Abstract
Background: Exosomes function as an intercellular communication system conveying messages from donor to target cells in nearby or distant tissues. Many aspects of exosome trafficking remain unresolved, however. Here, we investigated uptake of ten radiolabeled murine or human exosomes of various cellular origins by the liver, kidney, spleen, and lung of male CD-1 mice. Methods: We radioactively labeled 10 exosomes from mouse or human cancerous or non-cancerous lines, injected them intravenously into male CD-1 mice, and studied their tissue uptake. We examined the ability of wheatgerm agglutinin (WGA), mannose-6 phosphate (M6P), and inflammation induced by lipopolysaccharide (LPS) to modulate uptake. We measured uptake rate using multiple-time regression analysis and used heat mapping and path analysis to correlate tissue and exosomal influences on uptake. Results: Except for the uptake of SCCVII exosomes by kidney, all exosomes were taken up by all tissues, although the uptake levels varied broadly among exosomes and tissues. The liver/serum uptake ratio for exosomes from primary human T-cells was the highest at 4,500 mL/g. Species of origin (mouse vs human) or source (cancerous vs noncancerous cells) did not influence tissue uptake. The uptake of some exosomes was altered by WGA and LPS but not by M6P, except for uptake inhibition of J774A.1 exosomes by liver, suggesting use of the M6P receptor. WGA or LPS treatments enhanced uptake of exosomes by brain and lung but inhibited uptake by liver and spleen. Response to LPS was not, however, predictive of response to WGA. No evidence for a universal binding site controlling exosome uptake was obtained. Applying path analysis and heat map analysis to the data, including our published results for brain, we found that exosome uptake patterns for lung and brain responded similarly to WGA or to LPS, whereas those for liver and spleen clustered together. In path analysis, the 10 exosomes clustered into distinct groups, suggesting that their bindings sites are similarly clustered. Conclusions: Uptake of exosomes by peripheral tissues is differentially regulated by both exosomes and target tissues and is dependent on the number and types of mutually interactive binding sites.
Variability and trends of climate extremes indices from the observed and downscaled GCMs data over 1950–2020 period in Chattogram City, Bangladesh
