Tumor Necrosis Factor-α-Induced Protein-8-like 2 Transfected Adipose-Derived Stem Cells Regulated the Dysfunction of Monocrotaline Pyrrole-Induced Pulmonary Arterial Smooth Muscle Cells and Pulmonary Arterial Endothelial Cells

Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) activation. For decades, the therapies for PAH based on stem cells have been shown to be effective. Meanwhile, tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) promote the viability of human amniotic mesenchymal stem cells. Therefore, we aimed to explore the role of TIPE2 in adipose-derived stem cells (ADSCs) and the function of TIPE2-transfected ADSCs in the regulation of PAH. We first explored the role and underlying molecular mechanism of TIPE2 in viability and migration of ADSCs. Moreover, the ADSCs transfected with TIPE2 were cocultured with monocrotaline pyrrole (MCTP)-stimulated PASMCs or PAECs. The effects and mechanisms of TIPE2-transfected ADSCs on MCTP-induced PASMCs and PAECs were further investigated. The results showed that TIPE2 overexpression promoted viability and migration of ADSCs by activating the TLR4-ERK1/2 pathway. In addition, TIPE2-transfected ADSCs inhibited the abnormal proliferation and the impaired apoptosis of PASMCs via NF-κB signaling and promoted the conversion of PASMCs from synthetic to contractile. Meanwhile, TIPE2-transfected ADSCs reduced the apoptosis, endothelial-to-mesenchymal transition, and migration of PAECs via PI3K/AKT signaling after MCTP treatment. MCTP-induced oxidative stress and inflammation of PAECs were significantly decreased by TIPE2-transfected ADSCs. In rat model, TIPE2-ADSCs administration further decreased the monocrotaline-induced increase in the right ventricular systolic pressure and ratio of right ventricle weight/left ventricle and septa weight (L + S) and right ventricle weight/body weight compared with the ADSCs group. In conclusion, TIPE2-transfected ADSCs dramatically attenuated the PAH via inhibiting the dysfunction of PASMCs and PAECs.