Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?

Abstract

Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0–3.0 × 106 cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells.

Local Inhibition of Complement Improves Mesenchymal Stem Cell Viability and Function After Administration

“…In both animal and human studies, it is widely known that, after administration, MSCs mysteriously disappear within a short period of time, suggesting that these cells are recognized and attacked by the host. Contrary to the long-held belief that MSCs are immunoprivileged and can escape host immune surveillance, clinical studies have shown increased levels of the complement activation product C3a in patients' blood immediately after MSC infusion, 22,23 indicating complement activation. We have reported that MSCs propagated in vitro activate complement through all three complement-activating pathways and are attacked by MACs, resulting in cell damage and impaired function.…”

Stromal cells–are they really useful for GVHD?

“…100 Stromal cells may also be used for chronic GVHD, but they should probably be used before fibrosis occurs. 101 Stromal cells have a profound effect on coagulation, 18,20 which partly explains their effectiveness in stopping major hemorrhages. 90,102,103 BM must be accessed by aspiration, and this source of MSCs has been challenged by MSCs from adipose tissue, umbilical-cordderived MSCs and stromal cells from the placenta-such as DSCs.…”

“…Although no acute toxicity has been reported, the coagulation system is activated 18,20 and there is a concern regarding pulmonary embolism. 104 Patients treated with stromal cells need to be followed closely for the possible risk of tumor formation.…”

“…19 BM-MSCs also elicit the formation of clotting factors when in contact with blood. 20 The immunosuppressive capacity of MSCs may not only be a positive feature when treating patients who are already highly susceptible to infections. Co-infusion of BM-MSCs with cord blood transplantation delays immune reconstitution, as shown by lower levels of T-cell receptor excision circles and serum IgG and IgM.…”

Mesenchymal Stem Cells: How Can we Realize their Therapeutic Potential in Cancer Therapy?

“…MSCs are reported to express pro-coagulant molecules such as Tissue Factor and Collagen I in vesicles close to the cell surface, and this expression increases with passage number [73]. However, so far, thrombotic events following MSC therapy have not been reported in humans.…”