Apoptotic cells are cells that have reached the end of their life cycle. They would normally be cleared by other cells the body that recognize an “eat me” signal to suppress them. However, patients with lupus have difficulty clearing those apoptotic cells – while already dead, the cells continue releasing secretions that can offset the balance of the immune system, leading to eventual necrosis (death of tissue). In this 2019 study, researchers found that mesenchymal stem cells derived from umbilical cord (UC-MSCs) were able to “eat” apoptotic cells both in the lab and in 22 patients lupus patients. UC-MSCs were activated in the presence of apoptotic cells and secreted immunosuppressive factors (COX2 expression and PGE2 production to inhibit T cell response). This is the first time this mechanism was reported for lupus.
Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2.
Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown.
Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4+ T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively.
Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4+ T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation.
Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy.
PMID: 31248835 PMCID: PMC6642220 DOI: 10.1016/j.ebiom.2019.06.016