Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein

• UC-MSC-derived conditioned medium (CM) significantly reduces lung injury, edema, and fibrosis in a mouse model of SARS-CoV-2 spike protein-induced acute lung injury. • CM restores thrombomodulin levels and reduces von Willebrand factor expression, mitigating vascular dysfunction and thrombo-inflammation. • The protective effects are mediated by preservation of endothelial glycocalyx, leading to reduced complement C3 accumulation and NF-κB signaling. • These findings support the therapeutic potential of UC-MSC secretome for COVID-19-associated lung microvascular complications.