Bone marrow-derived mesenchymal stem cells modified with IGFBP-3 inhibit the proliferation of pulmonary artery smooth muscle cells

摘要

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.