Healthyversusinflamed lung environments differentially affect mesenchymal stromal cells

Abstract

BackgroundDespite increased interest in MSC-based cell therapies for the acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and understanding of the potential in vivo mechanisms of MSC actions in ARDS remain limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation, and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined.AimTo comparatively assess how the inflammatory environment present in ARDS lungs versus the lung environment present in healthy volunteers alters MSC behaviors.MethodsClinical grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties including viability, levels of expression of inflammatory cytokines, gene expression, cell surface HLA expression, and activation of coagulation and complement pathways.ResultsPro-inflammatory, pro-coagulant, and major histocompatibility complex (self recognition) related gene expression was markedly up-regulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. In contrast, these changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples.ConclusionThese data provide new insights into how hMSCs behave in healthy versus inflamed lung environments strongly suggesting that the inflamed environment in ARDS induces hMSC responses potentially benefical for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.

The Inflammatory Lung Microenvironment; a Key Mediator in MSC Licensing

“…In the context of BALF from ARDS patients, a range of pro and anti-inflammatory mediators are induced in human MSCs following exposure to ARDS BALF (taken from ARDS patients without sepsis). Of particular interest, IL-1β present in these ARDS BALF samples was predictive of the induction of IL-6, IL-8 and FAS by human BM-MSCs following ex-vivo exposure to the BALF [ 124 ]. MSCs exposed to ARDS patient BALF samples were less effective at driving an anti-inflammatory macrophage phenotype compared to MSCs exposed to BALF from other lung conditions (including acute exacerbations of CF) [ 121 ].…”

“…MSCs are usually detected for only a short time (72 h) in the lung or any other organ following systemic administration [ 29 , 140 , 144 ], however, their longevity can be enhanced in an injured lung or in licensed MSCs. Interestingly, exposure to healthy control BALF promotes human BM-MSC expression of HLA-DR, arguably increasing recognition and clearance of the MSCs [ 124 ]. This doesn’t occur with ARDS BALF exposure, suggesting that the ARDS inflammatory environment may be protective of MSC survival [ 124 ].…”

“…Interestingly, exposure to healthy control BALF promotes human BM-MSC expression of HLA-DR, arguably increasing recognition and clearance of the MSCs [ 124 ]. This doesn’t occur with ARDS BALF exposure, suggesting that the ARDS inflammatory environment may be protective of MSC survival [ 124 ]. We have also demonstrated that IFN-γ licensing of human BM-MSCs enhances their longevity in the short-term, in vivo, while pre-exposure to a PPARδ agonist significantly reduces MSC longevity in vivo in a humanised mouse model of aGvHD [ 49 ].…”

Mesenchymal stem/stromal cell-based therapies for severe viral pneumonia: therapeutic potential and challenges

“…MSCs respond to microenvironmental cues as demonstrated by their release of anti-inflammatory mediators when placed in an inflammatory lung environment [ 84 ]. This is mediated by MSC response to damage and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) [ 85 ]. MSC toll-like receptors (TLRs) 3 and 9 are activated by viral RNA and viral unmethylated CpG-DNA, respectively, leading to activation of downstream signalling pathways [ 2 ].…”

“…MSC toll-like receptors (TLRs) 3 and 9 are activated by viral RNA and viral unmethylated CpG-DNA, respectively, leading to activation of downstream signalling pathways [ 2 ]. Recent reports have characterized MSCs responsiveness to the in vivo inflammatory lung environment by exposing them to either clinical bronchoalveolar lavage fluid (BALF) or serum samples from patients with ARDS [ 85 – 89 ]. Exposure of MSCs to a healthy lung environment (i.e., BALF obtained from healthy volunteers) induced expression of genes encoding for recognition as foreign to the host immune system and for inflammation [ 85 ].…”