Background: Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)-expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli-induced lung injury and enhance resolution after ventilator-induced lung injury.Methods: In vitro studies determined whether CD362(+) human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362(+) human mesenchymal stromal cells attenuated Escherichia coli-induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group).Results: CD362(+) human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362(+) human mesenchymal stromal cells attenuated Escherichia coli-induced injury in rodents, improving arterial oxygenation (mean SD, 83 +/- 9 vs. 60 +/- 8 mmHg, P < 0.05), improving lung compliance (mean +/- SD: 0.66 +/- 0.08 vs. 0.53 +/- 0.09 ml.cm H2O-1, P < 0.05), reducing bacterial load (median [interquartile range], 1,895 [100-3,300] vs. 8,195 [4,260-8,690] colony-forming units, P < 0.05), and decreasing structural injury compared with vehicle. CD362(+) human mesenchymal stromal cells were more effective than CD362(-) human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362(+) human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean +/- SD: 113 +/- 11 vs. 89 +/- 11 mmHg, P < 0.05) and lung static compliance (mean +/- SD: 0.74 +/- 0.07 vs. 0.45 +/- 0.07 ml.cm H2O-1, P < 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362(+) human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells.Conclusions: A CD362(+) human mesenchymal stromal cell population decreased Escherichia coli-induced pneumonia severity and enhanced recovery after ventilator-induced lung injury.