We have previously demonstrated that mesenchymal stromal/stem cells (MSCs) in spheroids (MSCsubsp/sub) tolerate ambient and hypoxic conditions for a prolonged time. Local administration of MSCsubsp/sub, but not dissociated MSCs (MSCsubdiss/sub), promotes wound healing and relieves multiple sclerosis and osteoarthritis in mice and monkeys. These findings indicate an advantage of MSCsubsp/subover MSCsubdiss/subin sustaining cell viability and efficacy following transplantation, which, however, does not appear to apply to intravenous (i.v.) injection for the principal concern that MSCsubsp/submight cause embolism in small blood vessels of the host, leading to sudden death. Here, we addressed this concern by injecting human MSCsubsp/sub(∼450 μm) or MSCsubdiss/subi.v. into cynomolgus monkeys. Surprisingly, no deaths occurred until sacrifice at day 21 or 60 post injection, and no remarkable physiological changes were found in the animals following the i.v. injection. The big diameters of large blood vessels in monkeys, compared to small animals like mice, may allow sufficient time for MSCsubsp/subto dissociate into single cells so they can pass through small vessels without causing embolism. Retention of MSCsubsp/subwas lower in the lungs but higher in the blood than retention of MSCsubdiss/subat 1 h post injection and both disappeared at day 21. In vitro, MSCsubsp/subtolerated fluidic shear stress with higher survival than MSCsubdiss/sub. Thus, i.v. injection of MSCsubsp/subinto nonhuman primates is feasible, safe, and probably associated with better survival, less lung entrapment and higher efficacy than administration of MSCsubdiss/sub.
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