Perinatal nicotine exposure drives the differentiation of alveolar lipofibroblasts (LIFs), which are critical for lung injury repair, to myofibroblasts (MYFs), which are the hallmark of chronic lung disease. Bone marrow-derived mesenchymal stem cells (BMSCs) are important players in lung injury repair; however, how these cells are affected with perinatal nicotine exposure and whether these can be preferentially driven to a lipofibroblastic phenotype are not known. We hypothesized that perinatal nicotine exposure would block offspring BMSCs lipogenic differentiation, driving these cells toward a MYF phenotype. Since peroxisome proliferator activated-receptor γ (PPARγ) agonists can prevent nicotine-induced MYF differentiation of LIFs, we further hypothesized that the modulation of PPARγ expression would inhibit nicotine's myogenic effect on BMSCs. Sprague Dawley dams were perinatally administered nicotine (1 mg/kg bodyweight) with or without the potent PPARγ agonist rosiglitazone (RGZ), both administered subcutaneously. At postnatal day 21, BMSCs were isolated and characterized morphologically, molecularly, and functionally for their lipogenic and myogenic potentials. Perinatal nicotine exposure resulted in decreased oil red O staining, triolein uptake, expression of PPARγ, and its downstream target gene adipocyte differentiation-related protein by BMSCs, but enhanced α-smooth muscle actin and fibronectin expression, and activated Wnt signaling, all features indicative of their inhibited lipogenic, but enhanced myogenic potential. Importantly, concomitant treatment with RGZ virtually blocked all of these nicotine-induced morphologic, molecular, and functional changes. Based on these data, we conclude that BMSCs can be directionally induced to differentiate into the lipofibroblastic phenotype, and PPARγ agonists can effectively block perinatal nicotine-induced MYF transdifferentiation, suggesting a possible molecular therapeutic approach to augment BMSC's lung injury/repair potential.
Keywords: PPARγ; bone marrow-derived mesenchymal stem cells; lipofibroblasts; lung; nicotine.
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.