Repetitive human UC-MSC administration limits the progression of pulmonary fibrosis induced by repetitive bleomycin instillation

The anti-fibrotic effects of mesenchymal stem cells (MSC) have been demonstrated in animal models of pulmonary fibrosis, but it is being difficult to translate these results in patients with idiopathic pulmonary fibrosis (IPF). Preclinical studies mostly analyzed the effects of a single MSC administration in immunocompetent mice. Here, we studied the anti-fibrotic effects of repetitive MSC instillation administrated within the period of lung damage induction in nude mice. Time- and dose-dependent effects of bleomycin (BLM) in nude and nu/+ Swiss CD-1 mice were preliminary analyzed. To study the effect of MSC, mice were subjected to repetitive BLM instillation to better mimic IPF. Thus, nude mice received one instillation of 6 U/kg BLM or PBS each 2 weeks with a total of three BLM administrations. One week after the first BLM administration, mice received 2x10⁵ human umbilical cord MSC (hUC-MSC) or PBS. The same dose of hUC-MSC was administrated each 2 weeks with a total of three administrations. Nude mice were more resistant to BLM than nu/+ mice. 6 U/kg BLM concentration exerted the greatest lung damage in nude mice. The repetitive i.t. administration of hUC-MSC decreased signs of inflammation, including the lung Il-1β expression (2.0-fold-reduction, P<0.05). Likewise, hUC-MSC treatment blunted signs of lung fibrosis, including fibronectin expression (3.2-fold-reduction, P<0.05) and the myofibroblast marker Acta2 (3.8-fold-reduction, P<0.05). These results highlight the therapeutical potential of UC-MSC to treat IPF and suggest that the repetitive administration of UC-MSC might be an effective clinical approach.