Real time PCR analysis of MSCs co-cultured with sepsis whole blood.

ABSTRACT: Mesenchymal stem/stromal cells (MSCs) are actively being explored as a potential therapy for disorders with immune dysregulation, including sepsis. However, little is known about the crosstalk and specific molecular mechanisms underlying the acute inflammatory environment and MSC-mediated immunomodulation of myeloid cells. We utilized ex vivo human and in vivo animal models to perform deep immune phenotyping, investigating the effects of MSCs on neutrophil and monocyte populations during acute inflammation. This was complemented by temporal analysis of neutrophil markers in septic shock patients who received ascending doses of MSC therapy. Our results demonstrated that MSCs positively altered the myeloid cell, promoting anti-inflammatory phenotypes and correcting dysfunctions of myeloid cells. Using MSCs retrieved after exposure to sepsis patient whole blood, transcriptomic and cytokine analyses revealed activation of caspase-1/interleukin-1 converting enzyme pathway as an essential molecular switch mediating immunomodulatory effects of MSCs on dysfunctional neutrophils and monocytes. Notably, non-apoptotic, viable MSCs with caspase-1 activation enhanced the outcome of MSCs to facilitate myeloid modulation, bacterial clearance ex vivo and increase sepsis mice survival in vivo. In contrast, caspase-1 knockdown abolished the ability of MSCs to modulate myeloid cells. Overall, our findings demonstrate an adaptive crosstalk between MSCs and the host immune environment in sepsis-like acute inflammation enhances the therapeutic activity of MSCs. Specifically, MSCs can facilitate pleiotropic modulation of multiple immune cell populations, accelerating immune resolution in sepsis. These novel insights can be leveraged to refine MSC-based therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306139 | GEO | 2025/08/31

REPOSITORIES: GEO