Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

Abstract

Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emphysema the efficacy of human MSC therapy and optimal cell dose were investigated. Protective effects were examined in the lung through histological examination. Further in vivo experiments examined the reparative abilities of MSCs after tissue damage was established and the role played by soluble factors secreted by MSCs. The mechanism of MSC action was determined in using shRNA gene knockdown. Human MSC therapy and MSC conditioned media exerted significant cytoprotective effects when administered early at the onset of the disease. These protective effects were due to significant anti-inflammatory, anti-fibrotic and anti-apoptotic mechanisms, mediated in part through MSC production of hepatocyte growth factor (HGF). When MSC administration was delayed, significant protection of the lung architecture was observed but this was less extensive. MSC cell therapy was more effective than MSC conditioned medium in this emphysema model.

The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

“…While recent years have seen progress in clarifying the manner by which MSC and macrophages interact, the underlying mechanisms behind the phenomena observed in inflammatory diseases are less clear. The current candidates for cell therapy (including MSC and MAPC) suppress inflammation effectively in murine models of inflammatory disease [4,7,13,41,[49][50][51][52]. Efficacy is linked to migration of MSC to target organs, suppression of T cell proliferation, induction of T reg , cytoprotection of damaged tissue and suppression of inflammation.…”

“…A role for PGE 2 has been demonstrated in MSC-and MAPC-mediated suppression of pathology in murine models of GVHD [53,54], while in murine models of colitis TSG-6 production is required for efficacy of BM-MSC [41]. Similarly, preclinical studies using MSC in pulmonary disorders have provided promising results [2,4,26,[55][56][57][58][59][60], with MSC therapy being associated with expansion of T reg , promotion of antiinflammatory macrophages, suppression of Th2-and Th17-associated cytokines and enhanced microbial clearance by macrophages in ARDS [45,48,61].…”

“…Both BM-MSC and AD-MSC administered intravenously and intratracheally have shown efficacy in a murine model of elastase-induced emphysema [4,59]. However, while BM-MSC and AD-MSC reduced the number of M1 macrophages in the lung, intratracheally administered MSC from either tissue source did not [59].…”

Mesenchymal Stromal Cells to Regenerate Emphysema: On the Horizon?

“…Furthermore, human- derived BM-MSCs were recently shown to reduce alveolar damage in an elastase mouse model of emphysema (6 doses over 2 weeks [19]).…”

Cell therapy for lung disease

“…Human bone marrow-derived (bm)MSCs reduced fibrosis as analysed by histological scoring of lung sections using the Ashcroft scale; apoptosis as measured by a reduction of DNA strand breaks; and inflammation as seen by a reduction of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α levels in an elastase-induced mouse model of COPD [10]. Interestingly, findings from our own laboratory indicate that the efficacy of bmMSCs in this model can be improved further if the cells are genetically modified to express the potent protease inhibitor α 1 -antitrypsin [37,38] (S. Geiger, unpublished data).…”