Mesenchymal Stem Cells Correct Inappropriate Epithelial–mesenchyme Relation in Pulmonary Fibrosis Using Stanniocalcin-1

Abstract

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-β1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-β1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-β1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

“…These studies have implicated a range of mechanisms of action including reduction of IL-1 and TNF-a by IL-1 receptor antagonist [13], amelioration of oxidative stress, endoplasmic reticulum stress, and TGF-b1 production in alveolar epithelial cells in a staniocalcin-1 dependent mechanism [58]. Evidence from the literature supports a protective role for HGF in fibrotic lung disease.…”

“…Many studies have shown the capacity for MSCs to protect against bleomycin-induced lung fibrosis [12,13,37,57,58]. These studies have implicated a range of mechanisms of action including reduction of IL-1 and TNF-a by IL-1 receptor antagonist [13], amelioration of oxidative stress, endoplasmic reticulum stress, and TGF-b1 production in alveolar epithelial cells in a staniocalcin-1 dependent mechanism [58].…”

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

“…Multiple alveolar injuries are characterized by abnormal activation of alveolar epithelial cells (AEC), which secrets numerous mediators, like matrix metalloproteinase (MMP) that not only modify lung environment but also able to release, cleave and activate a wide range of growth factors, cytokines, chemokines such as transforming growth factor- β (TGF- β ), interleukin (IL)-1 β , IL-13 and C-C motif chemokine ligand-2 (CCL2) (3, 4). Continuous TGF- β 1 secretion by AEC in abnormal wound healing has a critical role in affecting numerous cell functions including adhesion, proliferation and promoting fibroblast differentiation into myofibroblasts through the process of epithelial mesenchymal transition (EMT) (5). However, recent studies have not shown EMT role in the context of pulmonary fibrosis (6).…”

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…The A549 cell line is frequently used in research regarding alveolar type II epithelial cells (52)(53)(54)(55). Therefore, The Regulatory Effect of `7 nAChR on TGF-a Signaling Depends on PTP1B It has been reported that PTP1B deficiency confers resistance to TGF-β through Smad inhibition in hepatocytes (57).…”