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. 2015 Nov;10(5):1657-1664.
doi: 10.3892/etm.2015.2722. Epub 2015 Sep 1.

Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension

Junfeng Liu  1 , Zhibo Han  2 , Zhongchao Han  2 , Zhixu He  3
Affiliations

Mesenchymal stem cells suppress CaN/NFAT expression in the pulmonary arteries of rats with pulmonary hypertension

Junfeng Liu et al. Exp Ther Med. 2015 Nov.

Abstract

Inflammation and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered the primary pathological feature of pulmonary hypertension (PH). The present study determined that mesenchymal stem cells (MSCs) suppress the expression of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT) in the pulmonary arteries of rats, and this may exert a therapeutic effect on PH. The potential therapeutic effects of MSCs on PH were assessed via the transplantation of human umbilical cord-derived MSCs, which were cultured in serum-free medium, into a monocrotaline (MCT)-induced PH rat model. Subsequently, the expression levels of tumor necrosis factor (TNF)-α in lung tissue and plasma, and of CaN and NFATc2 in pulmonary arteries were assessed. In the rat model of MCT-induced PH, investigated in the present study, TNF-α expression levels were detected in the lung tissue, and the levels of TNF-α in the plasma were increased. Furthermore, in addition to hemodynamic changes and the evident medial hypertrophy of the pulmonary muscular arterioles, CaN and NFATc2 expression levels were significantly upregulated in the pulmonary arteries. In the present study, the transplantation of MSCs, cultured in serum-free medium, decreased the levels of TNF-α in the lung tissue and plasma of rats, and downregulated CaN and NFATc2 expression in the pulmonary arteries. Furthermore, hemodynamic abnormalities and medial hypertrophy of the pulmonary muscular arterioles were notably improved. Therefore, the results of the present study may suggest that the administration of MSCs in PH may suppress the production of TNF-α, and downregulate the expression of CaN and NFATc2 in pulmonary arteries, which may provide an effective treatment for PH by suppressing the pathological proliferation of PASMCs.

Keywords: calcineurin; mesenchymal stem cell; model; nuclear factor of activated T-cells; pulmonary hypertension; transplantation.

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Figures

Figure 1.
Figure 1.
Identification of mesenchymal stem cells (MSCs). (A) Passage 3 MSCs cultured in vitro. (B) Osteogenic differentiation of MSCs was identified using Alizarin red S stain. (C) Adipogenic differentiation of MSCs was identified using Oil Red O stain. (D) Phenotypic analysis of MSCs.
Figure 2.
Figure 2.
Effects of mesenchymal stem cells (MSCs) on pulmonary hypertension. (A-C) CM-Dil labeled MSCs distributed in the lung 2 days following transplantation; (A) DIC, (B) CM-Dil and (C) merge. (D-F) Optical photomicrographs of lung tissue cells stained with hematoxylin and eosin. (D) Control group; (E) model group; (F) MSCs transplantation group.
Figure 3.
Figure 3.
Changes in the (A) mean aortic pressure (MAoP), (B) right ventricular systolic pressure (RVSP) and (C) the medial wall thickness of the pulmonary arteriole (WT) in each group (n=8). Data are presented as the mean ± standard deviation,.*P<0.01, **P<0.05.
Figure 4.
Figure 4.
Effect of transplantation with mesenchymal stem cells (MSCs) on tumor necrosis factor (TNF)-α, calcineurin (CaN) and nuclear factor of activated T-cells (NFATc2) expression levels. Immunohistochemical staining of lung tissue for TNF-α in (A) the control group, (B) the model group and (C) the MSC transplantation group. The expression levels of TNF-α in (D) the lung tissue and (E) the plasma of rats. (F) CaN and (G) NFATc2 expression in the pulmonary arteries of rats. Data are presented as the mean ± standard deviation. n=8. *P<0.01. AOD, average optical density.
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