Journal Article

Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria

Krasnodembskaya, Anna, Song, Yuanlin, McKenna, David H., Matthay, Michael A., Abbott, Jason, Lee, Jae W.

2013

Overview

Abstract Rationale Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells’ immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury. Objectives Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance. Methods We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury. Measurements and Main Results Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria. Conclusions In E. coli–injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Acute Lung Injury - etiology / Acute Lung Injury - microbiology / Analysis of Variance / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Antimicrobial agents / Applied cell therapy and gene therapy / Bacteria / Bacterial diseases / Bacterial diseases of the respiratory system / Bacterial infections / Biological and medical sciences / Cells, Cultured / Clinical trials / Cytokines / E coli / Escherichia coli Infections - complications / Fibroblast Growth Factor 7 - secretion / Growth factors / Human bacterial diseases / Humans / Infectious diseases / Inflammation / Inflammation - therapy / Intensive care medicine / Lungs / Macrophages, Alveolar - microbiology / Medical sciences / Mesenchymal Stem Cell Transplantation - methods / Mesenchymal Stromal Cells - secretion / Phagocytosis - physiology / Pneumonia / Pneumonia, Bacterial - complications / Pulmonary Alveoli - metabolism / Pulmonary arteries / Receptor, Fibroblast Growth Factor, Type 2 - metabolism / Respiratory distress syndrome / Sepsis / Stem cells / Transfusions. Complications. Transfusion reactions. Cell and gene therapy / Transplants & implants