Induced Pluripotent Stem Cell-Derived Conditioned Medium Promotes Endogenous Leukemia Inhibitory Factor to Attenuate Endotoxin-Induced Acute Lung Injury.

Wen-Kuang Yu,Hao Chen,Shih-Hwa Chiou,Huai-Hsuan Wu,Wei-Chih Chen,Kuang-Yao Yang,Vincent Yi-Fong Su

doi:10.3390/ijms22115554

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 intratracheal 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 attenuated 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 antibody 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.

Highlights

Introduction distributed under the terms andSepsis is characterized by an excessive inflammatory response to infectious pathogens.Acute lung injury (ALI) is a common respiratory complication of severe sepsis that is characterized by acute and severe hypoxia
Intratracheal injection of the endotoxin resulted in extensive ALI, as evidenced histopathologically by lung edema, alveolar spaces filled with mononuclear/neutrophilic infiltrates, and the thickening of the alveolar walls and interstitium
bronchoalveolar lavage fluid (BALF) analyses revealed a marked accumulation of polymorphonuclear neutrophils (PMNs) in the lungs of LPS-induced ALI mice, whereas Murine Induced pluripotent stem cells (iPSCs) (miPSCs) or miPSC-CM-treated mice had significantly reduced numbers of PMN (Figure 1b)

Summary

Introduction

Acute lung injury (ALI) is a common respiratory complication of severe sepsis that is characterized by acute and severe hypoxia. ALI/ARDS is characterized by the diffuse infiltration of neutrophils to the alveolar space, loss of alveolar–capillary membrane integrity, and increased permeability of pulmonary capillary endothelial cells [1]. Accumulating studies have shown that stem cell therapy is becoming one of the emerging treatment strategies for ALI/ARDS. Research about stem cell-based therapies for ALI have been published; our previous study showed that mesenchymal stem cells (MSCs) attenuate endotoxin-induced ALI by inducing neutrophil apoptosis, which is associated with inhibition of the NF-κB pathway [2]. We investigated the regulatory mediators enhanced by iPSC-CM to attenuate endotoxin-induced ALI

Methods

Results

Conclusion