still capable of inducing monocyte recognition, phagocytosis, and selective apoptosis. These strategies include optimizing culture conditions, MSC activation before administration, and, probably the most important, alteration of MSC biodistribution
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