Paracrine Factors of Multipotent Stromal Cells Ameliorate Lung Injury in an Elastase-induced Emphysema Model

Abstract

Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.

Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

“…Recent studies also report that Hgf is an important mediator of the effects of MSCs to ameliorate elastase injury [7,63]. This suggests that induction of IL-6 and Hgf in this model was a relevant mechanism of tissue healing.…”

“…In the lung, most studies have focused attention on therapeutic effects of extra-pulmonary MSCs. For instance, BM or adipose-derived MSCs significantly reduced injuries caused by elastase [4][5][6][7], lipopolysaccharide [8,9], sepsis [10,11], hyperoxia [12][13][14][15][16][17], and bleomycin [18][19][20][21][22]. In general, the reparative effects of MSCs were compared with control treatments such as irradiated BMMSCs, lung fibroblasts, dermal fibroblasts, or embryonic fibroblast cell lines, rather than MSCs of lung origin, which have only recently been described in mice [23][24][25][26][27], humans [28][29][30], and sheep [31,32].…”

Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model

“…Furthermore, MSCs secrete antiapoptotic and anti-inflammatory paracrine factors (Meirelles Lda et al 2009;Akram et al 2013), and reduce lung injuries (Katsha et al 2011). Despite reported successes, the amount of engrafted MSCs decreased dramatically 24 h post-transplantation most likely due to exposure to toxic and oxidative microenvironments (Leblond et al 2009;Lan et al 2015).…”

Cell Therapy in Chronic Obstructive Pulmonary Disease: State of the Art and Perspectives

“…Accordingly, it is possible that MSC and BMMC hold a potential role to deliver the required cellular strain diversity during the tissue regeneration process, possibly by paracrine mechanisms (Katsha et al, 2011) and to check, in a significant and effective way, the repair of the lesion in the pulmonary tissue.…”