Induced pluripotent stem cell‐derived conditioned medium promotes endogenous leukemia inhibitory factor to attenuate endotoxin‐induced acute lung injury

Abstract

The conditioned medium of induced pluripotent stem cells (iPSC‐CM) can attenuate neutrophil recruitment and endothelial leakage of lipopolysaccharide (LPS)‐induced acute lung injury (ALI). Therefore, we investigated the mechanisms by which iPSC‐CM regulate the interaction between neutrophils and the endothelium in ALI. Murine iPSCs (miPSCs) were delivered intravenously to male C57BL/6 mice (8–12 weeks old) 4 h after intratracheal LPS injection. A miPSC‐derived conditioned medium (miPSC‐CM) was delivered intravenously to mice after in-tratracheal LPS injection. DMSO‐induced HL‐60 cells (D‐HL‐60, neutrophil‐like cells) and human umbilical vein endothelial cells (HUVECs) were used as in vitro models to assess the interaction of neutrophils and endothelial cells. miPSC‐CM diminished the histopathological changes in the lungs and the neutrophil count in bronchoalveolar lavage fluids of ALI mice. miPSC‐CM attenu-ated the expression of adhesion molecules in the lungs of ALI mice. Human iPSC conditioned medium (hiPSC‐CM) reduced the expression of adhesion molecules in a HUVEC and D‐HL‐60 co‐culture after LPS stimulation, which decreased the transendothelial migration (TEM) of D‐HL‐60. A human angiogenesis factors protein array revealed that leukemia inhibitory factor (LIF) was not detected in the absence of D‐HL‐60 and hiPSC‐CM groups. hiPSC‐CM significantly promoted the production of endogenous LIF in in vitro models. Administration of an anti‐LIF anti-body not only reversed the effect of iPSC‐CM in ALI mice, but also blocked the effect of iPSC‐CM on neutrophils TEM in in vitro models. However, a controlled IgG had no such effect. Our study demonstrated that iPSC‐CM promoted endogenous LIF to inhibit neutrophils TEM and attenuate the severity of sepsis‐induced ALI.