Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection worldwide, with most of the population over the age of ten having been infected. Despite its high revalence, pathogenesis is still not entirely elucidated. Many cell types are susceptible to HMPV infection, including stem cells. Our previous results suggested the susceptibility and permissiveness of mesenchymal stem cells (MSC) to HMPV. We focused specifically on the expression and localization of the cytoskeleton proteins and their role during syncytium formation, implicating either the actin or the microtubule network, however, we only observed changes in the distribution of actin without modifications of tubulin. We also studied the annexin V, this biomarker is a molecule associated with cytoskeleton proteins. Annexin V was increased by HMPV infection as a result of the membrane modification via viral entry caused by fusion and/or viral exit by gemmation/budding. The plasticity of MSC was studied using a differentiation protocol and soluble mediators, specifically growth factors Angiopoietin-2 (Ang-2), EGF, EPO, FGF-basic, G-CSF, GM-CSF, HGF, M-CSF, PDGF-AA, PDGF-BB, SCF, TGF-α, and VEGF) which were determined by flow cytometry. Finally, we demonstrate that the HMPV infection induces a significant decrease in EGF and VEGF secretion compared to the mock-infected cultures; in contrast, Ang-2 and PDGF-AA were significantly elevated in infected MSC compared to the mock-infected cells. These data suggest that this increment might be associated with migration and proliferation of both resident and migratory MSC, to resolve the lung injury caused by a severe HMPV infection.