Abstract
We assessed the ability of human embryonic stem cells (HUES-3) to differentiate into functioning alveolar type II cells (ATIICs), engraft into damaged lungs and ameliorate pulmonary fibrosis, thereby reducing mortality, in a mouse model of silica-induced pulmonary inflammation and fibrosis.
Nude mice (Charles River, Italy) were intranasally administered either silica oxide powder (99.9% Alfa Aesar) intranasally (5mg/mL, 50 μl/mice/day) or saline for 15 days followed by intratracheal 2.5×106 HUES-3-ATIICs (n=50, HUES-3-ATIICs treated) or saline (n=50, Sham treated). Ten silica treated mice were instilled mature fibroblasts.
In vitro differentiated HUES-3-ATIICs displayed an alveolar phenotype (multilamellar body, SP-B, SP-C and ZO-1 expression and CFTR-mediated chloride ion transport). After transplantation into silica-damaged mice, HUES-3-ATIICs were capable of engraftment as they showed persistence of human SP-C and of human DNA and effectively reduced inflammation and fibrosis. HUES-3-ATIICs treated mice showed reduced expression of IL-6, TNF-α, MIP-2 and TGF-β and of collagen marker Col1-α1 (p<0.05) and reduced histological scores (Ashcroft score p<0.01). Also showing preserved oxyhemoglobin saturation and reduced mortality at 20 days (Sham treated, 100%; HUES-3-ATIICs treated, no mortality with 95% weight recovery; p<0.05).
In conclusion, the data show that HUES-3-ATIICs intratracheal instillation can reduce silica-induced lung injury and fibrosis in the mouse model of silica-induced lung fibrosis, indicating stem cell therapy as a viable approach for pulmonary fibrosis treatment.
- © 2011 ERS