Therapeutic potential of mesenchymal stem cells for severe acute lung injury

Abstract

Preclinical studies indicate that allogeneic human mesenchymal stem cells (MSC) may be useful for the treatment of several clinical disorders, including sepsis, acute renal failure, acute myocardial infarction, and more recently, acute lung injury (ALI). This article provides a brief review of the biologic qualities of MSC that make them suitable for the treatment of human diseases, as well as the experimental data that provide support for their potential efficacy for critically ill patients with acute respiratory failure from ALI. The article then discusses which patients with ALI might be the best candidates for cell-based therapy and provides a template for the regulatory and practical steps that will be required to test allogeneic human MSC in patients with severe ALI. There is a dual focus on how to design trials for testing both safety and efficacy.

Figure 1.

Therapeutic potential of mesenchymal stem cells and their paracrine factors in acute lung injury. This figure shows an injured alveolus with protein-rich edema fluid with an influx of inflammatory cells secondary to both endothelial and epithelial injury. As shown in the diagram, mesenchymal stem cells can be delivered via the air spaces or via the circulation. Some of the potential repair pathways are illustrated as the mesenchymal stem cells interact with injured resident alveolar epithelial or lung endothelial cells or immunomodulate the responses of monocytes, PMN, activated macrophages, and lymphocytes, with the release of several secreted products, including Ang-1, PGE₂, IL-1ra, TGF-β, and KGF. Several other paracrine factors may be important in reducing lung injury and enhancing repair. Ang-1 = angiotensin-1; IL-1ra = interleukin-1 receptor antagonist; KGF = keratinocyte growth factor; PGE₂ = prostaglandin E₂; PMN = polymorphonuclear leukocytes; TGF-β = transforming growth factor-β.

Figure 2.

Intratracheal treatment with mouse MSC improved survival at 48 h in an endotoxin model of acute lung injury in mice. MSC or PBS was administered intratracheally (IT) 4 h after IT instillation of endotoxin (5 mg/kg). Forty-eight hour survival was 80% in MSC group vs 42% in PBS group (n = 30 for MSC group, n = 31 for PBS group, **P < .01 using a log-rank test). MSC = mesenchymal stem cells; PBS = phosphate-buffered saline. (Reprinted with permission from Gupta et al.)

Figure 3.

Allogeneic human MSC or its conditioned medium restored lung endothelial permeability to protein and wet/dry ratio to normal levels in the ex vivo perfused human lung following injury with Escherichia coli endotoxin. Instillation of MSC or its CM into the E coli endotoxin-injured (0.1 mg/kg) right middle lobe 1 h following injury restored (A) lung endothelial permeability to protein and (B) wet/dry ratio to control values. Data are expressed as mean % endothelial permeability or wet/dry ratio ± SD, n = 4 to 5 lungs, *P < .0001 vs control lobe, ^†P < .0011 vs LPS–injured (0.1 mg/kg) lobe for lung endothelial permeability, and *P < .0014 vs control lobe, ^†P < .005 vs LPS–injured (0.1 mg/kg) lobe for the wet/dry ratio by analysis of variance (ANOVA) (Bonferroni). CM = conditioned medium; LPS = lipopolysaccharide. See Figure 2 legend for expansion of other abbreviation. (Reprinted from Lee et al.)

Figure 4.

(A) Allogeneic human MSC or its CM restored alveolar fluid clearance to a normal level in the ex vivo perfused human lung injured with Escherichia coli endotoxin. MSC or its CM restored the decrease in alveolar fluid clearance in the lung lobe injured by E coli endotoxin (0.1 mg/kg) to control values at 4 h. N = 3 to 4, *P < .0006 vs control AFC; ^†P < .0001 vs LPS (0.1 mg/kg) AFC by ANOVA (Bonferroni). (B) Beneficial effect of the CM of human MSC on alveolar fluid clearance was mediated in part by KGF. Administration of the CM of MSC grown for 24 h pretreated with the KGF siRNA (Ambion) into the E coli endotoxin-injured lung lobe after 1 h prevented the restoration of AFC with the CM alone. The addition of recombinant KGF (100 ng) to the CM pretreated with KGF siRNA restored the decrease in AFC to control values. Data are expressed as mean AFC ± SD, N =4 to 5 lungs, *P < .0012 vs control lobe by ANOVA (Bonferroni). AFC = alveolar fluid clearance. See Figures 1-3 legends for expansion of other abbreviations. (Reprinted from Lee et al.)