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Mesenchymal stromal/stem cells are multipotent adult cells that can be extracted from numerous tissues, including the lungs. Lung-resident MSCs (LR-MSCs) are localized to perivascular spaces where they act as important regulators of pulmonary homeostasis, mediating the balance between lung injury/damage and repair processes. LR-MSCs support the integrity of the lung tissue via modulation of the immune response and release of trophic factors. However, in the context of chronic lung diseases, the ability of LR-MSCs to maintain pulmonary homeostasis and facilitate repair is diminished. In this setting, LR-MSC can contribute to the pathogenesis of disease, through their altered secretory and immunomodulatory properties. In addition, they are capable of differentiating into myofibroblasts, thereby contributing to the fibrotic aspects of numerous lung diseases. For example, in idiopathic pulmonary fibrosis, a variety of factors can stimulate their differentiation into myofibroblasts including tumor necrosis factor-α (TNF-(α), transforming growth factor-β1 (TGF-β1), endoplasmic reticulum (ER) stress, Hedgehog (HH), and Wingless/integrated (Wnt) signaling. Here, we review the current literature on the characterization of LR-MSCs and describe their roles in pulmonary homeostasis/repair and in the pathogenesis of chronic lung disease.

Background: Colistin is a last-line agent for treating severe multidrug resistant Klebsiella pneumoniae ( Kp ) infections. Recent studies highlight the emergence of colistin resistant Kp arising from inducible inactivation of the mgrB gene, a negative PhoPQ signalling system regulator. Objectives: To determine the molecular mechanisms of colistin resistance and its impact upon Kp fitness and virulence. Methods: We constructed a mgrB deletion Kp mutant. Mass spectrometry (MS) was used to identify lipid-A modifications informing the generation of additional mutants in associated genes. Wild-type and mutant strains underwent MS, polymyxin and antimicrobial peptide (AMP) susceptibility, transcriptional, biofilm, growth curve and virulence ( Galleria and mouse) analyses. Results: The mgrB mutant showed a 128-fold decrease in colistin susceptibility in a PhoPQ dependant manner. We also observed enhanced resistance of the mutant to several human AMPs. Mutant lipid-A modifications included 2-hydroxymyristate, phosphoethanolamine, aminoarabinose and palmitate. Upregulation of the phoPQ , lpxO , pmrC , pmrH and pagP genes governing these modifications was confirmed. Growth fitness and biofilm forming capacity of the mutant and wild-type strains were similar. In contrast, the mutant exhibited hypervirulence in the virulence models. Complementation of the mgrB gene restored all phenotypes to wild-type levels. Conclusion: Our data highlight the importance of several novel lipid-A modifications linked with mgrB inactivation in Kp . We also show for the first time that mgrB inactivated Kp displays enhanced virulence. Overall, these data have important implications for patient management and antimicrobial stewardship.