Donor variability among anti-inflammatory pre-activated mesenchymal stromal cells

Area of Science:

• Immunology
• Cell Therapy
• Regenerative Medicine

Background:

• Mesenchymal stromal cells (MSCs) possess immunomodulatory properties via paracrine factors like prostaglandin E2 (PGE2).
• Clinical efficacy of MSCs is hindered by challenges in demonstrating consistent therapeutic effects and understanding donor variability.
• Pre-clinical data show promise, but translating this to clinical success requires optimizing MSC function.

Purpose of the Study:

• To develop methods for pre-inducing desired functions in naive MSCs.
• To investigate the impact of pre-activation on MSC immunomodulatory capabilities.
• To assess MSC donor variability in response to pre-activation and inflammatory stimuli.

Main Methods:

• MSCs from six human donors were pre-activated with optimal concentrations of interleukin-1 beta (IL-1β) or interferon gamma (IFN-γ).
• PGE2 secretion was measured after pre-activation and secondary exposure to pro-inflammatory molecules.
• Modulation of macrophage tumor necrosis factor alpha (TNF-α) secretion by co-cultured pre-activated MSCs was assessed.

Main Results:

• IL-1β pre-activation significantly upregulated PGE2 secretion and enhanced MSC-mediated attenuation of macrophage TNF-α secretion.
• Both IL-1β and IFN-γ pre-activation increased MSC sensitivity to secondary pro-inflammatory stimuli.
• IFN-γ pre-activation, however, led to enhanced TNF-α secretion from macrophages.
• Significant donor variability was observed in PGE2 secretion, upregulation, and macrophage modulation efficacy.

Conclusions:

• Pre-activation with IL-1β can enhance MSCs' therapeutic potential by upregulating PGE2 and improving macrophage regulation.
• IFN-γ pre-activation presents a different immunomodulatory profile, potentially enhancing pro-inflammatory responses.
• MSC donor variability is a critical factor influencing therapeutic outcomes and requires careful consideration for clinical applications.