We sought to explore the treatment effects and the repair mechanisms of bone marrow derived mesenchymal stem cells (MSCs) during HCl-induced acute lung injury (ALI). MSCs were delivered through the tail veins of rats 24 h after intranasal instillation of HCl. The results showed that MSCs did not ameliorate the histopathologic changes of ALI and pulmonary fibrosis. We found that the activated Wnt/β-catenin signaling may regulate the differentiation of MSCs and is associated with lung fibroblasts activation, pulmonary fibrosis and tissue repair process in ALI rats. Immunofluorescence and histology analysis indicated that activated canonical Wnt/β-catenin signaling induced most MSCs to differentiate into myofibroblasts or fibroblasts in vivo. However, inhibition of Wnt/β-catenin signaling by Dickkopf-1 (DKK1) promotes epithelial differentiation of MSCs induced by native alveolar epithelial cells which are beneficial to repair the injured lung epithelium. Inhibition of Wnt/β-catenin signaling after MSCs transplantation ameliorated pulmonary fibrosis and improved pulmonary function which attenuated the lung injury. In vitro study, activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblasts markers, which was attenuated by DKK1. Furthermore, Wnt3α activated Wnt/β-catenin signaling in lung fibroblasts to enhance the expression of collagen I, vimentin and α-smooth muscle actin, but DKK1 attenuated these proteins expression. These findings demonstrated that canonical Wnt/β-catenin signaling plays a key role in regulating differentiation of MSCs in vivo or in vitro and the pathogenesis of fibrotic diseases. Our study suggested that inhibition of abnormal activated Wnt/β-catenin signaling would promote MSCs epithelial differentiation to repair lung injury and reduce pulmonary fibrosis.
Controversies and risks continue to be reported about exogenous mesenchymal stem cell-based therapies. In contrast with employing exogenous stem cells, making use of lung resident mesenchymal stem cells (LR-MSCs) could be advantageous. Our study sought to isolate the LR-MSCs and explore their potential to differentiate into alveolar epithelial type II cells (ATII cells). Total lung cells were first precultured, from which the Sca-1(+) CD45(-) CD31(-) population was purified using fluorescence activated cell sorting (FACS). By these methods, it would seem that the Sca-1(+) CD45(-) CD31(-) cells were LR-MSCs. Similar to bone marrow derived mesenchymal stem cells (BM-MSCs), these cells express Sca-1, CD29, CD90, CD44 and CD106, but not CD31 or CD45. They share the same gene expression file with the BM-MSCs and have a similar DNA content during long-term culturing. Furthermore, they could be serially passaged with all these properties being sustained. Above all, LR-MSCs could differentiate into ATII cells when co-cultured with ATII cells in a trans-well system. These findings demonstrated that the Sca-1(+) CD45(-) CD31(-) cells appear to be LR-MSCs that can differentiate into ATII cells. This approach may hold promise for their use in the treatment of lung disease.
Bone marrow MSCs (mesenchymal stem cells) can differentiate into various tissue cells, including epithelial cells. This presents interesting possibilities for cellular therapy, but the differentiation efficiency of MSCs is very low. We have explored specific inducing factors to improve the epithelial differentiation efficiency of MSCs. Under inducing conditions, MSCs differentiated into epithelial cells and expressed several airway epithelial markers using RTE (rat tracheal epithelial) cell secretions. Rat cytokine antibody array was used to detect cytokines of the RTE secretion components, in which 32 kinds of protein were found. Seven proteins [TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), VEGF (vascular endothelial growth factor), BDNF (brain-derived neurotrophic factor), TGFβ1 (transforming growth factor β1), MMP-2 (metalloproteinases-2), OPN (osteopontin) and activin A in RTE secretions] were assayed using ELISA kits. The four growth factors (VEGF, BDNF, TGFβ1 and activin A) were involved in regulating stem cell growth and differentiation. We speculated that these four play a vital role in the differentiation of MSCs into epithelial cells by triggering appropriate signalling pathways. To induce epithelial differentiation, MSCs were cultured using VEGF, BDNF, TGFβ1 and activin A. Differentiated MSCs were characterized both morphologically and functionally by their capacity to express specific markers for epithelial cells. The data demonstrated that MSCs can differentiate into epithelial cells induced by these growth factors.
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