Abstract
COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities. LMSCs were isolated from lung tissue of severe COPD patients and non-COPD controls. Effects of LMSC conditioned-medium (CM) on H2O2-induced, electric field- and scratch-injury were studied in A549 and NCI-H441 epithelial cells. In organoid models, LMSCs were co-cultured with NCI-H441 or primary lung cells. Organoid number, size and expression of alveolar type II markers were assessed. Pre-treatment with LMSC-CM significantly attenuated oxidative stress-induced necrosis and accelerated wound repair in A549. Co-culture with LMSCs supported organoid formation in NCI-H441 and primary epithelial cells, resulting in significantly larger organoids with lower type II-marker positivity in the presence of COPD-derived versus control LMSCs. Similar abnormalities developed in organoids from COPD compared to control-derived lung cells, with significantly larger organoids. Collectively, this indicates that LMSCs’ secretome attenuates alveolar epithelial injury and supports epithelial repair. Additionally, LMSCs promote generation of alveolar organoids, with abnormalities in the supportive effects of COPD-derived LMCS, reflective of impaired regenerative responses of COPD distal lung cells.
Highlights
Chronic Obstructive Pulmonary Disease (COPD) is a prevalent inflammatory lung disease that has high mortality
In a more recent study, BM-mesenchymal stem/stromal cell (MSC) administration improved lung function in COPD patients with high systemic levels of C-reactive protein (CRP), it remains to be established whether these effects can be mainly attributed to anti-inflammatory effects or whether tissue repair was supported [13]
We investigated whether endogenous lung-derived MSCs (LMSCs) exert beneficial effects on distal lung epithelial damage and repair responses within the context of COPD
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a prevalent inflammatory lung disease that has high mortality. The use of MSCs has been widely evaluated for improvement of lung performance in animal models of emphysema, confirming reduced inflammation, while supporting repair of alveolar damage and restoring lung structure [8]. Whereas human clinical trials with autologous bone marrow-derived MSCs (BM-MSCs) demonstrated safety and reduced circulating levels of inflammatory marker C-reactive protein (CRP), beneficial effects on lung function in emphysema patients were limited [11,12]. In a more recent study, BM-MSC administration improved lung function in COPD patients with high systemic levels of CRP, it remains to be established whether these effects can be mainly attributed to anti-inflammatory effects or whether tissue repair was supported [13]. MSCs from other sources may be less equipped to support lung tissue repair, as tissue-resident lung-derived MSCs (LMSCs) have been reported to possess unique lung-specific properties [15], while BM-MSCs were reported to lack specific mechanisms that enhance their lung retention [16]
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