Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study

Abstract

Background: Recent studies have demonstrated that mesenchymal stem cells (MSCs) modulate the immune response and reduce lung injury in animal models. Currently, no clinical studies of the effects of MSCs in acute respiratory distress syndrome (ARDS) exist. The objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived MSCs in ARDS patients and second to determine potential efficacy of MSCs on ARDS.

Methods: Twelve adult patients meeting the Berlin definition of acute respiratory distress syndrome with a PaO2/FiO2 ratio of < 200 were randomized to receive allogeneic adipose-derived MSCs or placebo in a 1:1 fashion. Patients received one intravenous dose of 1 × 106 cells/kg of body weight or saline. Possible side effects were monitored after treatment. Acute lung injury biomarkers, including IL-6, IL-8 and surfactant protein D (SP-D), were examined to determine the effects of MSCs on lung injury and inflammation.

Results: There were no infusion toxicities or serious adverse events related to MSCs administration and there were no significant differences in the overall number of adverse events between the two groups. Length of hospital stay, ventilator-free days and ICU-free days at day 28 after treatment were similar. There were no changes in biomarkers examined in the placebo group. In the MSCs group, serum SP-D levels at day 5 were significantly lower than those at day 0 (p = 0.027) while the changes in IL-8 levels were not significant. The IL-6 levels at day 5 showed a trend towards lower levels as compared with day 0, but this trend was not statistically significant (p = 0.06).

Conclusions: Administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS. However, the clinical effect with the doses of MSCs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ARDS.

Trial registration: Clinical trials.gov, NCT01902082.

Figure 1

Differentiation potential of human adipose MSCs. A) Osteogenic differentiation: cells stained positive for ALP activity; and B) Adipogenic differentiation: cells stained positive for Oil Red O. Magnification, 100×.

Figure 2

Histology of kidneys, liver and lungs after MSCs treatment. Mice were administered intravenously with one dose of 2 × 10⁸ MSCs/kg of body weight or placebo. After 2 days, kidney, liver and lung samples were harvested for H&E staining.

Figure 3

Time course of PaO₂/FiO₂ ratio after MSCs or saline treatment. Values are depicted as mean ± SD. *indicates p < 0.05 when compared with the baseline values for that particular study group. No significant differences were found between the two study groups at any of the time points.

Figure 4

Paired serum ARDS biomarkers at day 0 and day 5 within MSCs and placebo groups. SP-D, IL-8 and IL-6 levels at day 0 and day 5 in the MSCs group (A, C, and E) and the placebo group (B, D and F) were determined by ELISA. Values are the measured concentrations for individual patients. p-values within each group between day 0 and day 5 were calculated using paired t-test.