title: Bone marrow-derived mesenchymal stem cells modified with IGFBP-3 inhibit the proliferation of pulmonary artery smooth muscle cells.
abstract: Pulmonary arterial hypertension (PAH) is a common clinical cardiovascular disease, leading to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells, and is associated with a high mortality rate. Recently, stem- and progenitor cell-mediated gene therapies have provided a novel approach for the treatment of PAH. However, the function of human bone marrow-derived mesenchymal stem cells (hBM‑MSCs) modified with the insulin-like growth factor binding protein-3 (IGFBP-3) gene in the regulation of PAH is not yet fully understood. In this study, we explored the biological role of IGFBP‑3-modified hBM‑MSCs in the proliferation of human PASMCs (hPASMCs), and also investigated the potential underlying molecular mechanisms. Our results revealed that IGFBP-3-modified hBM‑MSCs inhibited the proliferation of angiotensin II-stimulated hPASMCs following co-culture on cell culture inserts. In addition, total DNA synthesis and the protein levels of hPASMCs in co-culture were decreased. Moreover, the IGFBP‑3-modified hBM‑MSCs promoted apoptosis and downregulated the expression of B-cell lymphoma-2 (Bcl-2), but increased the expression of Bcl-2 associated X protein (Bax) in hPASMCs. Furthermore, the IGFBP‑3-modified hBM‑MSCs significantly induced a phenotypic change in the hPASMCs from the synthetic to the contractile phenotype in co-culture. Importantly, the levels of several related proteins in the hPASMCs, including phosphorylated (p-)insulin receptor substrate-1 (p-IRS-1), phosphoinositide 3-kinase (p-PI3K), serine/threonine-protein kinase (p-Akt), mitogen-activated protein kinase (p-p38), p-Jun N-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK), were markedly decreased by the IGFBP-3-modified hBM‑MSCs following co-culture. Taken together, our findings suggest that IGFBP-3-modified hBM‑MSCs inhibit the proliferation and promote the apoptosis of hPASMCs, and promote the swithc to a contractile phenotype in more effectively than wild-type hBM‑MSCs, possibly through the activation of the PI3K/Akt and Ras-mitogen-activated protein kinase (MAPK) signaling pathways. The findings of our study suggest that IGFBP‑3‑modified hBM‑MSCs may be a promising therapeutic strategy for the treatment of PAH.
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Ge Sheng
authors.initials: GS
authors.lastname: Cheng
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Yu Shun
authors.initials: YS
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xing Ye
authors.initials: XY
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D000804:Angiotensin II; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology*; D015854:Up-Regulation
chemical_list: D000199:Actins; D018972:Insulin-Like Growth Factor Binding Protein 3; D053495:Osteopontin; D000804:Angiotensin II; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt